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1
Fast, LD, CR Valeri, and JP Crowley. "Immune responses to major histocompatibility complex homozygous lymphoid cells in murine F1 hybrid recipients: implications for transfusion-associated graft-versus-host disease." Blood 86, no. 8 (1995): 3090–96. http://dx.doi.org/10.1182/blood.v86.8.3090.3090.
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Abstract Graft-versus-host disease (GVHD) is currently encountered after bone marrow transplantation and transfusion. GVHD associated with transfusion (TA-GVHD) in apparently immunocompetent recipients has been recently reported with increasing frequency. A consistent finding in many of these cases is that the recipient received blood from a donor homozygous for one of the recipient's HLA haplotypes. However, the observed frequency of TA-GVHD is much lower than the estimated probability of this donor/recipient combination. The potential role of recipient immune responses in controlling TA-GVHD was investigated using an analogous murine model in which GVHD is induced by the injection of parental lymphoid cells into unirradiated F1 hybrid recipients. The effect of various immune manipulations of the recipient of GVHD induction was assessed by determining the number of donor lymphoid cells required to induce GVHD responses. Whereas depletion of recipient CD4+ cells increased the number of donor cells needed to induce GVHD, depletion of recipient CD8+ and natural killer cells resulted in fewer donor cells being needed to induce a GVHD response. These studies suggest a central role for functioning recipient CD8 and natural killer cells in the down-regulation of TA-GVHD development in recipients.
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Fast, LD, CR Valeri, and JP Crowley. "Immune responses to major histocompatibility complex homozygous lymphoid cells in murine F1 hybrid recipients: implications for transfusion-associated graft-versus-host disease." Blood 86, no. 8 (1995): 3090–96. http://dx.doi.org/10.1182/blood.v86.8.3090.bloodjournal8683090.
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Graft-versus-host disease (GVHD) is currently encountered after bone marrow transplantation and transfusion. GVHD associated with transfusion (TA-GVHD) in apparently immunocompetent recipients has been recently reported with increasing frequency. A consistent finding in many of these cases is that the recipient received blood from a donor homozygous for one of the recipient's HLA haplotypes. However, the observed frequency of TA-GVHD is much lower than the estimated probability of this donor/recipient combination. The potential role of recipient immune responses in controlling TA-GVHD was investigated using an analogous murine model in which GVHD is induced by the injection of parental lymphoid cells into unirradiated F1 hybrid recipients. The effect of various immune manipulations of the recipient of GVHD induction was assessed by determining the number of donor lymphoid cells required to induce GVHD responses. Whereas depletion of recipient CD4+ cells increased the number of donor cells needed to induce GVHD, depletion of recipient CD8+ and natural killer cells resulted in fewer donor cells being needed to induce a GVHD response. These studies suggest a central role for functioning recipient CD8 and natural killer cells in the down-regulation of TA-GVHD development in recipients.
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Zheng, Yama W. L., K. C. Allen Chan, Hao Sun, et al. "Nonhematopoietically Derived DNA Is Shorter than Hematopoietically Derived DNA in Plasma: A Transplantation Model." Clinical Chemistry 58, no. 3 (2012): 549–58. http://dx.doi.org/10.1373/clinchem.2011.169318.
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Abstract BACKGROUND Plasma DNA is predominantly hematopoietic in origin. The size difference between maternal- and fetal-derived DNA in maternal plasma prompted us to investigate whether there was any discrepancy in molecular size between hematopoietically and nonhematopoietically derived DNA in plasma. METHODS Plasma DNA samples from 6 hematopoietic stem cell transplant recipients and 1 liver transplant recipient were analyzed by massively parallel paired-end sequencing. The size of each fragment was deduced from the alignment positions of the paired reads. In sex-mismatched transplant recipients, the reads from chromosome Y were used as markers for the male donor/recipient. For other transplant recipients, the reads of the donor- and recipient-specific alleles were identified from the single-nucleotide polymorphism genotypes. RESULTS In male patients receiving female hematopoietic stem cells, more chromosome Y–derived DNA molecules (nonhematopoietically derived) were ≤150 bp than the autosome-derived ones (mainly hematopoietically derived) (median difference, 9.9%). In other hematopoietic stem cell transplant recipients, more recipient-specific DNA molecules (nonhematopoietically derived) were ≤150 bp than the donor-specific ones (hematopoietically derived) (median difference, 14.8%). In the liver transplant recipient, more donor-derived DNA molecules (liver derived) were ≤150 bp than the recipient-derived ones (mainly hematopoietically derived) (difference, 13.4%). The nonhematopoietically derived DNA exhibited a reduction in a 166-bp peak compared with the hematopoietically derived DNA. A 10-bp periodicity in size distribution below approximately 143 bp was observed in both DNA populations. CONCLUSIONS Massively parallel sequencing is a powerful tool for studying posttransplantation chimerism. Plasma DNA molecules exhibit a distinct fragmentation pattern, with the nonhematopoietically derived molecules being shorter than the hematopoietically derived ones.
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Teipel, Raphael, Johannes Schetelig, Michael Kramer, et al. "Prediction of Hematopoietic Stem Cell Yield after Mobilization with GCSF in Healthy Unrelated Donors." Blood 124, no. 21 (2014): 1128. http://dx.doi.org/10.1182/blood.v124.21.1128.1128.
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Abstract Introduction: The collection of hematopoietic stem cells from the peripheral blood in healthy donors has been established as a highly efficient method in clinical practice. Nevertheless, there are some donors who mobilize poorly despite adequate mobilization regimes. Several factors influencing the process of stem cell mobilization have previously been discussed in the literature. Methods: In total, the data of 7.216 unrelated donors who underwent GCSF-induced stem cell mobilization and collection in two German apheresis centers between July 1997 and August 2012 were retrospectively reviewed. We systematically analyzed more than 30 factors with potential influence on the mobilization process and established a statistically stable model in order to predict the mobilization efficacy and the harvest success in unrelated stem cell donors. Based on empirical data and standard values, we created three model donors of each gender with different donor profiles (favorable/average/unfavorable). In those model donors we calculated the corresponding likelihood of a successful stem cell harvest dependent on the recipient’s weight. Results: Overall, ten variables with high statistical significance were included in the prediction model. Body mass index, platelet count, absolute lymphocyte count and the relative monocyte count correlated positively with the CD34+ count in the peripheral blood after five days of GCSF use (p < 0.0001 in a multivariate analysis). In contrast, female sex, age, smoking, lactate dehydrogenase (ldh), relative monocyte count, and the relative large unstained cell count were associated negatively with the CD34+ count on day five (p < 0.0001 in a multivariate analysis). In order to predict the harvest success (collection of > 2 x 10^6 CD34+ cells/kg recipient weight after first apheresis) three different models were compared in a ROC-analysis. The first model was purely based on female sex and recipient weight. The second model additionally contained the predicted CD34+ counts. Finally, in the third model the actual observed CD34+ counts were included. By adding the predicted CD34+ counts to the simple model, a significant improvement of the predictability of a harvest success could be viewed although a considerable difference comparing these results to the model with the observed CD34+ counts remained (figure 1). Furthermore, the prediction of harvest success in model donors (figure 2) revealed that donors with a favorable donor profile (covariates set to the most favorable values within the normal range) showed a particular high likelihood for a successful harvest (100 % likelihood, irrespective to donor’s gender or recipient’s weight). The likelihood for a successful harvest in male donors with an average distribution of covariates (covariates set to the empirical mean value) was nearly 100% as well even in donations for heavy recipients. Contrary, the likelihood for an average female donor was high in normal weight recipients (97 %; 60 kg recipient) but decreased with rising recipient weight (78 %; 140 kg recipient). In donors with an unfavorable profile (covariates set to the worst values within the normal range), especially in females, the chance for a successful stem cell collection was poor even when donating for light recipients (54 % in males, 10 % in females; 60 kg recipient). Conclusions: In conclusion, multiple factors with influence on the CD34+ count after GCSF mobilization in healthy donors have been identified. With the prediction model a significant gain in the predictability of a harvest success could be achieved though a certain amount of unexplained variance still remains. Model donors with a favorable or average donor profile had a high likelihood for a successful stem cell collection. In donors with an unfavorable profile, especially in females, the chance for a harvest success was very low. Figure 1: Prediction of harvest success (> 2 x 10^6 CD34+ cells/kg recipient weight after 1st apheresis) Figure 1:. Prediction of harvest success (> 2 x 10^6 CD34+ cells/kg recipient weight after 1st apheresis) Abb.: AUC – area under the curve Figure 2: Probability of harvest success in model donors (> 2 x 10^6 CD34+ cells/kg recipient weight after 1st apheresis) Figure 2:. Probability of harvest success in model donors (> 2 x 10^6 CD34+ cells/kg recipient weight after 1st apheresis) Disclosures Schmidt: Cellex GmbH: Employment. Ehninger:Cellex GmbH: Equity Ownership. Off Label Use: G-CSF.
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Onishchenko, N. A., A. O. Nikolskaya, Z. Z. Gonikova, L. A. Kirsanova, M. Yu Shagidulin, and V. I. Sevastianov. "Regenerative and hepatospecific activity of total RNA from xenogenic bone marrow cells." Russian Journal of Transplantology and Artificial Organs 23, no. 1 (2021): 43–48. http://dx.doi.org/10.15825/1995-1191-2021-1-43-48.
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Objective: to study the peculiarities of the induction effect of total RNA (tRNA) from xenogenic bone marrow cells (BMCs) on regeneration processes in the recipient's native liver with extensive liver resection using an adoptive transfer model. Materials and methods. The study was carried out on an adoptive transfer model using male Wistar rats (n = 20) and guinea pigs (n = 17). The donors were rats (n = 10). 12 hours after extensive liver resection (70-75%), tRNA was isolated from BMCs and injected into intact (non-operated) recipients intraperitoneally at a dose of 30 μg/100 g of weight. The induction effect of the tRNA on operated rats was studied in 3 groups of recipients: Group 1 (control, n = 5) - administration of saline to guinea pigs; Group 2 (control, n = 10) - administration of tRNA from a donor rat to a recipient rat (allogeneic transfer); Group 3 (experiment, n = 12) - administration of tRNA from a donor rat to a recipient guinea pig (xenogeneic transfer). In histological preparations of recipient livers, after 48, 72 hours and 7 days, we studied the mitotic activity of hepatocytes and the features of the microscopic picture of the liver. The significance of differences in the compared groups was assessed using the parametric Student's t-test. Results. The ability of BMC tRNA to tissue-specifically activate regenerative and immune responses in the liver after extensive resection was found to depend on the donor and recipient species identity. Introduction of allogeneic donor tRNA in the recipient's liver resulted in predominant enhancement in hepatocyte mitotic activity (p < 0.05). The use of xenogeneic donor tRNA leads to enhanced activity of only immuno-inflammatory reactions in the recipient's liver, such as sinusoidal cell activation, lymphocytic infiltration into sinusoids, and portal tract infiltration by inflammatory cells. Conclusion. To induce regenerative processes in the liver, tRNA obtained from allogeneic BMCs should be used.
6
Heinemann, Jack A., Heidi E. Scott, and Meredith Williams. "Doing the Conjugative Two-step: Evidence of Recipient Autonomy in Retrotransfer." Genetics 143, no. 3 (1996): 1425–35. http://dx.doi.org/10.1093/genetics/143.3.1425.
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Abstract Bidirectional exchange of genetic information, called retrotransfer, during bouts of bacterial conjugation has drawn the interest of those concerned with the risk of releasing genetically engineered microbes, the fluidity of genes among species, and the mechanism of DNA transport between cells. The phenomenon has generated two models in explanation, both of which yield highly testable predictions. The first model, called the one-step, predicts that the flow of genes from recipient bacteria to donor bacteria is mechanistically distinct from, but dependent on, conjugation between donors and recipients. The second model, called the two-step, predicts that the same genetic requirements and mechanistic constraints apply to the process of gene flow from recipients to donors as for gene flow from donors to recipients. The requirement for expression of at least 10 plasmid-encoded genes in recipients, sensitivity of the reverse flow (recipient to donor) to restriction of DNA transferring from the donor, and the requirement of an additional 30–90 min for DNA to flow from recipients back to donors are predictions of the two-step model and directly refute the one-step model. Retrotransfer of genes to donors during conjugation remains genetically and physically indistinguishable from two successive rounds of conjugation between neighbors.
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Xu, Yajing, Heather F. Johnston, Stephen J. Forman, and Defu Zeng. "Oral Administration of Ibrutinib Is Ineffective at Preventing Scleroderma in Chronic Gvhd in Two Preclinical Mouse Models." Blood 124, no. 21 (2014): 3818. http://dx.doi.org/10.1182/blood.v124.21.3818.3818.
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Abstract We have established two mouse models of chronic graft versus host disease (cGVHD): one is an MHC-matched DBA/2 donor to BALB/c recipient, and this model amplifies the role of CD4+ T and B cells in transplants; the other model is an MHC-mismatched C57BL/6 donor to BALB/c recipient, and this model amplifies the role of de novo-developed CD4+ T and B cells. BALB/c recipients in both models started to develop scleroderma ~35 days after transplantation of donor spleen and bone marrow cells and this peaked ~50 days after transplantation. BALB/c recipients given DBA/2 transplants also developed proteinuria due to IgG anti-dsDNA autoantibody deposition in the glomeruli. We have reported that donor CD4+ T and B cells play critical roles in the pathogenesis of chronic GVHD (J. Immunol 2012 and 2013). Administration by I.V. injection of depleting anti-CD20 prevented induction of chronic GVHD in both models (Biol. Blood and Marrow Transplant 2014). In the current studies, using these two models, we tested whether oral administration of Ibrutinib could prevent induction of cGVHD. Ibrutinib was gavaged at 12.5 mg/kg/day from day 0 to day 30 or given in drinking water at 35 mg/kg/day (0.16 mg/ml) from day 0 to day 50. We found that administration of Ibrutinib significantly delayed the onset of proteinuria in the model of DBA/2 donor to BALB/c recipient, but accelerated the onset and increased the severity of scleroderma in 20/20 recipients given DBA/2 transplants and 9/9 recipients given C57BL/6 transplants as measured by a clinical score system. Administration of Ibrutinib significantly reduced CD138+B220lo plasma cells but not CD138-B220+ B cells in the spleen and peripheral lymph nodes of both recipients. Administration of Ibrutinib slightly reduced CD4+ T cell numbers in the spleen but significantly increased CD4+ T cell numbers in the peripheral lymph nodes, although there was no significant impact on CD4+ T cell expression of IFN-g and TNF-α in both recipients. These results indicate that, although oral administration of Ibrutinib is able to reduce B cell activation and differentiation into plasma cells, it is ineffective at inhibiting the CD4+ T cell expansion that mediates scleroderma in the models of DBA/2 donor to MHC-matched BALB/c recipient and C57BL/6 donor to MHC-mismatched BALB/c recipient. Our result is in contrast to a previous report showing that oral administration of Ibrutinib prevented induction of chronic GVHD with bronchiolitis obliterans in a mouse model and reversed scleroderma in another mouse model (Poster 2591, AACR 2014, San Diego). Further discussion about the differences is warranted. (This work was supported by Nesvig Lymphoma Foundation). Disclosures No relevant conflicts of interest to declare.
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Hendrickson, Jeanne E., Nicole H. Smith, Kathryn R. Girard-Pierce, et al. "Development of a Murine Model of Weak Kel: Similarities to Weak Rh(D)." Blood 120, no. 21 (2012): 842. http://dx.doi.org/10.1182/blood.v120.21.842.842.
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Abstract Abstract 842 Introduction: Aspects of RBC antigens that define their immunogenicity are not fully understood. Multiple studies in humans have demonstrated Rh(D) to be the most immunogenic RBC antigen, yet the same antigen present in lower copy number (weak Rh(D)) is, with rare exception, considered non-immunogenic. A better understanding of factors influencing RBC alloimmunogenicity would be helpful in predicting antibody responses in transfusion and pregnancy situations alike, as well as in managing donor RBC inventory. Herein, we describe the generation of transgenic mice with different levels of RBC specific expression of the clinically significant human KEL2 antigen, and test the hypothesis that antigen density impacts recipient immune response post-transfusion. Materials and Methods: Mice with RBC specific expression of KEL2 were generated utilizing constructs containing the human KEL2 sequence expressed behind a B-globin promoter, using a random integration approach. TER119+, CD45+, and CD41+ cells were evaluated by flow cytometry for KEL expression using monoclonal anti-Jsa and anti-Kpb, and RBC antigen density was estimated utilizing QIFIKIT beads. MuMT recipients were transfused with RBCs labeled with a lipophilic dye, and post-transfusion RBC recovery and antigen expression were evaluated by flow cytometry. To determine the immunogenicity of KEL2 or weak KEL2 RBCs, RBCs were transfused into C57BL/6 recipients every 2–3 weeks in the presence or absence of poly (I:C) pre-treatment. Recipient serum was analyzed by flow cytometric crossmatch with KEL2 or C57BL/6 RBC targets, using IgM or IgG secondary antibodies. To determine the effect of recipient RBC expression of weak KEL2 on the immunogenicity of KEL2 RBCs, weak KEL2 animals were transfused with KEL2 RBCs, the clearance of lipophilic labeled RBCs was tracked, and anti-KEL was evaluated on the transfused RBCs and also in the serum. Results: KEL2 RBCs have approximately 1200 antigenic sites per cell, whereas weak KEL2 RBCs have fewer than 200 sites; flow cytometric studies of TER 119+, CD45+, and CD41+ cells suggest both strains have RBC specific KEL expression. Transfusion of KEL2 or weak KEL2 RBCs into muMT animals resulted in stable post-transfusion RBC recovery and antigen expression. In 3/3 experiments (n=30 animals), all C57BL/6 recipients of KEL2 RBCs generated detectable anti-KEL IgM and IgG, which boosted with subsequent transfusions and which was enhanced in the presence of recipient inflammation with poly (I:C). However, in 2/2 experiments (n=20 animals), weak KEL RBCs led to no detectable antibody (IgM or IgG) in C57BL/6 recipients following 3 transfusions, even in the presence of recipient pre-treatment with poly (I:C). Furthermore, weak KEL2 recipients of KEL2 RBCs generated no detectable IgG and demonstrated no clearance of KEL2 RBCs, though low levels of anti-KEL IgM were detectable on the transfused RBCs and in the serum from approximately 5–12 days post-transfusion. Discussion: As hypothesized, antigen density significantly impacts the immunogenicity of KEL RBCs in this reductionist murine alloimmunization model. C57BL/6 recipients, like Rh(D) negative recipients, lack the human antigen in question (KEL2 in this case), and recipient antibody responses to weak KEL2 are, like most recipient responses to weak Rh(D), undetectable. Strengths of the KEL2 and weak KEL2 system include the fact that these animals are, to the best of our knowledge, genetically identical except for RBC KEL antigen copy number. Thus, this system allows for detailed analyses of the immune response to KEL RBCs with different antigen densities, on both the donor and recipient side of the equation, without confounding factors encountered in human studies (such as HLA presentation issues or considerations of the molecular basis of a particular type of weak Rh(D)). A better understanding of primary, secondary, and other immune responses in the KEL2 and weak KEL2 system may lay the groundwork for strategies to induce non-responsiveness to RBCs in humans, not only in the setting of transfusion medicine but also potentially in the setting of hemolytic disease of the fetus and newborn. Furthermore, translation of these and future findings in the KEL and weak KEL systems to Rh(D), weak Rh(D), and other human antigen systems may ultimately allow for creative solutions in blood inventory management. Disclosures: No relevant conflicts of interest to declare.
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Toomey, Niamh, �ine Monaghan, S�amus Fanning, and Declan Bolton. "Transfer of Antibiotic Resistance Marker Genes between Lactic Acid Bacteria in Model Rumen and Plant Environments." Applied and Environmental Microbiology 75, no. 10 (2009): 3146–52. http://dx.doi.org/10.1128/aem.02471-08.
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ABSTRACT Three wild-type dairy isolates of lactic acid bacteria (LAB) and one Lactococcus lactis control strain were analyzed for their ability to transfer antibiotic resistance determinants (plasmid or transposon located) to two LAB recipients using both in vitro methods and in vivo models. In vitro transfer experiments were carried out with the donors and recipients using the filter mating method. In vivo mating examined transfer in two natural environments, a rumen model and an alfalfa sprout model. All transconjugants were confirmed by Etest, PCR, pulsed-field gel electrophoresis, and Southern blotting. The in vitro filter mating method demonstrated high transfer frequencies between all LAB pairs, ranging from 1.8 � 10−5 to 2.2 � 10−2 transconjugants per recipient. Transconjugants were detected in the rumen model for all mating pairs tested; however, the frequencies of transfer were low and inconsistent over 48 h (ranging from 1.0 � 10−9 to 8.0 � 10−6 transconjugants per recipient). The plant model provided an environment that appeared to promote comparatively higher transfer frequencies between all LAB pairs tested over the 9-day period (transfer frequencies ranged from 4.7 � 10−4 to 3.9 � 10−1 transconjugants per recipient). In our test models, dairy cultures of LAB can act as a source of mobile genetic elements encoding antibiotic resistance that can spread to other LAB. This observation could have food safety and public health implications.
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Slichter, Sherrill J., Esther Pellham, S. Lawrence Bailey, et al. "Leukofiltration plus pathogen reduction prevents alloimmune platelet refractoriness in a dog transfusion model." Blood 130, no. 8 (2017): 1052–61. http://dx.doi.org/10.1182/blood-2016-07-726901.
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Key Points Eight weekly transfusions of F-LR + pathogen-reduced donor platelets were accepted by 31 of 32 (97%) recipient dogs. Among accepting recipients, none developed lymphocyte and only 2 had platelet antibodies not associated with platelet refractoriness.
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Fac-Beneda, Joanna. "Lakes in the cascade model of storage and drainage reservoirs." Limnological Review 11, no. 4 (2011): 143–50. http://dx.doi.org/10.2478/v10194-011-0036-y.
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Lakes in the cascade model of storage and drainage reservoirsThe study area covers a compact, decentric hydrographic system called the Kashubian hydrographic system, which includes the drainage basins of the Słupia, Łupawa, Łeba, Reda, Wda, Wierzyca and Radunia. The Kashubian hydrographic system can be presented in the form of a cascade model of storage-drainage reservoirs - kord. One of the properties of a hydrographic system is its extent. Its horizontal extent is delimited by topographic watersheds, and its vertical extent is delimited at the bottom by the surface of the drainage base and in the roof by the land surface. Since reservoirs of the kord model are inscribed one into another, the upper border of all the reservoirs of the cascade is assumed to be the land surface, and the lower border of particular reservoirs of the cascade is a surface going through the level (elevation) of recipients receiving their waters. In the kord model on all its levels there are water reservoirs; however they differ in terms of origin, development, hydrological features and the role they play in the system. Depending on the type of recipient, drainage and storage can occur with various intensity. As follows from the hydrographic analysis the deepest lakes are situated in local and regional recipients, hence in these types of recipient, drainage and storage have greater intensity. On the other hand, in the transit recipient, transport is dominant.
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Markey, Kate A., Rachel D. Kuns, Renee J. Robb, et al. "Recipient CD8+ DC Delete Alloreactive Donor CTL and Promote Leukemic Relapse after Allogeneic BMT." Blood 126, no. 23 (2015): 4279. http://dx.doi.org/10.1182/blood.v126.23.4279.4279.
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Abstract Allogeneic bone marrow transplantation (BMT) remains the therapy of choice for many haematological malignancies, but despite the curative benefit of the immunological graft-versus-leukemia (GVL) effect, relapse remains a key cause of death. We have investigated the role of recipient dendritic cells (DC) in antigen presentation to donor CD8 cytotoxic T cells (CTL) in a model of BMT where GVHD and GVL are directed to multiple minor histocompatibility antigens (mHA) and survival reflects GVL activity. C3H.Sw bone marrow and purified CD8 T cell grafts were transplanted with B6-derived MLL-AF9 induced primary acute myeloid leukemia (AML) into lethally irradiated B6.CD11c.DOG recipients (diphtheria toxin receptor (DTR), ovalbumin and GFP expression driven off the CD11c promoter) such that recipient DC can be deleted by DT administration. Surprisingly, depletion of recipient DC resulted in improved leukemic control (median survival 43 vs 31 days, P <0.001). The use of IRF8-/- BMT recipients (in which the CD8+ DC subset is absent) confirmed that recipient CD8+ DC were critical for regulating these GVL effects (median survival 43 vs 34 days, P = 0.0005). Conversely, when recipient CD8+ DC were expanded in a B6 to B6D2F1 model with bcr-abl/Nup98-HoxA9 induced primary AML, by using Flt3-L treatment for 10 days prior to BMT, GVL effects were completely eliminated, rendering relapse rate equivalent to that seen in the recipients of T cell depleted (TCD) grafts (median survival 11 days in BM+T and TCD groups where recipients were pre-treated with Flt3-L, vs. >45 days in the saline treated BM+T group). The use of B6.CD11c-Rac1 transgenic BMT recipients (who cannot process and present exogenously acquired antigen) confirmed that this effect was the result of endogenous alloantigen presentation by recipient DC and independent of cross-presentation.Using the same depletion strategies in an antigen-specific model (with donor OT-I T cells and B6.CD11c.DOG x DBA/2 F1 recipients) we confirmed that recipient DC invoked effector donor CTL activation, differentiation (CD25+ CD69+ CD62L-) and subsequent apoptosis (as measured by Annexin V; 52.4% vs. 23.9% in DC replete vs. depleted recipients, P = 0.01). There was a consequent profound contraction of the donor CTL compartment by day 10 in DC replete recipients. This contraction of the CTL compartment was associated with reduced expression of the cytolytic molecule granzyme B (MFI 1922 vs 1097, P = 0.02). Antigen presentation has a critical role in the initiation of donor T cell alloreactivity and GVL after BMT. Here we demonstrate that endogenous alloantigen presentation by recipient CD8+ DC to donor T cells leads to activation induced death of donor CTL early after BMT, which in turn facilitates leukemic relapse. This concept has critical implications for the design of therapies that target DC in the peri-transplant period and confirms that recipient DC regulate GVL effects. Disclosures No relevant conflicts of interest to declare.
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Rosinski, Steven Lawrence, Scott Stoll Graves, Rainer Storb, and Brad Stone. "Vaccinating Female Donors with Y Chromosome-Encoded Disparities in the Pre-Clinical Canine Model of Allogeneic Hematopoietic Cell Transplantation." Blood 120, no. 21 (2012): 4123. http://dx.doi.org/10.1182/blood.v120.21.4123.4123.
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Abstract Abstract 4123 Adoptive transfer of tumor antigen-sensitized lymphocytes has been a long-studied approach for the treatment of solid malignancies. Transfer of lymphocytes sensitized against minor histocompatibility (H) antigens, disparate between the marrow donor and recipient, may be a similar approach to enable improved host versus tumor responses in the treatment of hematological malignancies. We have developed a pre-clinical canine transplant model that establishes a state of stable mixed donor-recipient hematopoietic chimerism after a non-myeloablative conditioning regimen, dog leukocyte antigen (DLA)-identical sibling marrow graft, and a short course of post-grafting immunosuppression. Residual recipient hematopoiesis represents a surrogate for relapse from the underlying hematologic malignancy. The only way to eliminate the residual recipient hematopoiesis is by a donor lymphocyte infusion (DLI) from a donor sensitized by minor H antigens though either an infusion of cryopreserved recipient peripheral blood mononuclear cells, a kidney graft, or a skin graft. A DLI from an unsensitized donor does not alter chimerism in the recipient. This model lends itself to testing of vaccines to minor H antigens. We hypothesized that vaccinating donor dogs with autologous antigen presenting cells (APC) expressing recipient minor H antigens followed by DLI will result in conversion to full donor hematopoiesis in the mixed chimerism recipient, providing the experimental evidence in a large animal model of the potential therapeutic benefit for a minor H antigen vaccine to treat relapsed disease. To test our hypothesis, we sensitized two donor dogs with autologous APC's transfected with poly(A)-selected mRNA from their respective recipients followed by DLI into these mixed chimeric recipients. We performed subcutaneous injections into the donor of 5 to 12 x 10⋀6 CD40-ligand stimulated donor B-cells electroporated with mRNA isolated from PHA blasts from the chimeric recipient every three weeks for a total of three vaccinations. This was followed by a DLI infusion into the chimeric recipient. There was no change in chimerism in the recipient dogs, and we were unable to demonstrate an Elispot response in the donor dogs to the transfected recipient mRNA. Due to the difficulty in isolating sufficient quantities of mRNA and a lack of an ELISpot response, we changed the source of antigen. Utilizing the canine genome sequence database we identified non-synonymous disparities between the × and Y chromosome genes of SMCY, UTY, and SRY. We created ‘minigenes’ encoding these disparities flanked by a T7 promoter and a 3' beta globin untranslated region with a poly(A) tail. These minigenes encoded 80% of the Y chromosome-associated disparities between canine SMCY, UTY, and their × chromosome homologs. The entire SRY gene was included as there is no × homolog for SRY. Minigenes were transcribed in vitro with a cap analogue to produce fully translatable mRNA. These Y chromosome-specific minigenes produced a strongly positive ELISpot in a female dog that had been sensitized with cells from a DLA-identical male sibling. We then performed three consecutive intravenous vaccinations at least one week apart with a combination of 25 to 40 × 106̂ CD34-derived donor dendritic cells and CD40 ligand-stimulated B cells transfected with these Y chromosome-specific minigenes. Following the third vaccination, we demonstrated a weak positive ELISpot reaction to the Y chromosome-specific minigenes. However, a DLI into a mixed chimeric recipient failed to convert the recipient to full donor hematopoiesis and did not elicit any graft versus host disease. These studies suggest that in vivo sensitization of the marrow donor against recipient minor H antigens presented by autologous dendritic cells will require additional immune-modulation to accomplish improved graft versus tumor effects in the treatment of hematological diseases. Disclosures: No relevant conflicts of interest to declare.
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Shao, Jia, Chenyu Wang, Peng Fu, Fan Chen, Yi Zhang, and Jinxia Wei. "Impact of Donor and Recipient CYP3A5*3 Genotype on Tacrolimus Population Pharmacokinetics in Chinese Adult Liver Transplant Recipients." Annals of Pharmacotherapy 54, no. 7 (2019): 652–61. http://dx.doi.org/10.1177/1060028019897050.
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Background: Tacrolimus (TAC) is widely used after liver transplantation, but the therapeutic window is narrow. Objective: The purpose was to study both donor and recipient CYP3A5*3 genotypes affecting TAC apparent clearance rate (CL/F) and investigate a TAC population pharmacokinetic (PPK) model in Chinese liver transplant recipients for potential starting-dose individualized medication. Methods: A data set of 721 TAC concentrations was obtained from 43 adult liver transplant recipients. The TAC PPK model was analyzed using nonlinear mixed-effects modeling. Potential covariates, including demographic characteristics, physiological and pathological data, concomitant medications, and CYP3A5*3 genotype, were evaluated. The final model was validated using normalized prediction distribution errors and bootstrapping. Results: A 2-compartment model with first-order absorption and elimination was used to describe TAC disposition. Population estimates of TAC, CL/F, apparent central distribution volume (V2/F), rate of absorption (Ka), and apparent peripheral distribution volume (V3/F) were 18.1 L/h (12%), 72.7 L (34%), 0.163 h−1 (17%), and 412 L (21%), respectively. The model and estimated parameters were found to be stable. Other covariates did not influence TAC CL/F. Both donor and recipient CYP3A5*1 genotypes were significantly correlated with TAC clearance, and CL/F was 1.70-fold higher in both donor and recipient CYP3A5*1 carriers than in noncarriers among Chinese liver transplant recipients. Conclusion and Relevance: A PPK model of TAC was established in Chinese adult liver transplantation recipients for starting-dose individualized medication, which can be expanded to optimize clinical efficacy and minimize toxicity with therapeutic drug monitoring.
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Beltrame, Renato Travassos, Luis Gustavo Barioni, Breno Dala Maestri, and Celia Raquel Quirino. "Economic optimization of the number of recipients in bovine embryo transfer programs." Scientia Agricola 64, no. 3 (2007): 221–26. http://dx.doi.org/10.1590/s0103-90162007000300002.
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Purchase and maintenance of recipient females account for a large proportion of the costs and determine the number of calves that can be produced in an embryo transfer program. However, the large variability of embryo production by the donors and the need to purchase and synchronize the recipients before knowing the number of embryos collected make it difficult for the decision maker to identify the ideal number of recipient females to allocate. An ex-ante evaluation to determine the optimal number of recipient females was carried out through a sensitivity analysis for the ratio between the number of recipients and donors in a simulation model. The variability for the number of embryos collected was accounted for by applying the Monte Carlo simulation technique, assuming normal distribution and known values for mean and variance. The simulation considered monthly intervals between collections, during a 24 months program. The effect of embryo freezing on the number of pregnancies was considered by introducing a stock of frozen embryos into the mathematical model. Optimal recipient/donor ratio and the cost per pregnancy were compared for three recipient synchronization protocols (prostaglandin, progesterone - P4 and Ovsynch), based on the expected performance for synchronization, conception and transfer/treated rates for each protocol. Stochastic simulation associated with sensitivity analysis was effective in identifying the optimal donor to recipient ratio. Freezing embryos is effective to reduce the operational costs per pregnancy. The estimated optimal recipient/donor ratio was 20 for prostaglandin and 16.7 for the other protocols. The P4 protocol, although the most expensive, resulted in the lowest pregnancy cost estimation followed by prostaglandin and Ovsynch.
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Cho, Jinmyoung, and Alan Stevens. "The Relationship Between Functional Decline of Care Recipients and Health of Caregivers." Innovation in Aging 4, Supplement_1 (2020): 361. http://dx.doi.org/10.1093/geroni/igaa057.1161.
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Abstract Pearlin’s stress-process model (2010) depicts that functional decline in care-recipient would shape caregiving burden and impact on caregiver’s health. With this background, we explored how the changes in care-recipients’ physical and cognitive functioning are related to the caregivers’ physical health. A total of 853 care-recipients from the Rounds 1 and 5 of the National Health and Aging Trend Study (NHATS) and their 1,303 caregivers from Round 5 of National Study of Caregiving (NSOC) were included. Multiple regression analyses were conducted to identify correlates of self-rated health and the number of chronic conditions with the change in physical and cognitive functioning from Round 1 to 5 and multidimensional caregiver burden. Physical functioning measured by the NHATS short physical performance battery included balance stands, walking chair stands, grip strength, and peak airflow. Memory, orientation, and executive functioning measured cognitive functioning. Multidimensional caregiver burden includes four domains (emotional, psychological, relationship, and resilience) identified with factor analysis. Background factors (recipient’s age, assisting recipients for 5 years, race/ethnicity, and number of chronic conditions of recipient) were included as covariates. After controlling covariates, the data showed that 5-year change of physical functioning and caregiver’s emotional burden were negatively significant for self-rated health; and assisting care-recipients for 5 years or more was significant for more numbers of chronic conditions among caregivers. Findings highlight that caregivers’ physical health is closely associated with care-recipient’s functional decline for long-term caregiving experiences. Further investigation on caregiver’s physical health using multiple health outcomes is needed to promote physical health in long-term caregivers.
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Mathes, David, Scott Stoll Graves, George E. Georges, et al. "Long-Term Tolerance to Kidney Allografts After Induced Rejection of Donor Hematopoietic Chimerism in a Preclinical Canine Model." Blood 120, no. 21 (2012): 2991. http://dx.doi.org/10.1182/blood.v120.21.2991.2991.
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Abstract Abstract 2991 Allogeneic hematopoietic cell transplantation provides a reliable method for inducing tolerance towards solid organ grafts. However, this procedure can result in graft-versus-host disease (GVHD) thereby limiting its application. Here we test the hypothesis that mixed chimerism can be intentionally reverted to host hematopoiesis without rejection of a kidney graft. Recipient dogs were given 2 Gy total body irradiation (TBI) before and a short course of immunosuppression after marrow infusion from dog leukocyte antigen-identical littermates. All dogs achieved stable mixed chimerism. After a mean of 20 weeks, one cohort of dogs received kidney transplants from their respective marrow donors. Subsequently, recipients were reconditioned with 2 Gy TBI and given autologous granulocyte-colony stimulating factor-mobilized leukocytes (recipient leukocyte infusion) that had been collected before marrow transplant. Dogs receiving a second TBI and recipient leukocyte infusion without a kidney transplant rejected their donor hematopoietic graft within 3 weeks. Dogs that received kidney grafts, followed by a second TBI and recipient leukocyte infusion, rejected their marrow graft without rejecting their transplanted kidneys for periods greater than one year. Mixed chimerism may be clinically reverted to 100% recipient without rejection of a kidney allograft. This model has potential applications in understanding the mechanism of split tolerance. This finding may have application towards minimizing the risk of GVHD in solid organ transplant patients given hematopoietic cell transplantation from HLA-identical donors. Disclosures: No relevant conflicts of interest to declare.
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David, André Ibrahim, Valéria Vieira Chida, Andre Dong Won Lee, et al. "Multivisceral transplantation in pigs: a model for research and training." Einstein (São Paulo) 9, no. 3 (2011): 372–76. http://dx.doi.org/10.1590/s1679-45082011ao1956.
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ABSTRACT Objective: To present a model for research and training in multivisceral transplantation in pigs. Methods: Eight Large White pigs (four donors and four recipients) were operated. The multivisceral transplant with stomach, duodenum, pancreas, liver and intestine was performed similarly to transplantation in humans with a few differences, described below. Anastomoses were performed as follows: end-to-end from the supra-hepatic vena cava of the graft to the recipient juxta diaphragmatic vena cava; end-to-end from the infra-hepatic vena cava of the graft to the inferior (suprarenal) vena cava of the recipient; and end-to-side patch of the aorta of the graft to the infrarenal aorta of the recipient plus digestive reconstruction. Results: The performance of the multivisceral transplantion was possible in all four animals. Reperfusions of the multivisceral graft led to a severe ischemia-reperfusion syndrome, despite flushing of the graft. The animals presented with hypotension and the need for high doses of vasoactive drugs, and all of them were sacrificed after discontinuing these drugs. Conclusion: Some alternatives to minimize the ischemia-reperfusion syndrome, such as the use of another vasoactive drug, use of a third pig merely for blood transfusion, presence of an anesthesia team in the operating room, and reduction of the graft, will be the next steps to enable experimental studies.
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Dueñas-Jurado, J. M., P. A. Gutiérrez, A. Casado-Adam, et al. "New models for donor-recipient matching in lung transplantations." PLOS ONE 16, no. 6 (2021): e0252148. http://dx.doi.org/10.1371/journal.pone.0252148.
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Objective One of the main problems of lung transplantation is the shortage of organs as well as reduced survival rates. In the absence of an international standardized model for lung donor-recipient allocation, we set out to develop such a model based on the characteristics of past experiences with lung donors and recipients with the aim of improving the outcomes of the entire transplantation process. Methods This was a retrospective analysis of 404 lung transplants carried out at the Reina Sofía University Hospital (Córdoba, Spain) over 23 years. We analyzed various clinical variables obtained via our experience of clinical practice in the donation and transplantation process. These were used to create various classification models, including classical statistical methods and also incorporating newer machine-learning approaches. Results The proposed model represents a powerful tool for donor-recipient matching, which in this current work, exceeded the capacity of classical statistical methods. The variables that predicted an increase in the probability of survival were: higher pre-transplant and post-transplant functional vital capacity (FVC), lower pre-transplant carbon dioxide (PCO2) pressure, lower donor mechanical ventilation, and shorter ischemia time. The variables that negatively influenced transplant survival were low forced expiratory volume in the first second (FEV1) pre-transplant, lower arterial oxygen pressure (PaO2)/fraction of inspired oxygen (FiO2) ratio, bilobar transplant, elderly recipient and donor, donor-recipient graft disproportion requiring a surgical reduction (Tailor), type of combined transplant, need for cardiopulmonary bypass during the surgery, death of the donor due to head trauma, hospitalization status before surgery, and female and male recipient donor sex. Conclusions These results show the difficulty of the problem which required the introduction of other variables into the analysis. The combination of classical statistical methods and machine learning can support decision-making about the compatibility between donors and recipients. This helps to facilitate reliable prediction and to optimize the grafts for transplantation, thereby improving the transplanted patient survival rate.
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Ugai, Tomotaka, Keitaro Matsuo, and Yasuo Morishima. "ALDH2 Polymorphism Has a Significant Impact on Transplant Related Mortality after HLA-Matched Bone Marrow Transplantation." Blood 128, no. 22 (2016): 3391. http://dx.doi.org/10.1182/blood.v128.22.3391.3391.
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Abstract Background : Aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme known to degrade acetaldehyde metabolized from ethanol, is also involved in critically important biological processes such as drug metabolism and DNA repair in hematopoietic stem cells. Based on its role in these biological processes, we hypothesized that a functional ALDH2Glu504Lys polymorphism, which is highly prevalent in East Asian populations, could affect the outcome of hematopoietic transplant recipients. Here, we investigated the association between recipient and donor ALDH2 polymorphism and the clinical outcomes of bone marrow transplantation (BMT). Methods. : We analyzed the Japanese national registry data for 409 patients who underwent allogeneic BMT from an HLA-matched unrelated donor through the Japan Marrow Donor Program. The probability of overall survival (OS) was estimated according to the Kaplan-Meier method. The probabilities of relapse, transplant-related mortality (TRM), engraftment, and graft-versus-host disease (GVHD) were estimated based on cumulative incidence curves. Competing events were death without relapse for relapse, relapse for TRM, death without engraftment for engraftment, and death without GVHD for GVHD. To evaluate the impact of recipient and donor ALDH2 polymorphism on transplant outcomes, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) after adjusting for potential confounders. The Cox proportional hazards model was used to evaluate the effect on OS, whereas Fine and Gray's proportional hazards model was used for the other endpoints. Results.: The median follow-up period in survivors was 6.3 years (range, 0.3-13.1 years). The unadjusted 3-year OS rate was 51% (95% CI, 43%-57%) in Glu/Glu genotype recipients, 52% (43%-60%) in Glu/Lys genotype recipients, and 43% (25%-60%) in Lys/Lys genotype recipients. We did not observe a statistically significant association between the recipient ALDH2 polymorphism and OS. The cumulative incidence of unadjusted 3-year TRM was 28% (21%-34%) in Glu/Glu genotype recipients, 25% (18%-33%) in Glu/Lys genotype recipients, and 50% (29%-68%) in Lys/Lys genotype recipients. The recipient ALDH2 Lys/Lys genotype was significantly associated with a higher TRM, with a HR relative to Glu/Glu genotype of 2.45 (95% CI = 1.22-4.90, P = 0.01). Among the causes of TRM, the incidence rate of organ failure in recipients with the Lys/Lys genotype was twice as high as in recipients with the Glu/Glu genotype (5.9 vs. 3.0 per 1,000 person-days). A statistically significant association between the recipient ALDH2 polymorphism and relapse or GVHD was not observed. With regard to engraftment, the cumulative incidence of platelet engraftment at day 50 was 82% (76%-87%) in Glu/Glu genotype recipients, 80% (72%-85%) in Glu/Lys genotype recipients, and 65% (47%-78%) in Lys/Lys genotype recipients. Compared to the recipient Glu/Glu genotype, the recipient Lys/Lys genotype was marginally significantly associated with delayed platelet engraftment (HR = 0.60, 95% CI = 0.43-1.03, P = 0.06). In contrast, donor ALDH2 polymorphism did not show any significant association with transplant outcomes. Conclusions: We observed poor TRM and delayed platelet engraftment in HLA-matched unrelated BMT recipients with ALDH2 Lys/Lys genotype. Taken functional significance of this polymorphism, our results might indicate that recipient ALDH2 polymorphism could affect the metabolism of chemotherapeutic agents leading to higher TRM and delayed platelet engraftment. Disclosures No relevant conflicts of interest to declare.
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Slichter, Sherrill J., Esther Pellham, S. Lawrence Bailey, and Todd Christoffel. "Filtration Leukoreduction Followed by Pathogen-Reduction (Mirasol Treatment) Prevents Alloimmune Platelet Refractoriness in a Dog Platelet Transfusion Model." Blood 120, no. 21 (2012): 271. http://dx.doi.org/10.1182/blood.v120.21.271.271.
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Abstract Abstract 271 Background: The largest transfusion (tx) trial to evaluate methods of preventing platelet (plt) alloimmunization (TRAP Trial; NEJM 1997;337:1861) demonstrated residual alloimmunization rates of 17% to 21% in AML patients (pts) undergoing induction chemotherapy despite receiving either filter-leukoreduced (F-LR) or UV-B irradiated (UV-BI) blood products, respectively. Our pre-clinical dog plt tx studies, the basis for testing UV-BI in the TRAP Trial, demonstrated this model was able to predict pt results; i.e., prevention of alloimmunization was 45% in the dog but 79% in pts. The greater effectiveness in pts was probably because they had chemotherapy-induced immunosuppression compared to the immunocompetent dogs. Our current dog plt tx studies have focused on evaluating F-LR to remove antigen-presenting WBCs (APCs) or pathogen-reduction (PRT) (Mirasol treatment) to inactivate APCs. Methods: For pts, plts are obtained using either apheresis procedures or as plt concentrates prepared from whole blood (WB). To re-duplicate these types of plts in our dog model, we prepared plt-rich-plasma (PRP) from WB which would be equivalent to non-leukoreduced apheresis plts. The PRP was then either unmodified, F-LR, PRT, or the treatments were combined. Because the success rates were very poor with the single treatments of PRP (see table), the WB studies evaluated only combined F-LR and PRT treatments. In clinical practice, the treated WB would then be used to prepare a plt concentrate. The WB studies assessed either PRT of the WB followed by F-LR of PRP made from the WB or, conversely, F-LR of the WB using a plt-sparing filter (Terumo Immuflex WB-SP) followed by PRT of the WB and then preparation of PRP. After completion of all treatments, PRP from each study was centrifuged to prepare a plt concentrate, the plts were radiolabeled with 51Cr, injected into a recipient, and samples were drawn from the recipient to determine recovery and survival of the donor's (dnr's) plts. Dnr and recipient pairs were selected to be DLA-DRB incompatible and crossmatch-negative. Eight weekly dnr plt txs were given to the same recipient or until the recipient became refractory to the dnr's plts defined as ≤5% of the dnr's plts still circulating in the recipient at 24-hours post-tx following 2 sequential txs. Results: The table shows the percent of recipients who accepted 8 weeks of dnr plts and the total number of dnr plts and WBC injected. Using either filter, there was equal reduction in WBCs to 105/tx. Acceptance of unmodified dnr plts was 1/7 recipients (14%), PRT 1/8 recipients (13%), PL1-B filter 1/5 recipients (20%), and PLS-5A filter 4/6 recipients (66%). None of these differences were statistically significant. In contrast, combining F-LR of the PRP followed by PRT of the PRP was effective in 21/22 recipients (95%), regardless of the filter used. WB studies showed dnr plts were accepted by 2/5 recipients (40%) when WB was first treated with PRT followed by F-LR of the PRP made from the WB. Conversely, if the WB was first F-LR followed by PRT of the WB, 5/6 (83%) accepted dnr plts; more of these studies are in progress. Data are given as average ±1 S.D. Conclusions: F-LR of PRP or WB followed by PRT of the same PRP or WB is highly-effective in preventing alloimmune plt refractoriness in our dog plt tx model. These data suggest that most of the APCs must be removed by filtration before PRT can eliminate the activity of any residual APCs. Based on the high rate of success of this combined approach in our immunocompetent dog model, similar results should be achieved in pts even those who are not immunocompetent as were the AML pts receiving chemotherapy in the TRAP Trial. Disclosures: Slichter: Terumo BCT: Research Funding.
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Fast, Loren D. "Recipient elimination of allogeneic lymphoid cells: donor CD4+ cells are effective alloantigen-presenting cells." Blood 96, no. 3 (2000): 1144–49. http://dx.doi.org/10.1182/blood.v96.3.1144.
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Abstract The encounter with allogeneic major histocompatibility complex (MHC) molecules expressed on donor leukocytes during transfusion of blood products has been shown to impact the recipient's immune responses in a number of settings. To better understand the responses induced by the transfer of allogeneic cells, a murine model was used to characterize the recipient responses that control the fate of the allogeneic lymphoid cells. Recipient CD8+ cells could rapidly eliminate a large number of donor cells within 3 days after injection. When elimination responses were studied in the absence of CD8+ cells, it was found that alloantibody production was the secondary elimination mechanism. Optimal recipient CD8+ and B cell responses in this model required help from CD4+ cells that could be provided by 3 different pathways. Although recipient CD4+ cells could provide help when activated by direct recognition of allogeneic MHC class II molecules expressed on donor cells or by indirect recognition of processed alloantigen presented on recipient antigen-presenting cells (APCs), the most rapid recipient responses were generated by help provided by donor CD4+ cells. Purified donor CD4+ cells were also able to induce these rapid responses, indicating that activated donor CD4+cells expressing allogeneic MHC molecules were able to effectively stimulate responses by both recipient CD8+ and B cells.
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Fast, Loren D. "Recipient elimination of allogeneic lymphoid cells: donor CD4+ cells are effective alloantigen-presenting cells." Blood 96, no. 3 (2000): 1144–49. http://dx.doi.org/10.1182/blood.v96.3.1144.015k46_1144_1149.
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The encounter with allogeneic major histocompatibility complex (MHC) molecules expressed on donor leukocytes during transfusion of blood products has been shown to impact the recipient's immune responses in a number of settings. To better understand the responses induced by the transfer of allogeneic cells, a murine model was used to characterize the recipient responses that control the fate of the allogeneic lymphoid cells. Recipient CD8+ cells could rapidly eliminate a large number of donor cells within 3 days after injection. When elimination responses were studied in the absence of CD8+ cells, it was found that alloantibody production was the secondary elimination mechanism. Optimal recipient CD8+ and B cell responses in this model required help from CD4+ cells that could be provided by 3 different pathways. Although recipient CD4+ cells could provide help when activated by direct recognition of allogeneic MHC class II molecules expressed on donor cells or by indirect recognition of processed alloantigen presented on recipient antigen-presenting cells (APCs), the most rapid recipient responses were generated by help provided by donor CD4+ cells. Purified donor CD4+ cells were also able to induce these rapid responses, indicating that activated donor CD4+cells expressing allogeneic MHC molecules were able to effectively stimulate responses by both recipient CD8+ and B cells.
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Cohen, S. I. "Allocation of Foreign Aid in a Segmented International Context." Pakistan Development Review 34, no. 4III (1995): 987–1000. http://dx.doi.org/10.30541/v34i4iiipp.987-1000.
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Research on the topic of distribution of foreign aid among recipients is regaining momentum. This is understandable in the light of the knowledge that presently the richest 40 percent of the developing world receives twice as much aid per capita as the poorest 40 percent [UNDP (1994)], while once upon a time foreign aid was sought to accomplish exactly the opposite. The distribution of official development assistance (ODA) is conventionally studied in terms of two models: the ‘recipient needs’ model and the ‘donor interest’ model. In the first, foreign aid flows are seen to satisfy the socio-economic needs of the recipient countries. In the second, national interests of donors, whether these are military, political or commercial, are seen to determine the direction and size of the foreign aid. Empirical studies were made to ascertain and understand whether, on balance, foreign aid is motivated by recipient need or donor interest. There is one class of studies, for example, Mcgillivray (1989), which estimates for donors a compound measure of their allocation bias. The other class of studies, i.e., Maizels and Nissanke (1984) and Grilli and Riess (1992), employs regression analysis to explain allocation of foreign aid by representative variables of recipient need and donor interest.
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van den Wijngaard, Jeroen P. H. M., Asli Umur, Raymond T. Krediet, Michael G. Ross, and Martin J. C. van Gemert. "Modeling a hydropic recipient twin in twin-twin transfusion syndrome." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 288, no. 4 (2005): R799—R814. http://dx.doi.org/10.1152/ajpregu.00635.2004.
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We developed a mathematical model of twin-twin transfusion syndrome (TTTS) that includes a hydropic recipient twin, adding interstitial and intracellular fluid compartments, fetal congestive cardiac failure, and the dynamics of renin-angiotensin system (RAS) mediators to our previous TTTS model. Ten differential equations for each twin, coupled by the net fetofetal transfusion of blood and blood components, i.e., colloids, osmoles, and RAS mediators, describe the development of fetal arterial and venous blood volumes, blood osmolality and colloid osmotic pressure (COP), interstitial fluid volume and COP, intracellular fluid volume, amniotic fluid volume and osmolality, and RAS mediator concentration. We included varying placental anastomoses, placental sharing, and amnionicity. The 20 differential equations were solved numerically from 0 to 40 wk with a 0.6-s time step. Consistent with clinical experience, model predictions are as follows. Unidirectional arteriovenous anastomoses and arteriovenous anastomoses inadequately compensated by oppositely directed anastomoses cause severe TTTS that includes a hydropic recipient. Adequately compensated arteriovenous anastomoses simulated TTTS without hydrops. The probability that oppositely directed anastomoses prevent onset of a hydropic recipient after TTTS onset, i.e., the largest interval between onset of TTTS and onset of hydrops in the recipient, was best for a venovenous anastomosis, closely followed by an arterioarterial and finally an oppositely directed arteriovenous anastomosis. Hydropic recipients have decreased amniotic fluid volume. Unequal placental sharing and amnionicity modify hydrops onset. In conclusion, our model simulates a sequence of events that results in a hydropic recipient twin in severe TTTS. The model may allow an assessment of the efficacy of current therapeutic interventions for TTTS cases that include a hydropic recipient twin.
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Chou, Shih Yung, Charles Ramser, and Tree Chang. "When is helping considered helping? The recipient’s view of helping during the stages of receiving help." International Journal of Organization Theory & Behavior 22, no. 1 (2019): 79–95. http://dx.doi.org/10.1108/ijotb-03-2018-0034.
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PurposeThe purpose of this paper is to develop a theoretical model that describes when helping is considered helping from the recipient’s point of view.Design/methodology/approachThe theoretical model was conceptually developed by drawing upon attribution theory, self-consistency theory and social cognitive theory, as well as relevant literature.FindingsThe authors propose that receiving help encompasses three sequential stages: the pre-help-receiving stage, the help-receiving stage and the post-help-receiving stage. Additionally, the authors theorize that the more other-oriented helping motives are attributed by the recipient, the more likely the recipient views the helper’s help as helping, that the more self-esteem preserving behaviors along with helping actions the recipient receives from the helper, the more likely the recipient views the helper’s help as helping and that the more gaps between actual and desired level of task performance are closed by the helper’s help, the more likely the recipient views the helper’s help as helping.Originality/valueFrom a theoretical standpoint, this paper offers a process approach that may guide future research on help receiving in organizations.
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Kim, Yeunhee, Danielle Turner, Jacquelyn Nelson, Ina Dobrinski, Margaret McEntee, and Alexander J. Travis. "Production of donor-derived sperm after spermatogonial stem cell transplantation in the dog." REPRODUCTION 136, no. 6 (2008): 823–31. http://dx.doi.org/10.1530/rep-08-0226.
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Spermatogonial stem cell transplantation (SSCT) offers unique approaches to investigate SSC and to manipulate the male germline. We report here the first successful performance of this technique in the dog, which is an important model of human diseases. First, we investigated an irradiation protocol to deplete endogenous male germ cells in recipient testes. Histologic examination confirmed >95% depletion of endogenous spermatogenesis, but retention of normal testis architecture. Then, 5-month-old recipient dogs (n=5) were focally irradiated on their testes prior to transplantation with mixed seminiferous tubule cells (fresh (n=2) or after 2 weeks of culture (n=3)). The dogs receiving cultured cells showed an immediate allergic response, which subsided quickly with palliative treatment. No such response was seen in the dogs receiving fresh cells, for which a different injection medium was used. Twelve months post-injection recipients were castrated and sperm was collected from epididymides. We performed microsatellite analysis comparing DNA from the epididymal sperm with genomic DNA from both the recipients and the donors. We used six markers to demonstrate the presence of donor alleles in the sperm from one recipient of fresh mixed tubule cells. No evidence of donor alleles was detected in sperm from the other recipients. Using quantitative PCR based on single nucleotide polymorphisms (SNPs), about 19.5% of sperm were shown to be donor derived in the recipient. Our results demonstrate the first successful completion of SSCT in the dog, an important step toward transgenesis through the male germline in this valuable biomedical model.
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Leow, C. K., D. W. R. Gray, and P. J. Morris. "Successful Reversal of Diabetes by Single Donor Isologous Islet Transplantation in a Mouse Model." Cell Transplantation 6, no. 4 (1997): 429–30. http://dx.doi.org/10.1177/096368979700600410.
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A method for isolating mouse islets which consistently gives a high yield with good purity is described. Using a bovine serum albumin gradient, the mean yield of islets per pancreas is 425 (SEM ± 15) with a consistent purity of over 90%. Single donor to single recipient of islets transplanted under the renal capsule restores normoglycemia in the diabetic recipients within 2 to 5 days of transplantation.
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Enghofer, Michael, Jörg Bojunga, Ralf Ludwig, et al. "Lymphocyte transfer in streptozotocin-induced diabetes: adhesion of donor cells to islet endothelium." American Journal of Physiology-Endocrinology and Metabolism 274, no. 5 (1998): E928—E935. http://dx.doi.org/10.1152/ajpendo.1998.274.5.e928.
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The interaction between intravenously transferred lymphocytes derived from spleens of multiple low-dose streptozotocin-diabetic mice with islet, exocrine pancreatic, and gastric mucosal endothelium of nondiabetic recipient mice was investigated by in vivo microscopy. Donor lymphocytes were stained with acridine red in vitro. The adoptive transfer of these cells from diabetic donor animals resulted in significantly increased lymphocyte rolling (4.46 ± 1.32%, P < 0.05) and adhesion (3.86 ± 1.04%, P < 0.05) in islets of nondiabetic recipients that had been pretreated with a single subdiabetogenic dose of streptozotocin. No increased endothelial interaction was noted in nonpretreated recipients or in experiments with nondiabetic donors. Rolling (1.19 ± 0.61 to 2.71 ± 0.62%) and adhesion (0.61 ± 0.33 to 2.80 ± 0.97%) of donor lymphocytes were low in exocrine pancreatic and gastric mucosal control tissue. It is concluded that, in this animal model, lymphocytes from diabetic donors interact preferentially with recipient islet endothelium. However, additional stimulation of recipient islet endothelium by exogenous factors is necessary to enable transferred cells to adhere to pancreatic islets.
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Yang, Jingyan, Christine L. Sardo Molmenti, Joaquin Cagliani, et al. "Time-Effect of Donor and Recipient Characteristics on Graft Survival after Kidney Transplantation." International Journal of Angiology 28, no. 04 (2019): 249–54. http://dx.doi.org/10.1055/s-0039-1700500.
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AbstractThe kidney allocation system (KAS) is based on quality-based “longevity matching” strategies that provide only a momentary snapshot of expected outcomes at the time of transplantation. The purpose of our study was to define on a continuous timeline the relative and mutual interactions of donor and recipient characteristics on graft survival.Total 39,108 subjects who underwent kidney transplant between October 25, 1999 and January 1, 2007 were identified in the United Network for Organ Sharing dataset. Our primary outcome was graft survival. Time-dependent receiver operating characteristic (ROC) curves and area under time-dependent ROC curve (AUC) were used to compare the predictive ability of the two allocation systems.During the first year after transplantation, both donor and recipient models showed identical relevance. From the first to the sixth years, although the two ROC curves were nearly identical, the donor model outweighed the recipient model. Both models intersected again at the sixth year. From that time onward, the ROC curve for recipient characteristics model predominated over the ROC curve for donor characteristics model. The predictive value of the recipient model (AUC = 0.752) was greater than that of the donor model (AUC = 0.673)We hope that this model will provide additional guidance and risk stratification to further optimize organ allocation based on the dynamic interaction of both donor and recipient characteristics over time.
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Dreher, Axel, Jenny Simon, and Justin Valasek. "Optimal decision rules in multilateral aid funds." Review of International Organizations 16, no. 3 (2021): 689–719. http://dx.doi.org/10.1007/s11558-020-09406-w.
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AbstractWhile existing research has suggested that delegating foreign aid allocation decisions to a multilateral aid fund may incentivize recipient countries to invest in bureaucratic quality, our analysis links the fund’s decision rules to recipient-country investment by explicitly modeling the decision-making within multilateral aid funds. We find that majority rule induces stronger competition between recipients, resulting in higher investments in bureaucratic quality. Despite this advantage, unanimity can still be optimal since the increased investment under majority comes at the cost of low aid allocation to countries in the minority. The qualitative predictions of our model rationalize our novel empirical finding that, relative to organizations that use a consensus rule, organizations that use majority are more responsive to changes in recipient-country quality.
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Hagihara, Atsushi, Fumiko Harada, and Hiromitsu Shimakawa. "Estimation of posture and prediction of the elderly getting out of bed using a body pressure sensor." International Journal of Electrical and Computer Engineering (IJECE) 11, no. 2 (2021): 1208. http://dx.doi.org/10.11591/ijece.v11i2.pp1208-1222.
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We propose an IoT support system for estimating the posture of the care recipient on the bed from the body pressure of the care recipient measured by a sheet-type body pressure sensor, and detecting the posture related to leaving the bed in real time. In addition, we propose a method that predicts getting out of the bed before the care recipient takes a posture related to getting out of the bed by considering the state transition. Intervention experiment showed that using body pressure features as an explanatory variable and applying machine learning, 16 types of postures on the bed of care recipients with an F value of 0.7 or more could be identified. From the experiment without intervention, by applying the hidden Markov model, we calculated the transition probability to each hidden state when the care recipient getting out of the bed and the transition probability to each hidden state when the care recipient not getting out of the bed. As a result, there was a difference of about 0.1 in the transition probability of the state related to raising upper body.
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Hamidi, Ichsan, Suhel Suhel, and Abdul Latif. "The effectivities of zakat productive funds toward zakat recipient income in Palembang." Jurnal Ekonomi Pembangunan 17, no. 1 (2019): 24–30. http://dx.doi.org/10.29259/jep.v17i1.8965.
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This study to investigate effectivities of zakat productive funds toward zakat recipient income in Palembang. Data using primary data which collect through interviews, observation, and documentation with instruments a questionnaire. The method in this study uses the quantitative approach with applying a regression model. The population in this study are all the recipients who receive the funding of zakat productive from BAZNAS of South Sumatra. The findings of this study indicated that the capital of zakat productive, length of business and training has a significant effect on zakat recipient income in Palembang city.
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Li, Hongmei, Daniel Kaplan, Anthony Jake Demetris, Jennifer McNiff, Mark Shlomchik, and Warren D. Shlomchik. "Recipient Langerhans Cells Are Neither Required Nor Sufficient for GVHD Induction in MHC-Matched Allogeneic BMT, but a Langerin+ Cell Is a Pivotal Regulator of Langerhans Cell Turnover Post Transplantation." Blood 112, no. 11 (2008): 3511. http://dx.doi.org/10.1182/blood.v112.11.3511.3511.
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Abstract Graft-versus-host disease (GVHD) is initiated when alloreactive donor T cells are primed by professional antigen-presenting cells (APCs) to undergo clonal expansion and maturation. Host APCs that survive pretransplant conditioning play an essential role in this T cell activation, and are an attractive target for GVHD prevention and treatment. However, APCs are diverse in phenotype, location and function and an understanding of the roles of distinct subsets is an important first step in developing APC-targeted therapies. Skin is the most frequently affected organ in GVHD. Langerhans cells (LCs), characterized by expression of Langerin, are a major APC in the epidermis, and thus it was logical to hypothesize that host LCs would have a role in GVHD induction. Indeed, in an MHC-mismatched model, Merad et al. showed that host LCs persist after T cell-depleted (TCD) but not T cell-replete bone marrow transplant (BMT), and that these host LCs in donor→host chimeras are sufficient to induce skin GVHD after a second allogeneic bone marrow transplant (alloBMT). However, this work did not examine the role of recipient LCs when all other APCs are intact, the scenario at the time of transplant in all patients. To address this question, we created a transgenic mouse that constitutively lacks epidermal LCs. We did so by expressing diphtheria toxin A chain (DTA) driven by the human Langerin gene (Kaplan, et al 2005) in a bacterial artificial chromosome (BAC). We used Langerin-DTA BAC transgene positive (Tg+) mice or Tg-littermates as recipients in the C3H.SW (H-2b)→B6 (H-2b) strain paring, in which recipient APCs are necessary and sufficient for GVHD induction. Tg+ and Tg− CD8 recipients developed similar GVHD as measured by weight loss and clinical skin disease. Tg+ and Tg− CD8 recipients also had comparable pathologic GVHD of the skin, ear, liver and colon. To generalize these findings, we used B6bm12 →B6 strain pairing, an MHCII-mismatched CD4-dependent GVHD model, in which recipient APCs are also required (Teshima et al, 2002). Tg+ and Tg− CD4 recipients developed similar weight loss and pathologic changes in the tongue and liver, primary sites of GVHD in this model. Thus, in both MHC-matched and MHC-mismatched models in which recipient APCs are absolutely required, the specific absence of recipient epidermal LCs did not affect clinical or histological GVHD. We also analyzed LC turnover in these alloBMT recipients. As previously reported, LCs remained host-derived in B6 Tg− recipients of TCD C3H.SW bone marrow. Given our prior result that C3H.SW → B6 chimeras are resistant to GVHD induction by a second alloBMT from C3H. SW donors (Shlomchik, et al 1999), unlike in the MHC-mismatched model employed by Merad, residual host LCs are insufficient to initiate GVHD in this MHC-matched system. In B6 Tg− recipients of TCD C3H.SW bone marrow plus GVHD-inducing CD8 cells, LC turnover varied by mouse and ranged from all host or donor to a mix of donor and host LCs. This variability could relate to the extent of skin GVHD, as we previously found that epidermal MHCII+ cells in skin GVHD lesions in this model are donor-derived (Matte et all, 2004). Strikingly, in contrast to Tg− recipients, donor-derived LCs developed in Tg+ recipients of TCD C3H.SW bone marrow. Donor LCs also engrafted in Tg+ recipients of TCD bone marrow from Tg− but otherwise syngeneic littermates or B6 RAG1−/− T cell-deficient donors. Thus, in contrast to LC-replete mice, neither allogeneic donor T cells nor UV-induced inflammation was required for donor LC engraftment in LC-deficient hosts. These data indicate that a Langerin+ cell, absent in Langerin-DTA Tg+ mice, regulates LC turnover in the absence of inflammation. Work is underway to identify this key cell.
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Zengin, Hüseyin, and Abdurrahman Korkmaz. "Determinants of Turkey’s foreign aid behavior." New Perspectives on Turkey 60 (May 2019): 109–35. http://dx.doi.org/10.1017/npt.2019.1.
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AbstractThis paper analyzes a hundred Turkish aid recipient countries in order to explore the determinants of Turkey’s foreign aid behavior during the period 2005–2016. By estimating the model with the system-GMM estimator, it is demonstrated that Turkey is a regular donor whose amount of foreign aid is positively influenced by the export-based embeddedness of Turkish firms in the recipient countries. Recipients with low levels of per-capita income attract more Turkish aid. However, this income’s effect diminishes in states that were formerly part of Ottoman territory. Recipient countries in an aid relationship with OECD-DAC members also receive more foreign aid from Turkey. In addition, Turkey disburses more foreign aid to recipient countries that can be classified as Turkic republics. Turkish foreign aid behavior is also motivated by Ottomanism, especially in the Balkans and Eastern Europe. Finally, and interestingly, although Islam has a considerable impact on attracting Turkish aid overall, this impact disappears in former Ottoman states and Turkic republics.
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Kim, Dong-hwan, Do-hun Kim, Hyun Seok Kim, Seong-il Kim, and Dong-Ho Lee. "Determinants of Bilateral REDD+ Cooperation Recipients in Kyoto Protocol Regime and Their Implications in Paris Agreement Regime." Forests 11, no. 7 (2020): 751. http://dx.doi.org/10.3390/f11070751.
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A cooperative approach for REDD+ between developing and developed countries can be a sound means to achieve national and global mitigation targets. To accomplish the Nationally Determined Contribution (NDC) of countries and the global 2 °C climate target more effectively, it is necessary to explore the coordination options, based on the understanding of bilateral REDD+ cooperation. This study explains the current status of bilateral REDD+ cooperation and investigates determinants affecting REDD+ recipient decisions of donor countries, by analyzing bilateral REDD+ arrangements, which has been promoted for 10 years under the the Kyoto Protocol regime from 2006 until 2015. The results show that Norway and Japan supported more than half of the total financial pledges for bilateral REDD+ projects for 10 years. Out of 87 REDD+ recipients, four countries—Brazil, India, Indonesia, and China—accounted for more than half of the 10-year financial pledges. Approximately 78% of total financing was found to be concentrated in the top 10 recipients. The aid darlings and orphans problem, the concentration of bilateral supports in a few developing countries and the exclusion of several developing countries from the recipient selection process, which has been discussed in ODA researches, was also observed. Applying a shared frailty model, recipient need, recipient merit, and donor interest was found to be the main determinants of donors’ REDD+ recipient decision. Donor interest and recipient merit were found to have more significant effects on the decision than recipient need. A balanced two-track approach is further required, in which, along with the bilateral REDD+ cooperation in the REDD+ darling countries, international organizations and multilateral funds for REDD+ need to increase financial accessibility, including the result-based compensation system for the REDD+ orphan countries.
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Biswas, Chandra, Daniel Rittenberg, Xiaoling Luo, et al. "Double Haploidentical Hematopoietic Stem Cell Transplantation (HSCT) Results In Successful Engraftment of Bone Marrow From Both Donors without Graft Versus Host or Graft Versus Graft Effects." Blood 116, no. 21 (2010): 1453. http://dx.doi.org/10.1182/blood.v116.21.1453.1453.
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Abstract Abstract 1453 The use of haploidentical donors extends the potential clinical application of HSCT. However, relapse of resistant malignancy contributes to low success rates in high risk patients. Relapse may be due to the ability of leukemic cells to immunologically escape a single donor's GVL effects. We hypothesized that the use of two haploidentical donors, each targeting a different recipient haplotype, will increase anti- leukemia activity after double haploidentical SCT. We performed murine studies to establish new single haploidentical (SH) and double-haploidentical (DH) murine models that mimic the possible scenarios which might be encountered clinically rather that using more traditional Parent → F1 models. We first established a haploidentical transplant model using two different hybrid mouse strains as donor and recipient in the experiments. Lethally irradiated B6CBAF1 (H2Kb/k) recipients were transplanted with T cell depleted (TCD) bone marrow (BM) from B6D2F1 (H2Kb/d) donors. Recipient mice harvested at days 28, 42 and 56, showed more than 90% donor cell engraftment, including donor derived lymphopoiesis and myelopoiesis, without evidence of graft versus host disease. Subsequently, lethally irradiated B6CBAF1 (H2Kb/k) recipients were transplanted with TCD-BM from two haploidentical donors (DH model) including B6SJF1 (H2Kb/s) (donor 1 - D1) and B6D2F1 (H2Kb/d) (donor 2 - D2). We observed recipients for 90 days and all mice survived without evidence of GVHD or weight loss. Analyses of blood collected retro-orbitally at day 90 revealed that recipients of DH transplants had significantly higher WBC and neutrophil counts than recipients of SH HSCT from either D1 or D2 respectively. DH recipients consistently showed successful engraftment with mixed chimerism in both bone marrow and spleen. There was no difference in thymopoiesis, B cell and myeloid cell reconstitution compared to SH transplants. In contrast, the number of splenic T cells was higher in SH recipients of D1 marrow (B6SJF1). We then explored the effects of low dose T cell infusions (1×105) on chimerism of donor cells. Low dose T cell infusion from either D1 or D2 did not affect the BM cellularity, but did increase the degree of dominance of that donor's cells in the BM and spleen. A similar outcome was observed when this study was extended to other models such as B6C3 + C3D2F1 → B6D2F1 and B6CBAF1 + B6SJF1 → CB6F1 models where all recipients of DH transplants survived without evidence of GVHD. Recipients of TCD DH transplants were challenged with P815 tumor cells. We used B6SJF1 (D1) + B6CBAF1 (D2) → B6D2F1 model in tumor experiments. Interestingly, recipients of TCD-DH transplants exhibited a significantly better survival than recipients of D1 SH or D2 SH transplants. However, after a low dose T cell infusion (1 ×105), recipients of D2 BM survived significantly better than recipients of D1 BM. In contrast to the TCD model, recipients of DH BM + DH T cells show similar probability of survival with recipients of D2 SH BM + D2 SH T cells. We conclude that TCD DH HSCT results in successful engraftment of both types of BM cells. Additionally, infusion of low dose haploidentical T cells improves the anti-tumor effect without stimulating GVHD. Double haploidentical HSCT may be an ideal platform to enhance GVL effects after transplantation. Disclosures: No relevant conflicts of interest to declare.
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Gupta, Sanjay, Harvey M. Rappaport, and Lonnie T. Bennett. "Polypharmacy among Nursing Home Geriatric Medicaid Recipients." Annals of Pharmacotherapy 30, no. 9 (1996): 946–50. http://dx.doi.org/10.1177/106002809603000905.
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OBJECTIVE: To determine the factors that influence the number of different drugs prescribed to geriatric Medicaid recipients residing in Louisiana's intermediate care facilities I (ICFs I). DESIGN: Observational and cross-sectional with descriptive and analytic components. PARTICIPANTS: All geriatric Medicaid recipients in Louisiana ICFs I during 1994 (n= 19 932). METHODS: Relevant data on sex, age, race, geographic region of a recipient, number of prescribing physicians, number of pharmacies used, and the number of drugs prescribed to a recipient were extracted from the state Medicaid files. Frequencies for the seven study variables were calculated. Regression analysis was used to evaluate the influence of the six predictor variables on the number of drugs prescribed. RESULTS: The study population was 73.63% women, 60.07% 81 years of age and older, 70.65% white, 23.21% African-American, 6.14% other races, and 29.83% from predominantly rural north Louisiana. A total of 44.60% of the residents received prescriptions from one physician, 8.41% of the residents were single pharmacy users, and 45.65% were prescribed more than 10 drugs during the year. The regression model accounted for 20.53% of the total variation in the number of drugs prescribed to a recipient. Race, geographic region, number of prescribing physicians, and number of pharmacies used by a recipient influenced the number of drugs prescribed. CONCLUSIONS: To reduce the number of drugs prescribed and polypharmacy among geriatric Medicaid recipients, Louisiana's ICFs I should minimize the number of physicians and pharmacies used in this population.
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Jiang, Qianli, Yan-yan Ye, Le-zhong Yuan, et al. "Study Of Stem Cell Homing and Donor-Recipient Cellular Interaction In Allogenic Hematopoietic Stem Cell Transplantation Mice Model." Blood 122, no. 21 (2013): 5424. http://dx.doi.org/10.1182/blood.v122.21.5424.5424.
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Abstract Background Allogeneic hematopoietic stem cell transplantation is an effective method for treatment of hematological malignancies, while GVHD and graft rejection are main complications, which seriously affect patients' survival rates and quality of life. Aim Establishing allo-transplantation mice model with mRFP and GFP transgenic mice, to simulate clinical hematopoietic stem cell transplantation and explore the mechanism of stem cell homing and GVHD. Methods 1) Thirteen C57BL/6 GFP transgenic mice, used as recipients, were irradiated with 7 Gy. Each mouse was injected through caudal vein with 2*106 bone marrow cells isolated from FVB mRFP transgenic mice. 2) Symptoms like weight loss, depilation, diarrhea were observed as GVHD manifestation while survival rates were evaluated. Routine blood test and FACS were performed at different time points to confirm hematopoiesis reconstitution. 3) Mice were perfused with paraformaldehyde under anesthesia to fix the tissue, while pathological examination and real-time PCR were performed for studying donor and recipient cells interactions in different organs. 4) Semi-solid decalcification was used to treat the femora before observing under confocal microscope directly or after making frozen section, three-dimensional reconstruction were made to observe the cellular interaction, especially for cells within the bone marrow. Result 1) Depilation, wrinkled skin, hunchback and sharp decline of weight were observed in 8/13 mice. Routine blood test implicated hematopoietic reconstitution. FACS showed 86.1%±7.8% mRFP+ cells in peripheral blood of recipients. 2) mRFP+ cells were found distributing throughout the body's organs. mRFP+ Lymphocyte infiltration and inflammatory exudate were seen especially in the small intestine, lung, liver and skin (Fig.1). GFP+ cells were found surrounding mRFP+ cells in the bone marrow of the femora decalcified with semi-solid decalcification. Their interactions can be further observed clearly in bone marrow microenvironment in three-dimensional reconstruction by confocal microscope (Fig.2). Discussion Owing to RFP on donors' cells and GFP on recipients' cells, together with our novel protocol named semi-solid decalcification, we can visually observe the donor and recipient cells' location, ratio and cellular interaction, as well as morphological changes. Within various tissues especially for such tissues as bone marrow and lung, the details between cells can be studied lively by fluorescence microscope and confocal microscope. In recipient mice with GVHD, donor cells can be found in various target tissues such as intestine, lung, liver and skin. Gene marked cells with fluorescence protein can benefit morphological, immunological, cytogenetic and molecular studies in recipients after HSCT. Conclusion The allo-transplantation model with mRFP and GFP transgenic mice is powerful in study of Stem Cell Homing and Donor-Recipient Cellular Interaction. The cellular interaction can be easily observed by three-dimensional reconstruction after semi-solid decalcification, especially for bone marrow and lung. Disclosures: No relevant conflicts of interest to declare.
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Girod, Desha M., and Jennifer L. Tobin. "Take the Money and Run: The Determinants of Compliance with Aid Agreements." International Organization 70, no. 1 (2016): 209–39. http://dx.doi.org/10.1017/s0020818315000326.
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AbstractConditions on aid agreements aim to increase aid effectiveness, and are, therefore, an important component of aid agreements. Yet little is known about why aid-recipient governments comply with these conditions. Some scholars have suggested a strategic-importance hypothesis: recipients comply when donors enforce conditions—and donors enforce conditions when recipients are not strategically important. However, there are many cases where strategically important countries comply with conditions and strategically unimportant countries fail to do so. We argue that to explain compliance, we must also understand how the desire to maximize revenue from major income sources, such as FDI and natural resource rents, changes the recipient's incentive to comply. Using data on World Bank records of compliance from 1964 to 2010, we find strong support for our hypotheses even after accounting for different model specifications and potential endogeneity. Paradoxically, donors can secure compliance from recipients for reasons unrelated to the promise of additional aid.
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Zhao, Xiangyu, Yingjun Chang, Ling-Ling Xu, et al. "Lacking Of Missing Killer-Immunoglobulin-Like Receptor Ligand In Recipients Can Predict Better Prognosis After HLA-Mismatched/Haploidentical Transplantation Without T Cells Depletion In Vitro In Chronic Myeloid Leukemia Patients." Blood 122, no. 21 (2013): 2165. http://dx.doi.org/10.1182/blood.v122.21.2165.2165.
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Abstract Introduction HLA-mismatched/haploidentical stem cell transplantation (SCT) is a feasible therapeutic option for advanced hematologic malignancies patients who lack an HLA-matched related or unrelated donor. The effect of NK alloreactivity in HLA haploidentcial SCT is still under debate and in particular in transplantation for chronic myeloid leukemia (CML) the data are very limited and with conflicting outcome.The goal of this study was to explorethe predictive roles of missing self model in our HLA-mismatched/haploidentical transplantation without T-cell-depletion in vitro in chronic myeloid leukemia patients, and to develop a simple algorithm on the basis of recipients and donor HLA-C and HLA-Bw4 gene content that can be used today to identify HLA-mismatched donors who will associated withbetter prognosis in T cell¨Creplete transplants. Methods We studied the HLA genotype of 78 donor-recipient pairs and the KIR genotype of their donor, who underwent unmanipulatedHLA-mismatched/haploidentical transplantation without T cells depletion in vitro during 2003-2009 in our center. To applythe missing ligand model, the first step was to divide ourdonor-recipient pairs into 2 groups according to the number of KIR ligand indonor and recipient, ie, 3 KIR ligands (“without missing self”) versus fewer than 3(“with missing self”). Meanwhile, to apply the KIR ligand-ligand model, donors who were classified as NK alloreactive against their recipientstermed KIR ligand mismatched donors throughout, possessedHLA class I KIRligand(s) which were missing in the recipients. Results Among the 78 pairs of donor-recipients, 65 and 13 recipients receivedHLA¨Cmismatched/haploidentical transplants from “with missing self (R-L mismatch)” and “without missing self (R-L match)” donors, respectively. Using Ligand-ligand model, 59 and 19 recipients received haploidentical transplantation from “KIR ligand matched (L-L match)” and “KIR ligand mismatched (L-L mismatch)” donors, respectively. In contrast to Perugia's KIR ligand-ligand mismatched model or Handgretinger's KIR missing self model between donor-recipient pairs, we found that the 10-year disease free survival(DFS) rate were higher in patients received transplantation from “without missing self (R-L match)” donorscompared with those from “with missing self (R-L mismatch)” (92.3±7.4% vs. 55.2%±6.2%, p=0.024, Figure1A) , especially in high risk CML patients (100% vs. 37.2%±8.6%, p=0.029, Figure1B). When combined the above missing self model and Ligand-ligand model together, patients were subgrouped as receiving graft from “without missing self and without KIR ligand mismatch (R-L match and L-L match)” (n=13), “with missing self and without KIR ligand mismatch (R-L mismatch and L-L match)” (n=47), and “with missing self and with KIR ligand mismatch (R-L mismatch and L-L mismatch)” (n=18), respectively. Cox regression model showed the 10-yearDFSwas best predicted by the combination of missing self model and Ligand-ligand modelbetween recipients and donors pairs (HR 2.205(1.113-4.368), p=0.023, Figure1C). Meanwhile, donor KIR 2DS5 positive associated with higher DFS post-transplantation (84.2±8.4% vs. 56.8±7.7%, p=0.045) in CML patients. However, donor KIR haplotype B have no effect on DFS and overall survival after allogeneic hematopoietic stem cell transplantation for multiple myeloma Conclusions These data indicate thatpoor prognosis after transplantation is associated with the missing self and KIR ligand mismatch in recipients and T cell alloreaction may play apredominant role in this model.Based on recipients and donor HLA-C and HLA-Bw4 gene content, it could befeasible to identify HLA-mismatched donors who will predict the better prognosis in CML patients post T cell-replete transplant. Disclosures: No relevant conflicts of interest to declare.
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Rowe, Vanessa, Tatjana Banovic, Kelli P. MacDonald, et al. "Host B cells produce IL-10 following TBI and attenuate acute GVHD after allogeneic bone marrow transplantation." Blood 108, no. 7 (2006): 2485–92. http://dx.doi.org/10.1182/blood-2006-04-016063.
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Abstract Host antigen-presenting cells (APCs) are known to be critical for the induction of graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT), but the relative contribution of specific APC subsets remains unclear. We have studied the role of host B cells in GVHD by using B-cell–deficient μMT mice as BMT recipients in a model of CD4-dependent GVHD to major histocompatibility complex antigens. We demonstrate that acute GVHD is initially augmented in μMT recipients relative to wild-type recipients (mortality: 85% vs 44%, P < .01), and this is the result of an increase in donor T-cell proliferation, expansion, and inflammatory cytokine production early after BMT. Recipient B cells were depleted 28-fold at the time of BMT by total body irradiation (TBI) administered 24 hours earlier, and we demonstrate that TBI rapidly induces sustained interleukin-10 (IL-10) generation from B cells but not dendritic cells (DCs) or other cellular populations within the spleen. Finally, recipient mice in which B cells are unable to produce IL-10 due to homologous gene deletion develop more severe acute GVHD than recipient mice in which B cells are wild type. Thus, the induction of IL-10 in host B cells during conditioning attenuates experimental acute GVHD.
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Davis, Joanne E., Michael Harvey, Nicholas A. Gherardin, et al. "A Radio-Resistant Perforin-Expressing Lymphoid Population Controls Allogeneic T Cell Engraftment, Activation and Onset of Gvhd." Blood 124, no. 21 (2014): 3805. http://dx.doi.org/10.1182/blood.v124.21.3805.3805.
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Abstract Introduction Immunosuppressive pre-transplantation conditioning is essential for donor cell engraftment in allogeneic bone marrow transplant (BMT). The role of residual post-conditioning recipient immunity in determining engraftment is poorly understood. Although recipient perforin has previously been shown to modulate myeloid engraftment from mouse bone marrow, and adoptive transfer of natural killer (NK) cells can ameliorate the onset of graft-versus host disease (GVHD), the role of perforin-expressing endogenous recipient NK and NKT cells in modulating donor T cell engraftment has not been described. Using an MHC-mismatched mouse model, we examined the role of perforin-expressing NK cells in regulating both the rate and activation status of donor lymphocyte engraftment after allogeneic transplantation. Methods An MHC-disparate model of BMT was established transplanting BALB/c donor BM (H-2Kd), into female 6-14 week old C57BL/6 WT and C57BL/6.perforin KO (H-2Kb) recipients. On day 0, recipient mice were administered a split dose of lethal radiation using a caesium source (2 x 6 gray), and injected i.v. with 5e6 T cell depleted BM (TCD-BM) cells from MHC-mismatched or syngeneic donors. On day 2, recipient mice were injected i.v. with 1e6 BALB/c purified splenic T cells at a 2:1 CD4+:CD8+ T cell ratio. Mice were monitored daily, and killed at selected time points post-transplant (typically day 5-7 for short term engraftment, or day 20 for long term engraftment) to examine donor lymphoid cell engraftment. Results An HLA-mismatched BMT mouse model demonstrated that both the rate and proportion of donor lymphoid cell engraftment, and expansion of effector memory donor T cells in both spleen and BM were significantly increased within 5-7 days post BMT in perforin-deficient (pfn-/-) recipients, compared with wild-type (WT). Critically, we found that the absence of perforin resulted in the increased production of pro-inflammatory cytokines, in particular IL-6, from engrafting donor T cells. IL-6 has recently been identified as a primary driver of both mouse model and clinical GVHD. Correlating with pro-inflammatory cytokine secretion, effector memory donor T lymphocytes expanded more rapidly in pfn-/- recipients than in WT mice, possibly arising from more rapid proliferation or selective survival of these donor cells. In WT recipients, donor lymphoid cell engraftment was enhanced to that seen in pfn-/- recipients, by depleting NK cells prior to BMT, demonstrating that a perforin-dependent, NK-mediated host-versus graft effect limits the rate of donor cell engraftment and T cell activation. We found that radiation-resistant NKT cells survived in the BM of lethally irradiated mice and may drive NK cell activation, resulting in the host-versus graft effect. Furthermore, reduced pre-transplant irradiation doses in pfn-/- recipients permitted long-term donor lymphoid cell engraftment and improved survival (Figure 1). Figure 1: Reduced total body irradiation in perforin-deficient mice permits rapid donor lymphoid cell engraftment. On day 0, WT or pfn-/- (KO) mice were irradiated with variable doses (12-6 gray), and injected i.v. with 5e6 TCD-BM cells from BALB/c donors. On day 2, recipient mice were injected i.v. with 1e6 splenic BALB/c T cells. On day 7 (A) and day 20 (B) after BMT, the BM cells of WT or KO mice were stained for H-2Kd (donor cells) and engraftment determined as a percentage of donor lymphocytes. (C) Survival of KO mice administered 9 gray (closed circles), 7.5 gray (triangles) and 6 gray (lines) after BMT described above. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Conclusions The challenge in clinical HSCT is to promote reliable donor engraftment and full immunological reconstitution whilst minimizing pre-transplant conditioning and associated toxicity. Our findings suggest that suppression of perforin activity or selective depletion of recipient NK cells prior to BMT may allow the combined advantage of reduced transplant toxicity whilst maintaining donor engraftment and promoting the graft versus tumour effect. Disclosures No relevant conflicts of interest to declare.
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Weiler, Florian, and Franklins A. Sanubi. "Development and Climate Aid to Africa: Comparing Aid Allocation Models for Different Aid Flows." Africa Spectrum 54, no. 3 (2019): 244–67. http://dx.doi.org/10.1177/0002039720905598.
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This article examines the role different aid allocation models play not only for conventional development aid but also for two new financial flows, adaptation and mitigation aid. We first test the three models proposed in the literature – recipient need, recipient merit, and donor interests – using the latest available aid data and compare our results with findings of older studies on Africa, and with studies on aid allocation on a global scale. We find that the recipient merit model in more recent years no longer plays a role for development aid allocation in Africa, in line with findings reported globally. In contrast to such global studies, the logic of the donor interest model does not seem to dominate over the recipient need model in the African context, as both are of equal importance for aid allocation decisions. Finally, additionality seems to play a lesser role in Africa than globally.
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Slichter, Sherrill J., Kraig Abrams, Lakshmi Gaur, Karen Nelson, Esther Pellham, and Todd Christoffel. "Leukoreduction to Prevent Alloimmune Platelet (Plt) Refractoriness in a Dog Transfusion Model: Types of Residual White Blood Cells (WBCs) Directly Affect Transfusion Outcomes." Blood 104, no. 11 (2004): 835. http://dx.doi.org/10.1182/blood.v104.11.835.835.
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Abstract Introduction: Current practice assumes that just a quantitative reduction in the number of transfused wbcs to <1 to 5 x 106/transfusion is sufficient to prevent plt alloimmunization. However, our studies indicate that different leukoreduction strategies vary in their ability to remove immunizing wbcs, and this correlates with rates of alloimmune plt refractoriness in immunocompetent recipients. Experimental Design And Methods: Pairs of donor-recipient dogs were selected either at random, as having a shared DLA DR-B epitope, or as being specifically mismatched for this DLA locus. Non-leukoreduced or leukoreduced radiochromium-labeled donor plts were transfused weekly for up to 8 weeks or until the onset of plt refractoriness defined as <5% of the donor dog’s plts circulating in the recipient at 24 hours post-transfusion. Three methods of leukoreduction were evaluated: centrifugation leukoreduction (C-LR); filtration leukoreduction (F-LR) with different types of filters; or combined F-LR/C-LR. Flow cytometry was used to identify the types of residual wbcs following leukoreduction. Table 1 gives the number of residual wbcs and the transfusion outcomes based on the leukoreduction strategy used, while Table 2 gives the relative proportion of the types of residual wbcs after leukoreduction compared to the overall results for the leukoreduction method used. Results: Table 1 Method Of Leukoreduction Filter (Manufacturer) Average Residual WBCs Donor-Recipient DR-B Relationship Non-Refractory Recipients / Recipients Transfused ND-Not done. *Platelets were filtered sequentially using two PLF-1 filters. **Lower limit of detection of the assay. None --- 6.7 x 106 Random 1/3 (33%) Shared Epitope 0/4 (0%) C-LR --- 4.7 x 104 Random 3/21 (14%) F-LR: PL1-B (Pall) 5.0 x 104 ND ND PLF-1 (Pall) 7.9 x 104 Random 3/8 (38%) PLF-1 x2* (Pall) <3 x 103** Random 1/5 (20%) PLS-5A (Fenwal) 3.2 x 104 Mismatched 4/6 (66%) F-LR/C-LR: PL1-B (Pall) <3 x 103** Mismatched 1/9 (11%) <3 x 103** Shared Epitope 5/7 (71%) PLF-1 (Pall) <3 x 103** Random 15/16 (94%) <3 x 103** Mismatched 3/3 (100%) PLS-5A (Fenwal) <3 x 103** Mismatched 9/9 (100%) Table 2 RESIDUAL WBCs Lymphocytes Method of Leukoreduction T CD4 dim T CD4 bright B Monocytes Total Non-Refractory Recipients (%) ND-Not done. *Non-shared DR-B donor-recipient pairs/shared DR-B donor-recipient pairs (p=0.03). None ++ ++ +++ 14% C-LR + ++ + ++ 14% F-LR: PL1-B ++ ++ +++ +++ ND PLF-1 + +++ + 38% PLS-5A ++ + ++ 66% F-LR/C-LR: PL1-B ++ +++ + 11%/71%* PLF-1 ++ +++ 95% PLS-5A ++ + 100% Conclusions: 1) a quantitative reduction in wbcs does not prevent plt refractoriness; 2) the types of residual wbcs correlate directly with transfusion outcomes; 3) even after residual monocytes are removed by F-LR using PLF-1 and PLS-5A filters, residual CD4 bright T lymphocytes are associated with a high percentage of refractory recipients; 4) following F-LR/C-LR with PLF-1 and PLS-5A filters leaving B lymphocytes and CD4 dim T lymphocytes (NKT cells?), refractoriness is prevented even to DR-B mismatched donors; and 5) DLA DR-B matching significantly improves transfusion outcomes when residual monocytes remain following F-LR/C-LR using a PL1-B filter.
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Gibson, Christopher J., Haesook T. Kim, H. Moses Murdock, et al. "DNMT3A clonal Hematopoiesis in Older Donors Is Associated with Improved Survival in Recipients after Allogeneic Hematopoietic Cell Transplant." Blood 136, Supplement 1 (2020): 26. http://dx.doi.org/10.1182/blood-2020-142925.
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Background: Clonal hematopoiesis (CH) is an age-related condition in which somatic mutations can be detected in the blood of healthy individuals. In the non-transplant setting, CH is associated with an elevated risk of developing hematologic malignancy and an increased risk of non-hematologic outcomes due to altered inflammatory signaling. During hematopoietic cell transplantation (HCT), CH in older donors can engraft in recipients and could therefore influence outcomes through effects on graft immunologic function or by causing donor cell leukemia. A definitive link between donor CH and recipient outcomes has not been established. We therefore evaluated the impact of CH in donors aged 40 years or older on recipient clinical outcomes in 1727 donor-recipient pairs. Methods: We performed targeted, error-suppressed sequencing of 46 genes on 1727 samples from donors age 40 and older. We defined CH as pathogenic mutations at variant allele fraction (VAF) 0.005 or greater. Median donor age was 51 (range 40-80) and median recipient age was 55 (range 1-78). There were 889 matched related donors (51.5%), 454 haploidentical donors (26.3%), 273 matched unrelated donors (15.8%), 71 mismatched unrelated donors (4.1%), and 38 mismatched related donors (2.2%). 929 recipients (53.8%) had myeloid malignancies, 718 (41.6%) had lymphoid malignancies, and 80 (4.6%) had non-malignant diseases. 1022 (59.2%) recipients received peripheral blood stem cell products and 703 (40.7%) received bone marrow. 672 recipients (38.9%) received post-transplant cyclophosphamide (PTCy) for graft versus host disease (GVHD) prophylaxis. Median follow-up for survivors was 6.0 years. Results: We identified CH in 388 of 1727 (22.5%) donor samples. Mutations in DNMT3A were most common (302 mutations in 253 donors), followed by TET2 (96 mutations in 89 donors), ASXL1 (n=22) and PPM1D (n=14). No other genes were mutated in more than 10 donors (0.5%). The presence of donor CH was independently associated with older donor age, but not with donor sex, donor-recipient relatedness, graft source, or recipient disease. The presence of donor CH at VAF 0.01 or greater was associated with improved progression-free survival (PFS) in a multivariable model that included donor and recipient age, HCT-CI, disease category, Disease Risk Index score, conditioning intensity, and donor type (HR for death or relapse 0.81, 95% CI 0.68-0.97, P=0.019). This effect was driven by DNMT3A mutations, which were independently associated with improved overall survival (HR for death 0.75; 0.59-0.95, P=0.016) and reduced risk of relapse (sHR 0.76; 0.59-0.97, P=0.029) in the same model. CH involving other gene mutations, including TET2 and genes other than DNMT3A/TET2, was not significantly associated with any recipient outcome. Smaller clones (VAF 0.005-0.01) had no effect on any outcome. The association between donor DNMT3A-CH and recipient outcomes was limited to those who did not receive PTCy for GVHD prophylaxis (Figure 1A-C). In the model described above, donor DNMT3A-CH in the absence of PTCy was independently associated with improved PFS (HR 0.61; 0.45-0.84, P=0.002), reduced risk of relapse (sHR 0.59; 0.39-0.9, P=0.014) and an elevated risk of chronic GVHD (sHR 1.36; 1.01-1.83, P=0.042) compared to those without DNMT3A-CH. In recipients who received PTCy, there was no significant effect of donor DNMT3A-CH on PFS, relapse, or cGVHD (1D). Eight recipients developed donor cell leukemia (DCL), for a cumulative incidence of 0.7% at 10 years. In seven of these cases, we identified gene mutations in the corresponding donor products that matched the mutations found in the subsequent DCL, including 2 with TP53 mutations, 3 with splicing factor mutations, and 2 with germline DDX41 mutations that were present in both donor and recipient. No recipients who received products with sole DNMT3A-CH developed DCL. Conclusions: In HCT donors age 40 or older, the presence of DNMT3A clonal hematopoiesis at VAF &gt;/= 0.01 is independently associated with prolonged overall and progression-free survival in transplant recipients. This effect is driven by reduced risk of disease relapse and confined to recipients who do not receive PTCy, suggesting that it is mediated at least in part by effects on donor T cells. The risk of direct evolution of DNMT3A-CH to donor cell leukemia is low, and most DCLs were traced to atypical donor CH involving MDS-associated genes or germline risk alleles. Disclosures Nikiforow: Novartis: Honoraria; Nkarta Therapeutics: Honoraria; Kite/Gilead: Honoraria. DeZern:MEI: Consultancy; Abbvie: Consultancy; Astex: Research Funding; Celgene: Consultancy, Honoraria. Ritz:Rheos Medicines: Consultancy; Infinity Pharmaceuticals: Consultancy; Amgen: Research Funding; Equillium: Research Funding; Kite Pharma: Research Funding; Avrobio: Consultancy; Falcon Therapeutics: Consultancy; TScan Therapeutics: Consultancy; Talaris Therapeutics: Consultancy; LifeVault Bio: Consultancy. Soiffer:VOR Biopharma: Consultancy; Kiadis: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Juno: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; alexion: Consultancy; Be the Match/ National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy; Mana Therapeutics: Consultancy; Precision Bioscience: Consultancy; Cugene: Consultancy; Rheos Therapeutics: Consultancy. Lindsley:Jazz Pharmaceuticals: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; MedImmune: Research Funding; Bluebird Bio: Consultancy.
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Amsar, Amsar, Rizal Munadi, and Ramzi Adriman. "SELEKSI BEASISWA UNTUK PERGURUAN TINGGI BERDASARKAN PENDEKATAN KEPUTUSAN BERKEADILAN DENGAN FUZZY MAMDANI." Jurnal Inotera 2, no. 2 (2018): 1. http://dx.doi.org/10.31572/inotera.vol2.iss2.2017.id28.
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The scholarship is one of the funding schemes of study in an education system. Various models and names of scholarship schemes are offered on terms that have been determined by the scholarship provider. The essence of these conditions is the trust and confidence of the funders of the scholarship recipients and is projected to complete the study period as per the allocated funds. In general, funders are very concerned about the issue of academic qualification as one of the main indicators. However, for prospective students who wish to pursue higher education from coming from orphaned families and from less financially qualified families, with good academic qualifications, not yet a parameter in the selection process of scholarship recipients. Based on this fact, this problem would like to find solution in this research and submitted the selection model of scholarship with fair decision approach. This study aims to design a fair decision-making system as a tool for selection of scholarship recipients that prioritize the values ??of justice by prioritizing scholarship recipients from among orphans and poor. This research proposes two methods: Fuzzy Mamdani and weighting method, with 4 input parameters which are used as variables: children status and economic level, residence condition, children achievement and family dependent. Simulation testing performed by considering the parameters set is a more effective and efficient decision model for the prospective scholarship recipients. To obtain a competent recipient, then the screening process by ranking to be declared passed the selection and received as the recipient of scholarship in accordance with the number of quotas provided. This selection model becomes an alternative and provides opportunities for orphans and the poor to continue higher education and improve the human resource index as well as meet national education goals.
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Lundqvist, Andreas, Ramaprasad Srinivasan, Dante Suffredini, et al. "Potent Graft-Versus-Renal Cell Carcinoma (RCC) Effects in a Murine Minor Histocompatibility Antigen (mHa)-Mismatched Allogeneic Transplant Model." Blood 104, no. 11 (2004): 4982. http://dx.doi.org/10.1182/blood.v104.11.4982.4982.
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Abstract Donor immune-mediated anti-neoplastic effects make the greatest contribution to the durable disease remissions obtained in hematological malignancies following allogeneic hematopoietic cell transplantation (a-HCT). Recent studies have demonstrated that clinically meaningful graft-versus-tumor (GVT) effects can also be induced against select solid tumors following a-HCT. GVT effects have been most extensively documented in RCC, where response rates in the range of 20%–50% have been reported. Unfortunately, death from eventual disease progression and morbidity from graft-versus-host disease (GVHD) limit a broader application of a-HCT to manage this tumor. In order to explore mechanisms underlying GVT effects against RCC, and to optimize outcome following transplantation, we sought to establish a murine MHC-compatible, but mHA-disparate a-HCT model in mice with metastatic RCC. Recipient Balb/C (H-2d) mice were conditioned with a myeloablative regimen consisting of 950cGy total body irradiation and transplanted with bone marrow cells and splenocytes from either syngeneic (Balb/C) or allogeneic, mHA mismatched B10.d2 (H-2d) mice. Murine RCC cells (RENCA, 1x105 cells/mouse) were injected into the tail veins of both Balb/C recipient groups 3 days after transplantation and were followed for survival and the establishment of metastatic pulmonary lesions. Recipients of allo-HCT had improved survival (mean 54±2 days) compared to those receiving syngeneic transplants (mean 31±0 days: p<0.001). At death, 4/4 mice receiving syngeneic transplants demonstrated widespread pulmonary metastatic disease while none of the allo-HCT recipients (n=4) developed metastatic disease (Figure 1A). A slight improvement in survival for allo-HCT recipients was also noted when Balb/C mice were injected subcutaneously with RENCA (1x105 cells) three days following transplantation (31±0 for syngeneic and 40±7 for allogeneic recipients; p=0.04). Serial measurements of subcutaneous tumor nodules (Figure 1B) revealed significantly slower tumor growth in allo-HCT recipients (mean volume = 272mm3, day 31) compared to recipients of syngeneic grafts (mean volume = 11mm3, day 31). Graft-versus-host disease (GVHD) characterized by alopecia, weight loss and diarrhea occurred at a median 28±3 days after transplantation and was the primary cause of death in a-HCT recipients. Unlike previously reported murine a-HCT models for solid tumors, pre-transplant priming of donor mice with recipient splenocytes or tumor cells was not required for the generation of GVT effects. These data suggest donor immune responses against minor histocompatibility antigens can mediate potent GVT effects against RCC following allo-HCT. This murine model will serve as a platform for the development of tumor- targeted a-HCT strategies aimed at refining and enhancing GVT effects while mitigating GVHD. Figure Figure
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Grainger, John D., Lez J. Fairbairn, and Robert F. Wynn. "Murine Mesenchymal Stem Cells Improve Haemopoietic Engraftment in a Murine Transplant Model and Is Maximised through Osteogenic Stimulation." Blood 104, no. 11 (2004): 1183. http://dx.doi.org/10.1182/blood.v104.11.1183.1183.
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Abstract Several studies have preciously shown improved engraftment of human haemopoietic stem cells (HSC) following co-infusion of human mesenchymal stem cells (MSC). However, these studies have been criticised for using xenogeneic recipients which might support human haemopoiesis through the production of species-specific cytokines and growth factors by human MSC. To further investigate the potential for MSC to support HSC engraftment we used a murine to murine transplant model to co-infuse purified murine MSC and murine HSC. The MSC were derived from collagenase-treated bone fragments of the Rosa26 murine strain, had the phenotype CD45- CD31-CD11b- Sca-1bright VCAM1+ and could differentiate into osteocytes, chondrocytes and adipocytes. Donor and recipient HSC were obtained from unmanipulated bone marrow of either the C57Bl/6J murine strain, CD45 isotype CD45.2, or the PEP3b murine strain, expressing CD45.1. Following 10Gy irradiation to the recipients HSC and MSC were co-infused. Donor and recipient haemopoietic engraftment in the peripheral blood was quantified by FACS analysis of the CD45.1/CD45.2 ratio. Successive transplant experiments persistently showed improved donor haemopoietic engraftment following co-infusion of 2 x 105 BM cells and 1 x 106 MSC (three seperate transplant series p=0.001, p=0.09 and p=0.13). The beneficial effect was maximal at the lower HSC dose of 1 x 105 BM cells (p=0.004, p=0.045 and uninterpretable in the third transplant series due to excessive death observed in the non-MSC recipients). Increasing the MSC dose to 2 x 106 cells showed a non-significant increase in survival and donor haemopoietic engraftment but further MSC escalation resulted in fatal emboli post-infusion. LacZ staining of tissue sections failed to show evidence of MSC outside the lungs but was detected at very low levels in the bone from one recipient. As MSC are osteoblast precursors and recent literature suggests a role of osteoblasts as the HSC niche we investigated the effect of pre-culturing our MSC population in osteogenic media prior to transplant. Following 16 days of culture approximately 40% of colonies showed ALP activity. At this time point osteogenic-stimulated MSC (O-MSC) were removed from culture, washed to remove any residual osteogenic media, and infused in our standard method. O-MSC recipients receiving 1 x 105 BM cells showed a mean engraftment of 79% compared to 21% in non-msc recipients receiving 2 x 105 BM cells (p=0.000017), and 42% in recipients receiving standard MSC and 1 x 105 BM cells (p=0.01). In conclusion we confirm improved haemopoietic engraftment in a non-xenogeneic model and does not require significant MSC engraftment. The beneficial effect is maximised through osteogenic stimulation of MSC suggesting the possibility that the mechanism may be through priming of the HSC niche.
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Roussel, Arnaud, Edouard Sage, Gilbert Massard, et al. "Impact of donor, recipient and matching on survival after high emergency lung transplantation in France." European Respiratory Journal 54, no. 5 (2019): 1900096. http://dx.doi.org/10.1183/13993003.00096-2019.
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IntroductionSince July 2007, the French high emergency lung transplantation (HELT) allocation procedure prioritises available lung grafts to waiting patients with imminent risk of death. The relative impacts of donor, recipient and matching on the outcome following HELT remain unknown. We aimed at deciphering the relative impacts of donor, recipient and matching on the outcome following HELT in an exhaustive administrative database.MethodsAll lung transplantations performed in France were prospectively registered in an administrative database. We retrospectively reviewed the procedures performed between July 2007 and December 2015, and analysed the impact of donor, recipient and matching on overall survival after the HELT procedure by fitting marginal Cox models.ResultsDuring the study period, 2335 patients underwent lung transplantation in 11 French centres. After exclusion of patients with chronic obstructive pulmonary disease/emphysema, 1544 patients were included: 503 HELT and 1041 standard lung transplantation allocations. HELT was associated with a hazard ratio for death of 1.41 (95% CI 1.22–1.64; p<0.0001) in univariate analysis, decreasing to 1.32 (95% CI 1.10–1.60) after inclusion of recipient characteristics in a multivariate model. A donor score computed to predict long-term survival was significantly different between the HELT and standard lung transplantation groups (p=0.014). However, the addition of donor characteristics to recipient characteristics in the multivariate model did not change the hazard ratio associated with HELT.ConclusionsThis exhaustive French national study suggests that HELT is associated with an adverse outcome compared with regular allocation. This adverse outcome is mainly related to the severity status of the recipients rather than donor or matching characteristics.