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1
Owens, T., and I. N. Crispe. "Suppressor T cells, distinct from "veto cells," are induced by alloantigen priming and mediate transferable suppression of cytotoxic T lymphocyte responses in vivo." Journal of Immunology 135, no. 5 (1985): 2984–89. http://dx.doi.org/10.4049/jimmunol.135.5.2984.
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Abstract Primary and secondary cytotoxic T lymphocyte responses to minor alloantigens can be suppressed by priming host mice with a high dose (10(8) cells) of alloantigenic donor spleen cells (SC). Such suppression is antigen specific and transferable into secondary hosts with T cells. One interpretation of this is that antigen-specific host suppressor T cells (Ts) are activated. Alternatively, donor Lyt-2+ T cells, introduced in the priming inoculum, may inactivate host CTL precursors (CTLp) that recognize the priming (donor) alloantigens. Donor cells that act in this way are termed veto T cells. The experiments described here exclude veto T cell participation in transferable alloantigen-specific suppression, and demonstrate the operation of an alloantigen-specific host-derived T suppressor (Ts) cell. The origin of the Ts has been studied directly by using Thy-1-disparate BALB/c mice. The cell responsible for the transfer of suppression of a secondary CTL response to B10 minors was of the host Thy-1 allotype, and so originated in the host spleen and was not introduced in the priming inoculum. Secondly, antigen-specific Ts generated in CBA female mice against B10 minors could act on CTL responses to an unequivocally non-cross-reactive-third party antigen (H-Y), provided the two antigens were expressed on the same cell membrane. Such third-party suppression is incompatible with the operation of veto T cells. Depletion of Thy-1.2+ or Lyt-2+ cells from the suppression-inducing donor SC inoculum did not abrogate suppression induction in BALB/c mice; instead, suppression was enhanced. The demonstration of veto cell activity in similarly primed mice by other groups of investigators indicates that both types of suppression may operate. However, our results show that only antigen-specific Ts can mediate the transferable suppression of CTL responses to alloantigens.
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Chen, Benny J., Divino Deoliveira, Xiuyu Cui, et al. "Inability of memory T cells to induce graft-versus-host disease is a result of an abortive alloresponse." Blood 109, no. 7 (2006): 3115–23. http://dx.doi.org/10.1182/blood-2006-04-016410.
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Abstract Several groups, including our own, have independently demonstrated that effector memory T cells from non–alloantigen-primed donors do not cause graft-versus-host disease (GVHD). In the current study, we further investigated whether this approach could be extended to all memory T cells, and we studied the underlying mechanisms. Neither total memory T cells nor purified central memory T cells were able to induce GVHD. Memory T cells were at least 3-log less potent than bulk T cells in mediating GVHD. As expected, memory T cells failed to elicit cytotoxicity and proliferated poorly against alloantigens in standard 5-day mixed-lymphocyte cultures. However, the proliferative responses of memory T cells were more comparable with those of bulk and naive T cells when the culture time was shortened. Moreover, the frequencies of IL-2–secreting cells measured by 42-hour enzyme-linked immunosorbent spot (ELISPOT) assay were similar among naive, memory, and bulk T cells. These data indicated that memory T cells are able to respond to alloantigens initially but fail to develop to full potential. The abortive immune response, which was mediated by non–alloantigen-specific memory T cells in response to alloantigens, may explain why memory T cells from unprimed and non–alloantigen-primed donors could not induce GVHD.
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Patel, Seema R., Ashley Bennett, Kathryn Girard-Pierce, et al. "Recipient priming to one RBC alloantigen directly enhances subsequent alloimmunization in mice." Blood Advances 2, no. 2 (2018): 105–15. http://dx.doi.org/10.1182/bloodadvances.2017010124.
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Key Points CD4+ T cells primed to one RBC alloantigen promote humoral immunity to a disparate RBC alloantigen when both antigens are on the same RBC. These findings provide a potential explanation for how responses to one antigen may enhance antibody formation to other RBC alloantigens.
4
Bianchi, A. T., M. W. Schilham, R. Benner, P. Young, and I. Lefkovits. "In vivo priming of helper and suppressor T cells by alloantigens. Frequency analysis with the use of an in vitro limiting dilution assay." Journal of Immunology 139, no. 8 (1987): 2524–29. http://dx.doi.org/10.4049/jimmunol.139.8.2524.
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Abstract Earlier studies have demonstrated that T cells activated in mixed lymphocyte reactions can exert positive as well as negative allogeneic effects on B cells expressing the appropriate alloantigens on their surface. We investigated the effect of in vivo priming of T cells with alloantigens on their capacity to help or suppress allogeneic B cell cultures against sheep erythrocytes. We used immunization protocols that have been shown to be optimal for induction of alloantigen-specific delayed-type hypersensitivity (DTH) and alloantigen-specific suppressor T (Ts) cells for DTH. The results show that in vivo stimulation with alloantigens, depending on the immunization route and the lymphoid organ studied, can be as effective as in vitro stimulation in increasing the frequency of alloantigen-specific helper T (Th) cells and Ts cells. Subcutaneous immunization induced a 10-fold frequency raise of Th cells as well as of Ts cells in the lymph nodes. In the spleen the Th cell population was hardly affected by s.c. immunization, whereas the Ts cell population increased by at least a factor 20. Intravenous immunization, on the other hand, selectively expanded the Th cell population in the spleen, whereas the splenic Ts cell population and the Th and Ts cells in the lymph nodes were not affected. Comparison of these results with our previous data concerning characteristics and the requirements of in vivo activation of alloantigen-specific DTH reactive T cells and of alloantigen-specific Ts cells suggest that different Ts cell populations are involved in suppression of alloantigen-specific DTH in vivo and of allogeneic suppression of in vitro induced sheep erythrocytes specific antibody formation.
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Schadendorf, D., H. Yamaguchi, L. J. Old, and P. K. Srivastava. "A novel heteromorphic human cell surface alloantigen, gp60, defined by a human monoclonal antibody." Journal of Immunology 142, no. 5 (1989): 1621–25. http://dx.doi.org/10.4049/jimmunol.142.5.1621.
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Abstract A human mAb (DSM1) generated from a patient immunized with irradiated allogeneic melanoma cells detects a new cell surface alloantigen of restricted cell type distribution. The Ag is a 60,000-Da glycoprotein (gp60) that displays considerable heteromorphism in its cytosolic and cytoskeletal (52 to 62 kDa) and membrane forms (60 to 64 kDa). The gp60 Ag has been purified using lectin affinity, ion exchange, and Mono P fast performance liquid chromatography. Rabbit antiserum against purified gp60 recognizes a homologous gp60 molecule on DSM1-nonreactive cells. Molecular properties of gp60 and a partial amino acid sequence of a tryptic gp60-derived peptide distinguish it from other known human alloantigens. This is the first report of a human alloantigenic system whose definition required a cell type other than those of bone marrow derivation.
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Isakov, N., and F. H. Bach. "Participation of class II alloantigens in in vivo regulation of K/D region disparate thyroid graft rejection in mice." Journal of Immunology 134, no. 6 (1985): 3580–85. http://dx.doi.org/10.4049/jimmunol.134.6.3580.
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Abstract Class I and II molecules preferentially activate cytotoxic T cells and helper T cells, respectively, in primary in vitro alloactivation of T lymphocytes. Collaboration between these subpopulations leads to an efficient anti-class I specific cytotoxic response. We tested whether the presence of class II, in addition to class I, alloantigens on thyroid allografts in vivo induces augmentation of anti-class I antigen immune response and leads to rejection of K/D region disparate grafts which otherwise would have been accepted. Different pairs of K or D region disparate mouse strains were selected in which transplantation across a class I antigen disparity alone resulted in long-term graft acceptance. In some pairs of mouse strains, co-transplantation of recipient mice with a second thyroid graft sharing the K/D region of the first, but additionally expressing an allo class II molecule, led to accelerated K/D region disparate thyroid graft rejection. Transplantation of thyroid allografts expressing both class II and I alloantigens did not induce increased host anti-class I antigen cytotoxic response, or affect the frequency of specific precursor cytotoxic T cells. In one pair of congenic mouse strains, acute rejection of K/D region disparate thyroid grafts occurred in the absence of class II alloantigen stimulation; in other strains, co-transplantation of class I and II alloantigen disparate thyroid allografts was not sufficient to induce K/D region disparate graft rejection. The results thus demonstrate that a class II alloantigen on a thyroid graft may augment the rejection response directed against the graft class I alloantigens. The class II alloantigen stimulation was not always essential or sufficient for induction of class I antigen disparate thyroid graft rejection, and was dependent on the specific I region and/or K/D region gene allele.
7
Mizuochi, T., S. Ono, T. R. Malek, and A. Singer. "Characterization of two distinct primary T cell populations that secrete interleukin 2 upon recognition of class I or class II major histocompatibility antigens." Journal of Experimental Medicine 163, no. 3 (1986): 603–19. http://dx.doi.org/10.1084/jem.163.3.603.
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This study has characterized the primary T cell subpopulations that secrete IL-2 in response to recognition of either class I or class II MHC encoded determinants. The addition to culture of anti-IL-2-R mAb inhibited the consumption of IL-2 by activated lymphocytes during the response period, permitting a much more accurate assessment of the amount of IL-2 produced in the response cultures. Using this response system, we found that primary T cell populations contain two IL-2-secreting T cell subsets that express reciprocal phenotypes and different MHC recognition specificities: an L3T4+, Lyt-2- T cell subset responsive to both class I and class II MHC alloantigens, and an L3T4-Lyt-2+ T cell subset responsive only to class I MHC alloantigens. The L3T4+ T cell subset expressed a broad functional response repertoire in that L3T4+ T cells were triggered to secrete IL-2 upon recognition of unmodified self-Ia determinants, allogeneic Ia determinants, and class I alloantigens presented by self-Ia determinants. The activation of L3T4+ IL-2-secreting T cells, even those responsive to class I MHC alloantigens, could be blocked completely by anti-Ia mAbs, confirming that the L3T4+ T cell subset was in fact class II restricted. In contrast, the Lvt-2+ T cell subset expressed a narrow functional response repertoire in that they were triggered to secrete IL-2 only in response to allogeneic class I MHC determinants, and were not triggered to secrete IL-2 even in response to TNP-modified self-MHC determinants. The specificity of Lyt-2+ IL-2-secreting T cells for class I MHC allodeterminants was confirmed by the observations that: (a) their activation could be blocked completely by anti-class I mAbs, (b) they could be triggered by Ia- cell lines which expressed class I MHC alloantigens and possessed accessory function, and (c) they responded to class I MHC alloantigens but failed to respond to class II MHC alloantigens, even in the presence of exogenously added second signals that circumvented the requirement for alloantigen-bearing accessory cells. Finally, the frequency of primary Lyt-2+ T cells that secreted IL-2 in response to class I (Kbm1) MHC alloantigens was shown to be only minimally lower than that of L3T4+ T cells that secreted IL-2 in response to class II (I-Abm12) MHC alloantigens.(ABSTRACT TRUNCATED AT 400 WORDS)
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Chen, Benny J., Xiuyu Cui, and Nelson J. Chao. "Human Memory T Cells Proliferate but Do Not Elicit Cytotoxicity in Response to Alloantigens." Blood 104, no. 11 (2004): 1229. http://dx.doi.org/10.1182/blood.v104.11.1229.1229.
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Abstract We and others have recently demonstrated that memory T cells do not induce graft-versus-host disease in several different animal models. To test whether the same concept applies to humans, we compared the ability of memory T cells to respond to alloantigens with that of naive as well as bulk T cells. Purified T cells were first obtained from peripheral blood from healthy donors and then separated into memory and naive T cell subsets based on the expression of CD45RA (memory: CD45RA−, naive: CD45RA+). Memory T cells were subsequently tested for their ability to respond to alloantigens using proliferation and cytotoxicity assays in comparison with naive and bulk T cells. Proliferation assay was performed using 1.25x105 responder cells and 5x105 irradiated stimulator cells per well in 96-well flat-bottom plate. Cytotoxicity was measured by the standard 4-hour Cr-51 release assay after 5-day mixed lymphocyte culture. In contrast to the mouse data, memory T cells proliferated equally well as naive and bulk T cells did in mixed lymphocyte culture (Figure A). However, these same memory T cells failed to kill the allogeneic targets despite the vigorous proliferative responses against the same alloantigens (Figure B). These data demonstrated that human memory T cells proliferate but do not elicit cytotoxicity in response to alloantigens, suggesting that human memory T cells may not contain true alloantigen-specific T cells if they have never exposed to those alloantigens before and may not cause graft-versus-host disease upon in vivo transfer. These observations warrant the further testing of human memory T cells in clinically more relevant models and in vivo for their ability to induce graft-versus-host disease. Figure Figure
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Stroncek, David. "Neutrophil alloantigens." Transfusion Medicine Reviews 16, no. 1 (2002): 67–75. http://dx.doi.org/10.1053/tmrv.2002.29406.
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Zhang, Lanfang, and Chang-Qing Xia. "PD-1/PD-L1 Interaction Maintains Allogeneic Immune Tolerance Induced by Administration of Ultraviolet B-Irradiated Immature Dendritic Cells." Journal of Immunology Research 2016 (2016): 1–11. http://dx.doi.org/10.1155/2016/2419621.
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Our previous study demonstrated that transfusion of ultraviolet B-irradiated immature dendritic cells (UVB-iDCs) induced alloantigen-specific tolerance between two different strains of mice. Programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) have been suggested to play an important role in maintaining immune tolerance. In the present study, we seek to address whether PD-1/PD-L1 plays a role in the maintenance of UVB-iDC-induced tolerance. We first observe that the UVB-iDC-induced alloantigen-specific tolerance can be maintained for over 6 weeks. Supporting this, at 6 weeks after tolerance induction completion, alloantigen-specific tolerance is still able to be transferred to syngeneic naïve mice through adoptive transfer of CD4+ T cells. Furthermore, skin transplantation study shows that the survival of allogeneic grafts is prolonged in those tolerant recipients. Further studies show that PD-1/PD-L1 interaction is essential for maintaining the induced tolerance as blockade of PD-1/PD-L1 by anti-PD-L1 antibodies largely breaks the tolerance at both cellular and humoral immunological levels. Importantly, we show that PD-1/PD-L1 interaction in tolerant mice is also essential for controlling alloantigen-responding T cells, which have never experienced alloantigens. The above findings suggest that PD-1/PD-L1 plays a crucial role in maintaining immune tolerance induced by UVB-iDCs, as well as in actively controlling effector T cells specific to alloantigens.
11
Zhang, Nanyan, Huiying Zhi, Sridhar Rao, and Peter J. Newman. "Designer Platelets: Crispr/Cas-Mediated Conversion of Human Platelet Alloantigen Allotypes." Blood 124, no. 21 (2014): 573. http://dx.doi.org/10.1182/blood.v124.21.573.573.
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Abstract Human platelet alloantigens (HPAs) reside on functionally important platelet membrane glycoproteins, and are caused by single nucleotide polymorphisms in the genes that encode them. Antibodies that form against HPAs are responsible for several clinically important alloimmune bleeding disorders, including fetal and neonatal alloimmune thrombocytopenia, posttransfusion purpura, and multitransfusion platelet refractoriness. The HPA-1a/HPA-1b alloantigen system, also known as the PlA1/PlA2 polymorphism, is the most frequently implicated HPA among Caucasians, and a single C29523T nucleotide substitution, resulting in a Leu33Pro amino acid polymorphism within the PSI domain of the integrin β3 subunit (platelet glycoprotein IIIa) was shown 25 years ago to be responsible for generating the HPA-1a/HPA-1b alloantigenic epitopes. Like other low-frequency alloantigens, HPA-1b/b platelets are relatively rare in the population, and therefore often difficult to obtain for purposes of transfusion therapy and diagnostic testing. As a first step in producing designer platelets expressing low-frequency human platelet alloantigens, we employed a CRISPR/Cas9 RNA-guided nicking nuclease system to transform megakaryocyte-like cells expressing the Leu33 allele of integrin β3 to the Pro33 form. Two different guide RNAs that target the ITGB3 gene with a 13-base pair offset 53 bases and 0 nucleotides upstream of the C/T polymorphism site were designed and cloned into plasmids that co-express GFP as well as a mutated form of Cas9 that nicks only one strand of DNA (Cas9n). Such a double-nicking strategy has been shown in other systems to increase the specificity of gene targeting while minimizing off-target effects. A 200 bp single-stranded DNA oligonucleotide encompassing the single base C29523T mismatch was also synthesized to be used for homology-directed repair (HDR) of the endogenous ITGB3 gene sequence. The HDR oligo was then transfected, together with the two plasmids encoding the guide RNAs+Cas9n+GFP, into megakaryocyte-like DAMI cells. Twenty-four hours post-transfection, GFP positive cells were sorted by flow cytometry and isolated as single clones. Surveyor endonuclease assays revealed that ~30% of the GFP positive clones had been cleaved at the expected location, indicating efficient double nicking directed by the pair of guide RNAs. Additionally, two out of twenty seven isolated clones had incorporated the HDR repair template, as reported by a diagnostic NciI restriction enzyme site that is specific for the T29523-bearing HPA-1b allele. Sequence analysis further confirmed conversion of C29523 to T in these two clones. Finally, Western blotting using HPA-1b-specific human alloantisera verified that these DAMI cells now expressed the HPA-1b (PlA2) alloantigenic epitope. Taken together, these results establish that the CRISPR/Cas system can be successfully employed to genetically edit this and other clinically-important HPAs in human cells. Application of this technology for the generation of alloantigen-specific human induced pluripotent stem cells holds great potential as a general tool for producing designer platelets for diagnostic and therapeutic use. Disclosures No relevant conflicts of interest to declare.
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Gribben, JG, EC Guinan, VA Boussiotis, et al. "Complete blockade of B7 family-mediated costimulation is necessary to induce human alloantigen-specific anergy: a method to ameliorate graft- versus-host disease and extend the donor pool." Blood 87, no. 11 (1996): 4887–93. http://dx.doi.org/10.1182/blood.v87.11.4887.bloodjournal87114887.
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Graft-versus-host disease (GVHD) is initiated by adoptively transferred donor T cells that recognize host alloantigens. Whereas the absence of donor T-cell proliferation to host alloantigens in a mixed-leukocyte reaction does not predict freedom from GVHD, the frequency of alloreactive precursor helper T lymphocytes (pHTL) is predictive. Complete blockade of 87 family-mediated costimulation, but not of major histocompatibility complex recognition or adhesion, induces host alloantigenic-specific energy by reducing cytokine production below threshold levels necessary for common gamma chain signaling. The associated reduction of alloreactive pHTL frequency below that predictive for GVHD, without depletion of either nonallospecific T cells or hematopoietic progenitors, has led us to embark upon human clinical trials of haplomismatched allogeneic bone marrow transplantation.
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Kroll, H., V. Kiefel, S. Santoso, and C. Mueller-Eckhardt. "Sra, a private platelet antigen on glycoprotein IIIa associated with neonatal alloimmune thrombocytopenia." Blood 76, no. 11 (1990): 2296–302. http://dx.doi.org/10.1182/blood.v76.11.2296.2296.
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Abstract A new platelet alloantigen, Sra, is described that was defined by an alloantibody detected in the serum of a healthy mother who delivered a child with typical clinical signs of neonatal alloimmune thrombocytopenia (NAIT). The antibody reacted strongly with the child's and father's platelets, but not with platelets of the mother or with those of a highly selected panel representing all known platelet alloantigens. Platelets from 300 unselected normal blood donors also tested negative, suggesting a phenotype frequency in the German population of less than 0.01. The antigen was present in 9 of 20 members within three generations of the paternal family, indicating autosomal codominant inheritance. By immunochemical analysis using a glycoprotein (GP)-specific immunoassay and a variety of GP IIb/IIIa- specific monoclonal antibodies for antigen immobilization (MAIPA assay), radioimmunoassay, and Western blotting, we could show that the antigen resides on a 68-Kd proteolytic fragment of GP IIIa. Immunogenetic data and gene dosage studies revealed that the Sra antigen is not related to any of the other known platelet alloantigens. In accordance with established criteria, the Sra antigen represents the first example of a “private” platelet alloantigen that bears significance in rare instances of NAIT.
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Kroll, H., V. Kiefel, S. Santoso, and C. Mueller-Eckhardt. "Sra, a private platelet antigen on glycoprotein IIIa associated with neonatal alloimmune thrombocytopenia." Blood 76, no. 11 (1990): 2296–302. http://dx.doi.org/10.1182/blood.v76.11.2296.bloodjournal76112296.
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A new platelet alloantigen, Sra, is described that was defined by an alloantibody detected in the serum of a healthy mother who delivered a child with typical clinical signs of neonatal alloimmune thrombocytopenia (NAIT). The antibody reacted strongly with the child's and father's platelets, but not with platelets of the mother or with those of a highly selected panel representing all known platelet alloantigens. Platelets from 300 unselected normal blood donors also tested negative, suggesting a phenotype frequency in the German population of less than 0.01. The antigen was present in 9 of 20 members within three generations of the paternal family, indicating autosomal codominant inheritance. By immunochemical analysis using a glycoprotein (GP)-specific immunoassay and a variety of GP IIb/IIIa- specific monoclonal antibodies for antigen immobilization (MAIPA assay), radioimmunoassay, and Western blotting, we could show that the antigen resides on a 68-Kd proteolytic fragment of GP IIIa. Immunogenetic data and gene dosage studies revealed that the Sra antigen is not related to any of the other known platelet alloantigens. In accordance with established criteria, the Sra antigen represents the first example of a “private” platelet alloantigen that bears significance in rare instances of NAIT.
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Sonoda, Y., and J. W. Streilein. "Impaired cell-mediated immunity in mice bearing healthy orthotopic corneal allografts." Journal of Immunology 150, no. 5 (1993): 1727–34. http://dx.doi.org/10.4049/jimmunol.150.5.1727.
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Abstract A very high proportion of orthotopically grafted, histoincompatible corneas are accepted in healthy condition for prolonged intervals (> 8 weeks) by naive untreated BALB/c mice. Because these grafts form the anterior surface of the anterior chamber of the eye and because alloantigens placed in the anterior chamber elicit a deviant, stereotypic, systemic immune response known as anterior chamber-associated immune deviation, we have examined the state of alloantigen-specific cell-mediated immunity in BALB/c mice with accepted corneal allografts, as well as mice that had rejected their corneal grafts. Attempts to induce alloantigen-specific delayed hypersensitivity (DH) by s.c. injections of lymphoid cells, genetically identical to the grafts, resulted in positive responses only in "rejector" mice; "acceptor" mice failed to develop or display DH. Spleens cells from acceptors and rejectors were then assayed for the ability to suppress local adoptive transfer of alloantigen-specific DH. It was found that transfer reactions failed to develop if spleen cells from acceptor mice were added to the inoculum, whereas spleen cells from rejected mice had no similar inhibitory effects. The suppression mediated by acceptor spleen cells in local adoptive transfer assays was determined to be specific for the alloantigens expressed on the long-standing corneal allografts. We conclude that, when orthotopic corneal allografts are accepted indefinitely by adult mice, graft success correlates with the induction of alloantigenically specific anterior chamber-associated immune deviation. It is proposed that suppression of alloantigen-specific DH, which is characteristic of mice with accepted grafts, plays a critical role in the success of grafted corneas.
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Martin, PJ. "Prevention of allogeneic marrow graft rejection by donor T cells that do not recognize recipient alloantigens: potential role of a veto mechanism." Blood 88, no. 3 (1996): 962–69. http://dx.doi.org/10.1182/blood.v88.3.962.962.
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Abstract Clinical trials and experimental studies have demonstrated that donor T cells can play a critical role in preventing allogeneic marrow graft rejection. Results of a previous study showed that donor T cells were most effective for preventing rejection when they recognize an alloantigen expressed by recipient T cells and can cause graft-versus- host disease (GVHD). The present study examined models where marrow graft rejection can be prevented by donor T cells that do not recognize host alloantigens and cannot cause GVHD. Donor T cells prevented rejection of major histocompatibility complex (MHC) class I and II- disparate F1 marrow in parental recipients prepared with > or = 800 cGy total body irradiation (TBI) but not in those prepared with < or = 750 cGy TBI. In recipients prepared with high TBI exposures, rejection was mediated entirely by host CD8 cells. With lower TBI exposures, rejection was mediated by host CD4 cells and CD8 cells. These observations suggested the hypothesis that donor T cells prevent rejection mediated by host effectors that recognize donor MHC class I alloantigens but do not prevent rejection mediated by host effectors that recognize donor class II alloantigens. Consistent with this hypothesis, further experiments showed that F1 donor T cells can prevent rejection of MHC class I-disparate marrow in irradiated parental recipients but have no detectable effect on rejection of MHC class II-disparate marrow. We propose that the expression of MHC class I molecules on donor T cells makes it possible for these cells to inactivate the host response against donor class I alloantigens through a veto mechanism, whereas the absence of MHC class II molecules on murine T cells explains why these cells cannot inactivate the host response against donor class II alloantigens. Finally, donor CD4 cells and CD8 cells were equivalently effective for preventing rejection of F1 marrow in parental recipients, suggesting that veto activity is not restricted solely to the CD8 subset of murine T cells. A veto mechanism could enable donor T cells to prevent allogeneic marrow graft rejection without causing GVHD.
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Martin, PJ. "Prevention of allogeneic marrow graft rejection by donor T cells that do not recognize recipient alloantigens: potential role of a veto mechanism." Blood 88, no. 3 (1996): 962–69. http://dx.doi.org/10.1182/blood.v88.3.962.bloodjournal883962.
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Clinical trials and experimental studies have demonstrated that donor T cells can play a critical role in preventing allogeneic marrow graft rejection. Results of a previous study showed that donor T cells were most effective for preventing rejection when they recognize an alloantigen expressed by recipient T cells and can cause graft-versus- host disease (GVHD). The present study examined models where marrow graft rejection can be prevented by donor T cells that do not recognize host alloantigens and cannot cause GVHD. Donor T cells prevented rejection of major histocompatibility complex (MHC) class I and II- disparate F1 marrow in parental recipients prepared with > or = 800 cGy total body irradiation (TBI) but not in those prepared with < or = 750 cGy TBI. In recipients prepared with high TBI exposures, rejection was mediated entirely by host CD8 cells. With lower TBI exposures, rejection was mediated by host CD4 cells and CD8 cells. These observations suggested the hypothesis that donor T cells prevent rejection mediated by host effectors that recognize donor MHC class I alloantigens but do not prevent rejection mediated by host effectors that recognize donor class II alloantigens. Consistent with this hypothesis, further experiments showed that F1 donor T cells can prevent rejection of MHC class I-disparate marrow in irradiated parental recipients but have no detectable effect on rejection of MHC class II-disparate marrow. We propose that the expression of MHC class I molecules on donor T cells makes it possible for these cells to inactivate the host response against donor class I alloantigens through a veto mechanism, whereas the absence of MHC class II molecules on murine T cells explains why these cells cannot inactivate the host response against donor class II alloantigens. Finally, donor CD4 cells and CD8 cells were equivalently effective for preventing rejection of F1 marrow in parental recipients, suggesting that veto activity is not restricted solely to the CD8 subset of murine T cells. A veto mechanism could enable donor T cells to prevent allogeneic marrow graft rejection without causing GVHD.
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Havelková, Helena, Vladimír Holáň, Igor Kárník, and Marie Lipoldová. "Mouse model for analysis of non-MHC genes that influence allogeneic response: recombinant congenic strains of OcB/Dem series that carry identical H2 locus." Open Life Sciences 1, no. 1 (2006): 16–28. http://dx.doi.org/10.2478/s11535-006-0002-x.
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AbstractAlloreactivity is the strongest known primary immune response. Its clinical manifestations are graft rejection, graft-versus-host disease and graft-versus-leukemia effect. The strongest stimulation by allogeneic cells is due to incompatibility at the major histocompatibility complex (MHC) genes. However, the non-MHC genes also participate in allogeneic response. Here we present a mouse model for study of the role of non-MHC genes in regulation of alloreactivity and show that they besides encoding antigens also regulate the responsiveness. Recombinant congenic strains (RCS) of O20/A (O20)-c-B10.O20/Dem (OcB/Dem) series have been derived from the parental strains O20 and B10.O20, which carry identical MHC haplotypes (H2pz) and therefore their differences in alloantigen response depend only on non-MHC genes. We have tested a MLR response by spleen cells of the strains O20, B10.O20, and 16 OcB/Dem strains through stimulation by cells from strains C57BL/10 (H2b), BALB/c (H2d), CBA (H2k), and DBA/1 (H2q) alloantigens. Proliferative response of O20, B10.O20 and OcB/Dem strains to these four alloantigens exhibited a similar but not completely identical pattern of reactivity. The responses to different alloantigens were highly correlated: C57BL/10-BALB/c r = 0.87, C57BL/10-CBA r = 0.84, C57BL/10-DBA/1 r = 0.83. Cluster analysis of the responses by O20, B10.O20, and OcB mice identified groups of strains with distinct patterns of response. This data shows that two main types of genes influence MLR: 1. structural genes for major and minor alloantigens and 2. genes regulating T-cell receptor signal transduction or mediating costimulatory signals by antigen-presenting cells.
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Qian, J., T. Hashimoto, H. Fujiwara, and T. Hamaoka. "Studies on the induction of tolerance to alloantigens. I. The abrogation of potentials for delayed-type-hypersensitivity response to alloantigens by portal venous inoculation with allogeneic cells." Journal of Immunology 134, no. 6 (1985): 3656–61. http://dx.doi.org/10.4049/jimmunol.134.6.3656.
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Abstract The present study investigates the effect of portal venous (p.v.) administration of allogeneic cells on the capacity of delayed-type-hypersensitivity (DTH) reactivity to alloantigens. BALB/c mice were inoculated with C3H/He spleen cells via intravenous (i.v.) or p.v. route. Intravenous injection of C3H/He spleen cells into BALB/c mice resulted in appreciable DTH responses to C3H/He alloantigens. In contrast, p.v. inoculation of the same number of C3H/He cells not only failed to induce any significant anti-C3H/He DTH responses but also abolished the capability of the animals to develop DTH responses as induced by subcutaneous (s.c.) immunization with C3H/He spleen cells. Such suppression was alloantigen-specific, since p.v. inoculation of C3H/He spleen cells resulted in selective inhibition of anti-C3H/He DTH potential without suppressing DTH responses to C57BL/6 alloantigens. This tolerance was rapidly inducible and long-lasting. When spleen cells from tolerant mice were transferred i.v. into 600 R X-irradiated syngeneic recipient mice alone or together with normal BALB/c spleen cells, these tolerant spleen cells themselves failed to induce DTH responses but did not exhibit any suppressive effect on the generation of DTH responses induced by normal spleen cells co-transferred. These results indicate that tolerance was not necessarily associated with the induction of suppressor cell activity but rather was associated with the elimination or functional impairment of clones specific for alloantigens. The results are discussed in the context of a) the role of the liver in immune responses, b) cellular mechanisms underlying the tolerance induction, and c) potential application of this approach to the future transplantation immunology.
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Chen, H., H. Luo, P. Daloze, D. Xu, and J. Wu. "Rapamycin-induced long-term allograft survival depends on persistence of alloantigen." Journal of Immunology 152, no. 6 (1994): 3107–18. http://dx.doi.org/10.4049/jimmunol.152.6.3107.
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Abstract In this study the mechanism of rapamycin-induced long-term allograft tolerance was investigated in a rat model. We have demonstrated that the tolerance is strain specific, but is not organ specific. The tolerized rats failed to generate high levels of donor-specific cytotoxic Ab and cytotoxic cells in vivo. Removal of the alloantigen from the tolerized rats with or without concomitant thymectomy could break down the status of tolerance, and the rats regained the capability to reject the grafts and to develop specific cytotoxic Ab and cytotoxic cells. These results clearly indicate that the maintenance of the rapamycin-induced long-term tolerance to allografts depends on the persistence of alloantigens. Mechanistically, we have shown that the reduced IL-2 production and the reduced antigenicity of the graft in the tolerized rat contribute to, but are not solely responsile for, the tolerance. The results of adoptive transfer experiments suggest that regulatory cells or suppressive serum factors are not involved in the tolerance. The fact that the removal of the alloantigen in the thymectomized rat could reverse the tolerance, indicates that there is no clonal deletion. We propose that chronic desensitization due to prolonged engagement of TCR by persistent alloantigens is the major mechanism at the late stage of the rapamycin-induced allograft tolerance.
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Santoso, Sentot. "Human platelet alloantigens." Transfusion and Apheresis Science 28, no. 3 (2003): 227–36. http://dx.doi.org/10.1016/s1473-0502(03)00040-5.
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Bux, J. "Human neutrophil alloantigens." Vox Sanguinis 94, no. 4 (2008): 277–85. http://dx.doi.org/10.1111/j.1423-0410.2007.01031.x.
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Opiela, Shannon Jacqueline, and Becky Adkins. "Exposure to NIMA-like alloantigens induces vigorous in vivo T cell responses in murine neonates (102.17)." Journal of Immunology 178, no. 1_Supplement (2007): S207. http://dx.doi.org/10.4049/jimmunol.178.supp.102.17.
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Abstract During early life, fetuses and neonates are exposed to allogeneic non-inherited maternal antigens (NIMA), through the passage of maternal cells and/or molecules across the placenta and in the breastmilk. Currently, it is thought that this early exposure results in the development of tolerance to NIMA. This is manifest in later life as an increased acceptance of grafts expressing the NIMA antigens. However, there also is evidence that exposure to NIMA during early life can lead to priming instead. In a murine model, we have shown that priming of neonates occurs when they are exposed to low doses of NIMA-like alloantigens. As these two possibilities, tolerance or priming, are extremely important for the outcome of transplantation, our lab has been engaged in studies to understand the in vivo responses of early life exposure to low doses of NIMA-like alloantigens. Following exposure, neonates developed both primary and memory cytotoxic responses to alloantigen. These responses were accompanied by vigorous Th1 and Th2 responses that exceeded the responses of adults similarly exposed. Overall, we conclude that exposure to low doses of NIMA-like alloantigens induces the development of robust cytotoxic and cytokine responses in neonates. This suggests that under specific conditions, early exposure to NIMA may lead to highly efficient immunological priming of all arms of T cell adaptive immunity, rather than tolerance. This work was supported by NIAID grant number R01 AI44923-02 (B.A.)
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Kelton, JG, JW Smith, P. Horsewood, JR Humbert, CP Hayward, and TE Warkentin. "Gova/b alloantigen system on human platelets." Blood 75, no. 11 (1990): 2172–76. http://dx.doi.org/10.1182/blood.v75.11.2172.2172.
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Abstract In this report we describe a platelet alloantigen system that is carried on a novel platelet protein of 175 Kd. Antisera against the two alleles (Gova/Govb) were found in two patients who had received large numbers of platelet transfusions. The anti-Gov alloantibodies could not be detected using a whole platelet solid phase enzyme immunoassay, or by a platelet glycoprotein capture enzyme immunoassay using monoclonal antibodies against glycoproteins Ib/IX, Ia/IIa, and IIb/IIIa. Using radioimmunoprecipitation techniques, a protein was precipitated that migrated at 175 Kd (reduced). Under nonreduced conditions, a 150-Kd protein was detected with a minor component at 175Kd. The detection of the alloantigens was not activation-dependent. Using immunodepletion studies, we demonstrated that each alloantiserum recognized an epitope on a discrete population of the 175-Kd platelet protein. Family studies demonstrated that the alloantigens designated as Gova and Govb were inherited in an autosomal codominant fashion. The phenotypic frequencies were Gova/Gova, 26%; Gova/Govb, 55%; Govb/Govb, 19%; giving gene frequencies of 0.532 and 0.468 for Gova and Govb, respectively (n = 33).
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Kelton, JG, JW Smith, P. Horsewood, JR Humbert, CP Hayward, and TE Warkentin. "Gova/b alloantigen system on human platelets." Blood 75, no. 11 (1990): 2172–76. http://dx.doi.org/10.1182/blood.v75.11.2172.bloodjournal75112172.
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In this report we describe a platelet alloantigen system that is carried on a novel platelet protein of 175 Kd. Antisera against the two alleles (Gova/Govb) were found in two patients who had received large numbers of platelet transfusions. The anti-Gov alloantibodies could not be detected using a whole platelet solid phase enzyme immunoassay, or by a platelet glycoprotein capture enzyme immunoassay using monoclonal antibodies against glycoproteins Ib/IX, Ia/IIa, and IIb/IIIa. Using radioimmunoprecipitation techniques, a protein was precipitated that migrated at 175 Kd (reduced). Under nonreduced conditions, a 150-Kd protein was detected with a minor component at 175Kd. The detection of the alloantigens was not activation-dependent. Using immunodepletion studies, we demonstrated that each alloantiserum recognized an epitope on a discrete population of the 175-Kd platelet protein. Family studies demonstrated that the alloantigens designated as Gova and Govb were inherited in an autosomal codominant fashion. The phenotypic frequencies were Gova/Gova, 26%; Gova/Govb, 55%; Govb/Govb, 19%; giving gene frequencies of 0.532 and 0.468 for Gova and Govb, respectively (n = 33).
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Wood, Kathryn J., Nick D. Jones, Andrew R. Bushell, and Peter J. Morris. "Alloantigen–induced specific immunological unresponsiveness." Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 356, no. 1409 (2001): 665–80. http://dx.doi.org/10.1098/rstb.2001.0840.
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When the immune system encounters alloantigen it can respond in any one of a number of different ways. The choice that is made will take into account factors such as where, when and how the contact with the alloantigen takes place, as well as the environmental conditions that prevail at the time the alloantigen is encountered. Alloantigen administration before transplantation either alone or in combination with therapeutic agents that modulate the functional activity of the responding leucocytes can be a powerful way of inducing specific unresponsiveness to alloantigens in vivo .The molecular mechanisms that influence the way the outcome of the immune response to alloantigen develops, either activation or unresponsiveness to the triggering antigen, hold the key to our ability to manipulate the immune system effectively by exposing it to donor antigen for therapeutic purposes. This review will focus on alloantigen–induced immunological unresponsiveness and how insights into the mechanisms of unresponsiveness have driven the development of novel tolerance–induction strategies that show promise for translation into the clinic in the future.
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Moritz, Elyse, Ângela M. M. I. Norcia, José D. B. Cardone, et al. "Human neutrophil alloantigens systems." Anais da Academia Brasileira de Ciências 81, no. 3 (2009): 559–69. http://dx.doi.org/10.1590/s0001-37652009000300019.
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Neutrophil alloantigens are involved in a variety of clinical conditions including immune neutropenias, transfusion-related acute lung injury (TRALI), refractoriness to granulocyte transfusions and febrile transfusion reactions. In the last decade, considerable progress has been made in the characterization of the implicated antigens. Currently, seven antigens are assigned to five human neutrophil antigen (HNA) systems. The HNA-1a, HNA-1b and HNA-1c antigens have been identified as polymorphic forms of the neutrophil Fcγ receptor IIIb (CD16b), encoded by three alleles. Recently, the primary structure of the HNA-2a antigen was elucidated and the HNA-2a-bearing glycoprotein was identified as a member of the Ly-6/uPAR superfamily, which has been clustered as CD177. The HNA-3a antigen is located on a 70-95 kDa glycoprotein; however, its molecular basis is still unknown. Finally, the HNA-4a and HNA-5a antigens were found to be caused by single nucleotide mutations in the αM (CD11b) and αL (CD11a) subunits of the leucocyte adhesion molecules (β2 integrins). Molecular and biochemical characterization of neutrophil antigenshave expanded our diagnostic tools by the introduction of genotyping techniques and immunoassays for antibody identification. Further studies in the field of neutrophil immunology will facilitate the prevention and management of transfusion reactions and immune diseases caused by neutrophil antibodies.
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Bux, Juergen. "Nomenclature of granulocyte alloantigens." Transfusion 39, no. 6 (1999): 662–63. http://dx.doi.org/10.1046/j.1537-2995.1999.39060662.x.
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Steffensen, Rudi, Kim Varming, and Casper Jersild. "Nomenclature of granulocyte alloantigens." Transfusion 40, no. 4 (2000): 491–92. http://dx.doi.org/10.1046/j.1537-2995.2000.40040491.x.
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Sawitzki, Birgit, Cherry I. Kingsley, Vanessa Oliveira, Mahzuz Karim, Manuela Herber та Kathryn J. Wood. "IFN-γ production by alloantigen-reactive regulatory T cells is important for their regulatory function in vivo". Journal of Experimental Medicine 201, № 12 (2005): 1925–35. http://dx.doi.org/10.1084/jem.20050419.
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The significance of cytokine production by CD4+ regulatory T (T reg) cells after antigen exposure in vivo and its impact on their regulatory activity remains unclear. Pretreatment with donor alloantigen under the cover of anti-CD4 therapy generates alloantigen reactive T reg cells that can prevent rejection of donor-specific skin grafts that are mediated by naive CD45RBhighCD4+ T cells. To examine the kinetics and importance of cytokine gene transcription by such alloantigen-reactive T reg cells, pretreated mice were rechallenged with donor alloantigen in vivo. CD25+CD4+ T cells, but not CD25−CD4+ T cells, showed a fivefold increase in IFN-γ mRNA expression within 24 h of reencountering alloantigen in vivo. This expression kinetic was highly antigen-specific and was of functional significance. Neutralizing IFN-γ at the time of cotransfer of alloantigen reactive T reg cells, together with CD45RBhighCD4+ effector T cells into Rag−/− skin graft recipients, resulted in skin graft necrosis in all recipients; the generation and function of alloantigen-reactive T reg cells was impaired dramatically in IFN-γ–deficient mice. These data support a unique role for IFN-γ in the functional activity of alloantigen-reactive T reg cells during the development of operational tolerance to donor alloantigens in vivo.
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Aït-Azzouzene, Djemel, Marie-Claude Gendron, Monique Houdayer, et al. "Maternal B Lymphocytes Specific for Paternal Histocompatibility Antigens Are Partially Deleted During Pregnancy." Journal of Immunology 161, no. 6 (1998): 2677–83. http://dx.doi.org/10.4049/jimmunol.161.6.2677.
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Abstract Although genetically different from its mother, a mammalian fetus bearing paternal alloantigens is normally not rejected. To investigate one of the many possible mechanisms involved in this important biologic phenomenon, we analyzed the consequences of fetal alloantigen recognition on maternal B lymphocytes. We used transgenic mice expressing a unique B cell receptor with a relatively high affinity for the MHC class I molecule H-2Kk on most B lymphocytes. We provide the first evidence for an alloantigen-specific B cell deletion in the spleens and bone marrow of transgenic mothers bearing H-2Kk-positive fetuses. This highly reproducible deletion affects ≤80% of Id-bearing B cells, starts at midpregnancy, and is only observed until term. Such a specific maternal B cell deletion could contribute to the success of the fetal allograft.
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Li, Jun, Kenrick Semple, Jessica Heinrichs, et al. "High Efficacy of Alloantigen-Specific Induced Regulatory T Cells in the Prevention of Acute Graft-Versus-Host Disease in Mice." Blood 120, no. 21 (2012): 4112. http://dx.doi.org/10.1182/blood.v120.21.4112.4112.
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Abstract Abstract 4112 Introduction: Naturally occurring regulatory T cells (nTregs) may prevent graft-versus-host disease (GVHD) while preserving graft-versus-leukemia (GVL) activity. However, clinical application of nTregs has been severely hampered by their scarce availability and non-selective suppression. To overcome these limitations, we took an alternative approach to generate antigen-specific induced Tregs (iTregs), and tested their efficacy and selectivity in the prevention of GVHD in pre-clinical models of bone marrow transplantation (BMT). Methods: We selected HY as target antigen, because it is a naturally processed and ubiquitously expressed minor histocompatibility antigen (miHAg) with a proven role in GVHD and GVL effect. To generate HY-specific iTregs, naïve CD4+CD25− cells were isolated from MHC II-restricted HY-specific transgenic mice, and were stimulated with HY peptide and APCs, in the presence of TGFb and retinoic acid. Using similar protocol, we also generated polyclonal iTregs from CD4+CD25− cells of normal C57BL/6 (B6) mice with allogeneic dendritic cells (DCs). iTregs were isolated by positively selecting CD4+CD25hi cells 6–7 days after generation. Frequency of T cells in recognizing alloantigens was measured using a limited dilution assay. Various MHC-mismatched or matched murine BMT models were used, where polyclonal T cells (Teffs hereafter) were transplanted with donor bone marrow to induce GVHD in myeloablative allogeneic recipients. Results: We first assessed the effect of HY-specific iTregs on GVHD using an MHC II-mismatched B6 ® (B6 × bm12)F1 BMT model, and found that HY-specific iTregs prevented GVHD mortality in male (HY+) but not female (HY−) recipients. On the per-cell basis, HY-specific iTregs were significantly more potent than polyclonal Tregs in the prevention of GVHD. By measuring iTregs and Teffs in spleen and liver of the recipients, we found that HY-specific iTregs expanded extensively and significantly suppressed expansion, activation and infiltration of Teffs in male but not female recipients. To exclude the possibility the observation was model specific, we evaluated the efficacy of HY-specific iTregs and found that those iTregs were highly effective in the prevention of GVHD in two additional BMT models, including one MHC-matched but miHAg-mismatched B6 ® BALB.b model and one haplo-mismatched B6 ® B6D2F1 model. To increase translational potential of our approach, we extended our studies to alloantigen-specific polyclonal iTregs. After 7-day culture in iTreg- generating condition with BALB/c DCs, the frequency of B6 iTregs in recognizing BALB/c alloantigens was increased for 16-fold than that of naïve CD4+CD25− T cells. Furthermore, these iTregs were 64–128 fold more suppressive than nTregs to conventional T-cell response against BALB/c alloantigens. Their highly suppressive activity was antigen-specific, because the same alloreactive iTregs had significant lower suppressive activity to T-cell response against the third-party alloantigens. In vivo using an MHC-mismatched B6 ® BALB/c BMT model, we found that these alloreactive iTregs could effectively prevent GVHD at 2:1 ratio of Teff:Treg, at which polyclonal nTregs had a minimal effect. Conclusion: Using monoclonal HY-specific or polyclonal alloantigen-specific iTregs, these studies demonstrate that antigen-specific iTregs were highly effective in controlling GVHD in an activation-dependent manner. Because iTregs specific for a given miHAg (e.g. HY) can control polyclonal Teffs in response to multiple alloantigens and prevent GVHD in allogeneic recipient, these data also indicate that Tregs may control GVHD through a linked-suppression on Teffs in vivo. In conclusion, the current study presents a promising strategy to generate alloantigen-specific iTregs for effective GVHD prevention in human allogeneic hematopoietic cell transplantation. Disclosures: No relevant conflicts of interest to declare.
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Via, C. S., G. C. Tsokos, N. I. Stocks, M. Clerici, and G. M. Shearer. "Human in vitro allogeneic responses. Demonstration of three pathways of T helper cell activation." Journal of Immunology 144, no. 7 (1990): 2524–28. http://dx.doi.org/10.4049/jimmunol.144.7.2524.
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Abstract In our study, we have measured in vitro proliferation and IL-2 production by human PBL to characterize the interactions between Th cells and accessory cells (AC) involved in responses to either conventional Ag or alloantigens. IL-2 production and proliferative responses to conventional Ag, such as influenza or tetanus, are exclusively dependent on the presence of CD4+ T cells and AC. In contrast, IL-2 and proliferative responses to alloantigen can be mediated by either CD4+ or CD8+ T cells. CD4+ T cells respond to alloantigen using either autologous AC (self-restricted), or allogeneic AC (allo-restricted), whereas CD8+ T cells respond to alloantigen using allogeneic AC only. The understanding of Th cell-AC interactions involved in in vitro allogeneic responses will be important for delineating the Th cell-AC interactions involved in transplantation immunity as well as in clinical disorders characterized by T cell dysfunction such as human immunodeficiency virus infection and systemic lupus erythematosus.
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Zhang, Nanyan, Huiying Zhi, Brian R. Curtis, et al. "CRISPR/Cas9-mediated conversion of human platelet alloantigen allotypes." Blood 127, no. 6 (2016): 675–80. http://dx.doi.org/10.1182/blood-2015-10-675751.
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Key Points The genome of iPSCs has been edited to encode antigenically-distinct human platelet alloantigens. The iPSC-derived megakaryocyte progenitor cells express the designed alloantigens for diagnostic, investigative, and future therapeutic use.
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Veerapathran, Anandharaman, Micheal Schell, Francisca Beato, et al. "CD4 Treg and CD4 Tcon Utilize Distinct TCR Vbeta Repertoires in Response to Alloantigen." Blood 126, no. 23 (2015): 4286. http://dx.doi.org/10.1182/blood.v126.23.4286.4286.
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Abstract Background: Regulatory CD4 T cells (Treg) are potent to suppress the responses of conventional CD4+ (Tcon) and CD8+ T cells to alloantigens and prevent graft-vs.-host diseases (GVHD). Since the mechanisms for thymic selection of Treg and Tcon are distinct, we hypothesized that the two cells types use distinct TCR repertoires in the response to same alloantigen. We have used high throughput deep sequencing to study the T cell receptor (TCR) Vbeta CDR3 repertoire of CD4 Treg and CD4 Tcon at baseline and again after expansion with alloantigen. Methods: CD4+CD25+CD127- Treg and CD4+CD25-CD127- Tcon were FACS-sorted from healthy donor PBMCs or umblical cord blood mononuclear cells. Aliquots of sorted Treg and Tcon were expanded separately by DC from the same Major Histocompatibility (MHC)-mismatched donor. Treg were cultured with DCs, IL-2, IL-15 and rapamycin, while Tcon were cultured with DCs and IL-2. Genomic DNA from baseline or expanded purified Treg and Tcon was sequenced, at least 10^6 deep, by Adaptive Biotechnologies multiplex kit to detect unique T cell receptor (TCR) Vbeta CDR3 sequences. Data was analyzed by the algorithm established for the Adaptive Biotechnologies software and characterized according to the IMGT (International ImmunoGeneTics information system) nomenclature. Results: The TCR Vbeta CDR3 sequences of baseline natural Treg and Tcon T cell have minimal overlap, indicating that the thymus shapes distinct TCR repertoires in these two cell types. However, the CDR3 length and the frequency of nucleotide deletion or insertion at the Vbeta-Dbeta and Dbeta-Jbeta junction were similar. By employing the "robust regression model", we identified expanded TCR Vbeta CDR3 sequences among both Treg and Tcon after in vitro culture with the same alloantigens. These expanded Treg and Tcon used unique TCR Vbeta CDR3 sequences that are not shared by the other cell type. Expanded Treg and Tcon displayed fewer nucleotide deletions and insertions at the Vbeta-Dbeta and Dbeta-Jbeta junction than at baseline. The frequency of the expanded sequences, insertions and deletions were of the same magnitude in Treg and Tcon suggesting that both undergo similar processes of antigen-driven TCR selection and magnitude of cell expansion in vitro. Conclusion: CD4 Treg and Tcon utilize largely distinct TCR Vbeta CDR3 repertoires at baseline and after expansion against the same alloantigens. Questions remain whether Treg and Tcon recognize the same or distinct peptides from the same antigen, and whether they bind peptide with different avidity. TCR Vbeta CDR3 deep sequencing ought to be used to track single Treg and Tcon after adoptive cell therapy. Figure 1. CDR3 nucleotide sequences of natural Treg and Tcon do not overlap before (Baseline) and after (End) expansion against alloantigen Figure 1. CDR3 nucleotide sequences of natural Treg and Tcon do not overlap before (Baseline) and after (End) expansion against alloantigen Disclosures No relevant conflicts of interest to declare.
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Kalb, Rainer, Sentot Santoso, Katja Unkelbach, Volker Kiefel, and Christian Mueller-Eckhardt. "Localization of the Br Polymorphism on a 144 bp Exon of the GPIa Gene and Its Application in Platelet DNA Typing." Thrombosis and Haemostasis 71, no. 05 (1994): 651–54. http://dx.doi.org/10.1055/s-0038-1642498.
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SummaryAlloimmunization against the human platelet alloantigen system Br (HPA-5) is the second most common cause of neonatal alloimmune thrombocytopenia (NAIT) in Caucasian populations. We have recently shown that a single base polymorphism at position 1648 on platelet mRNA coding for GPIa results in an aminoacid substitution at position 505 on the mature GPIa which is associated with the two serological defined Br phenotypes.Since DNA-typing of platelet alloantigens offers possibilities for useful clinical applications, we designed genomic DNA-based restriction fragment length polymorphism (RFLP) typing for Br alloantigens. To establish this technique we analyzed the genomic organization of GPIa adjacent to the polymorphic base. Using the polymerase chain reaction (PCR) of blood cell DNA we have identified two introns (approximately 1.7 and 1.9 kb) flanking a 144 bp coding sequence of the GPIa gene encompassing the polymorphic base 1648. Based on the in- tron sequence, a PCR primer was constructed to amplify a 274 bp fragment which was used for allele-specific RFLP to determine the Br genotypes. The results of RFLP analysis using Mnll endonuclease obtained from 15 donors (2 Br37*, 2 Br^ and 11 Brb/b) correlate perfectly with serological typing by monoclonal antibody-specific immobilization of platelet antigens (MAIPA) assay.
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Bray, PF, Y. Jin, and T. Kickler. "Rapid genotyping of the five major platelet alloantigens by reverse dot- blot hybridization." Blood 84, no. 12 (1994): 4361–67. http://dx.doi.org/10.1182/blood.v84.12.4361.bloodjournal84124361.
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Amino acid substitutions in platelet membrane glycoproteins result in alloantigens. Identifying these polymorphisms is important in alloimmune-mediated platelet disorders. Immunophenotyping platelet antigens can be limited by the unavailability of specific antisera. The goal of this work was to identify human platelet antigen genotypes in individuals using a technique that would circumvent the limitations of immunophenotyping and be clinically applicable. We have successfully applied the reverse dot-blot (RDB) technique to the genotyping of the five major human platelet alloantigen systems. Allele-specific oligonucleotides (ASOs) representing each allele of these alloantigens were covalently linked to a filter. Biotinylated oligonucleotides flanking the polymorphic sequences in genomic DNA were used to amplify genomic DNA by the polymerase chain reaction (PCR), and these products were hybridized to the filters containing the ASOs. Reactivity was detected with a chromogenic substrate. This nonradioactive methodology identifies all 15 possible genotypes in a well-defined control group of individuals and requires only two PCR reactions per patient sample. RDB analysis was used to successfully genotype women and family members with neonatal alloimmune thrombocytopenia and with posttransfusion purpura and to prenatally genotype the amniocytes from a fetus at risk for thrombocytopenia. The RDB methodology is specific, sensitive, and rapid and should enhance our ability to accurately diagnose disorders of alloimmune platelet destruction.
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Morecki, S., S. Slavin, and S. A. Ben-Sasson. "Selective abrogation of alloreactivity via priming in the presence of aphidicolin, a specific inhibitor of DNA polymerase." Journal of Immunology 143, no. 3 (1989): 838–43. http://dx.doi.org/10.4049/jimmunol.143.3.838.
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Abstract Aphidicolin, a specific and direct inhibitor of eukaryotic DNA polymerase alpha, was used to investigate its impact on immunologic reactions in vitro. Dose response curve of the inhibitory effect was studied in murine and human primary allogeneic responses, as well as the proliferative responses to both PHA and Con A mitogens. The presence of aphidicolin during the allosensitization phase in secondary MLR of mice splenocytes resulted in complete abolishment of the subsequent response directed against the priming alloantigens, whereas alloreactivity to unrelated alloantigen-bearing cells was inhibited to a much lesser degree. The allosensitized aphidicolin-treated cells lost the ability to respond to subsequent PHA stimulation, but were capable of exerting a high responsiveness to Con A. The presence of aphidicolin during the allosensitization phase in secondary MLR of human mononuclear cells resulted in markedly decreased alloreactivity directed against the priming cells, but spared the subsequent response to unrelated alloantigens and to both PHA and Con A mitogenic stimuli. It is suggested that aphidicolin may be used for selective inactivation of proliferating cells without interfering with immunologic functions of other quiescent subsets. Aphidicolin may thus be a useful agent for induction of specific unresponsiveness in experimental models of allogeneic transplantation.
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Adeegbe, Dennis O., Robert B. Levy, and Thomas R. Malek. "Adoptive therapy with allogeneic CD4+CD25+ Foxp3+ Treg cells induces transplantation tolerance (102.10)." Journal of Immunology 178, no. 1_Supplement (2007): S206. http://dx.doi.org/10.4049/jimmunol.178.supp.102.10.
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Abstract Alloantigen primed Treg cells offer the potential for non-toxic suppression of transplant rejection reactions. If they are not rejected by the recipient, MHC-mismatched Treg cells might also establish transplant tolerance to the MHC molecules that the Treg cells were selected on during their development. In this regard, we have shown that the adoptive transfer of allogeneic Treg cells into neonatal IL-2Rβ−/−mice, which lack Treg cells and develop rapid lethal autoimmunity, lead to long-term engraftment by the donor Treg cells, effective prevention of this autoimmunity, and simultaneous long-term tolerance to the skin grafts expressing alloantigens shared by the Treg cells. This tolerance depended upon active suppression by Treg cells, not deletion or anergy. Mice tolerant to allogeneic C57BL/6 skin grafts were also tolerant to MHC class II-deficient C567BL/6 skin grafts, but rejected bm3 and bm12 skin grafts. These latter findings demonstrate that Treg cells are not required to directly recognize alloantigens within the skin grafts and that a single neo-antigen was sufficient to break tolerance. Collectively, these data demonstrate induction of dominant donor-specific transplantation tolerance by allogeneic Treg cells provided that the MHC antigens of both the Treg cells and transplant are matched. (Supported by the NIH)
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Grabbe, S., R. L. Gallo, A. Lindgren, and R. D. Granstein. "Deficient antigen presentation by Langerhans cells from athymic (nu/nu) mice. Restoration with thymic transplantation or administration of cytokines." Journal of Immunology 151, no. 7 (1993): 3430–39. http://dx.doi.org/10.4049/jimmunol.151.7.3430.
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Abstract Epidermal Langerhans cells (LC) are a unique subtype of I-A+ dendritic cells able to present Ag for CD4-dependent immune responses. To investigate whether cutaneous Ag presentation is regulated by thymic elements or soluble factors produced by thymus-derived cells, we compared LC function in athymic nude mice and euthymic normal controls. Examination of the ability of LC to present alloantigens to T cell-enriched responder populations, and insulin to an insulin-specific T cell hybridoma, demonstrated that this function is deficient in LC from inbred and outbred strains of congenitally athymic (nu/nu) mice compared with euthymic litter mates. Adoptive transfer of thymic tissue from euthymic to athymic mice reconstituted the ability of LC derived from athymic mice to present alloantigens. To investigate whether an altered local cytokine microenvironment was responsible for the diminished LC function in athymic mice, various cytokines were administered in vivo and in vitro before determination of alloantigen presentation by epidermal cells from athymic and euthymic mice. Continuous intraperitoneal infusion of granulocyte-macrophage colony stimulating factor (GM-CSF) or TNF-alpha, but not IL-1 alpha or IL-2, restored alloantigen presenting ability in athymic LC. In vitro preincubation of LC in GM-CSF or TNF-alpha but not in other cytokines tested also reconstituted alloantigen presentation by LC from athymic mice in most, but not all, of the experiments performed. Furthermore, analysis of cytokine production by epidermal cells in athymic and euthymic mice revealed that epidermal cells from athymic mice produce less GM-CSF and more TNF-alpha, but normal amounts of various other cytokines. However, reconstitution of athymic mice with thymic tissue did not result in normalization of GM-CSF or TNF-alpha production by epidermal cells. These data suggest that LC Ag presenting ability is regulated by thymic factors and that adequate function of cutaneous APC in situ may require the continuous presence of sufficient amounts of cytokines including GM-CSF and TNF-alpha.
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Sato, S., T. Azuma, J. Shimizu, et al. "Property of class I H-2 alloantigen-reactive Lyt-2+ helper T cell subset. Abrogation of its proliferative and IL-2-producing capacities by intravenous injection of class I H-2-disparate allogeneic cells." Journal of Immunology 141, no. 3 (1988): 721–27. http://dx.doi.org/10.4049/jimmunol.141.3.721.
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Abstract The present study investigates the distinctiveness of Class I H-2 alloantigen-reactive Lyt-2+ helper/proliferative T cell subset in the aspect of tolerance induction. Primary mixed lymphocyte reactions (MLR) revealed that Lyt-2+ and L3T4+ T cell subsets from C57BL/6 (B6) mice were exclusively capable of responding to class I H-2 [B6-C-H-2bm1 (bm1)]- and class II H-2 [B6-C-H-2bm12 (bm12)]-alloantigens, respectively. Anti-bm12 MLR was not affected by i.v. injection of bm12 spleen cells into recipient B6 mice. In contrast, a single i.v. administration of bm1 spleen cells into B6 mice resulted in the abrogation of the capacity of recipient B6 spleen and lymph node cells to give anti-bm1 MLR. This suppression was bm1 alloantigen-specific, since lymphoid cells from B6 mice i.v. presensitized with bm1 cells exhibited comparable anti-bm12 primary MLR to that obtained by normal B6 lymphoid cells. Such tolerance was rapidly (24 h after the i.v. injection of bm1 cells) inducible and lasting for at shortest 3 wk. Addition of lymphoid cells from anti-bm1-tolerant B6 mice to cultures of normal B6 lymphoid cells did not suppress the proliferative responses of the latter cells, indicating that the tolerance is not due to the induction of suppressor cells but attributed to the elimination or functional impairment of anti-bm1 proliferative clones. The tolerance was also demonstrated by the failure of tolerant lymphoid cells to produce IL-2. It was, however, found that anti-bm1 CTL responses were generated by tolerant lymphoid cells which were unable to induce the anti-bm1 MLR nor to produce detectable level of IL-2. These results demonstrate that class I H-2 alloantigen-reactive Lyt-2+ Th cell subset exhibits a distinct property which is expressed by neither Lyt-2+ CTL directed to class I H-2 nor L3T4+ Th cells to class II H-2 alloantigens.
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Hambor, J. E., M. L. Tykocinski, and D. R. Kaplan. "Functional consequences of anti-sense RNA-mediated inhibition of CD8 surface expression in a human T cell clone." Journal of Experimental Medicine 168, no. 4 (1988): 1237–45. http://dx.doi.org/10.1084/jem.168.4.1237.
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An experimental approach for defining the function of CD8 has been developed by linking anti-sense RNA mutagenesis and T cell cloning technologies. We have transfected an anti-sense CD8 episomal expression vector into a CD8+ nontransformed human T cell clone that is specific for the human class I alloantigen HLA-B35. Expression of CD8 on this T cell clone, JH.ARL.1, was selectively and efficiently inhibited. Stimulation of this CD8- variant with specific alloantigen resulted in a marked loss of a number of functional responses, including cytotoxicity, proliferation, IL-2 secretion, and IL-2-R expression. However, these same functional responses could be elicited with stimuli that do not require antigen recognition to activate the T cell (anti-CD3 mAbs, PHA). The results of our study support the hypothesis that CD8 is required for recognition of class I MHC alloantigens that results in activation of T cell functional responses.
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Furuhata, Kenichi. "Molecular aspects of platelet alloantigens." Journal of the Japan Society of Blood Transfusion 41, no. 5 (1995): 419–27. http://dx.doi.org/10.3925/jjtc1958.41.419.
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ANTCZAK, DOUGLAS F., SUSAN M. BRIGHT, LINDA H. REMICK, and BEVERLEY E. BAUMAN. "Lymphocyte alloantigens of the horse." Tissue Antigens 20, no. 3 (2008): 172–87. http://dx.doi.org/10.1111/j.1399-0039.1982.tb00343.x.
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FULTON, J. E., R. W. BRILES, and S. J. LAMONT. "Monoclonal antibody differentiates chickenAsystem alloantigens*." Animal Genetics 21, no. 1 (1990): 39–45. http://dx.doi.org/10.1111/j.1365-2052.1990.tb03205.x.
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Santoso, S., and V. Kiefel. "Human Platelet-Specific Alloantigens: Update." Vox Sanguinis 74, S2 (1998): 249–53. http://dx.doi.org/10.1111/j.1423-0410.1998.tb05427.x.
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Piguet, P. F. "Helper T lymphocytes which recognize the MHC class I alloantigens in vivo are CD4+CD8-1." Journal of Immunology 141, no. 12 (1988): 4129–32. http://dx.doi.org/10.4049/jimmunol.141.12.4129.
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Abstract To determine the CD4 or CD8 phenotype of the Th lymphocyte which recognizes in vivo the MHC class I alloantigens, B10 recombinant mice were treated with anti-CD8 or anti-CD4 mAb and immunized with lymphoid cells from donors differing in the K or D region of the MHC. Alloantibodies were evaluated by a 51Cr-release assay or by indirect immunofluorescence. The production of IgG anti-Dd and anti-Kk alloantibodies was increased by the deletion of the CD8+ and absent in mice depleted of the CD4+ subset. These experiments indicate that the helper influence elicited by the recognition of a MHC class I alloantigen in vivo is due to cells of the CD4+CD8- phenotype.
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Bianchi, A. T., L. M. Hussaarts-Odijk, E. A. Wolters, A. Molendijk, and R. Benner. "Suppression of antigraft immunity by preimmunization. III. Characterization of suppressor T cells involved in suppression of the efferent phase of DTH against alloantigens." Journal of Immunology 137, no. 2 (1986): 433–42. http://dx.doi.org/10.4049/jimmunol.137.2.433.
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Abstract Suppressor T (Ts) cells that can suppress delayed type hypersensitivity (DTH) against histocompatibility (H) antigens can be isolated from spleen and lymph nodes a few days after i.v. immunization of mice with irradiated allogeneic spleen cells. In this paper we investigated the suppression of the efferent phase of DTH to characterize the Ts cells involved, and to compare them with the afferent phase Ts cells that have been characterized in a previous paper of this series. The DTH against third party alloantigens that were not used for the i.v. suppressive immunization could be suppressed by presenting the third party alloantigens together with the original alloantigens in the challenge inoculum for eliciting the DTH reaction. Thus the ultimate suppressive effect by the Ts cells that are active during the efferent phase of DTH is nonspecific. This non-specific suppression of DTH to alloantigens has previously been found for the afferent phase Ts cells as well. For suppression of the efferent phase of DTH to alloantigens, a population of Lyt-1+2+ Ts cells appeared to be essential, just like in the suppression of the afferent phase of DTH to alloantigens. We did not find evidence for the involvement of cyclophosphamide-sensitive auxiliary Ts cells in suppression of the efferent phase of DTH. Also no evidence was found for H-2 or Igh-restricted activation and function of the Ts cells that were active during afferent and efferent phases of the DTH response to H antigens. In view of these similarities between afferent phase and efferent phase Ts cells we conclude that there are no arguments as yet to suppose that there is more than one type of T cells involved in the suppression of the afferent and efferent limb of DTH against H antigens.
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McFarland, Hugh I., Kazuhide Tsuji, Karen P. Mason, and Amy S. Rosenberg. "MHC Disparate Resting B Cells Are Tolerogenic in the Absence of Alloantigen-Expressing Dendritic Cells." ISRN Transplantation 2013 (November 28, 2013): 1–8. http://dx.doi.org/10.5402/2013/701051.
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Resting B cell (rB) populations have been shown to tolerize to soluble proteins and to minor-H but not to MHC alloantigens. We speculated that the reason for failing to tolerize to MHC alloantigen is that the few remaining dendritic cells (DCs) contaminating purified rB cell populations efficiently activate MHC allospecific T cells which are present at a higher frequency than T cells specific for minor-H alloantigen and soluble proteins. We established that MHC disparate rB cells are indeed tolerogenic when devoid of DC populations, as parental strain mice showed delayed skin graft rejection when infused with rB cells from mice in which MHC class I alloantigen was specifically targeted to T and B cells (CD2- transgenic mice). In contrast, treatment of parental strain mice with allogeneic rB cells purified from MHC- transgenic mice, in which is ubiquitously expressed, including DCs, induced accelerated graft rejection. We also showed that adding only 5,000 expressing DCs to CD2- rB cells abrogated the tolerogenic effect. Surprisingly, allogeneic rB cells prolonged graft survival in -primed mice. Thus, MHC disparate rB cells are tolerogenic and their failure to delay graft rejection can be explained by contaminating allogeneic DCs.
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Morecki, S., B. Leshem, A. Eid, and S. Slavin. "Alloantigen persistence in induction and maintenance of transplantation tolerance." Journal of Experimental Medicine 165, no. 6 (1987): 1468–80. http://dx.doi.org/10.1084/jem.165.6.1468.
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Infusion of parental bone marrow cells into F1 hybrids conditioned by total lymphoid irradiation (TLI) results in chimeras with a high percentage of donor-type cells, and without clinical signs of graft-vs.-host reaction. In these chimeras, a state of tolerance has been shown to be associated with paucity of cytotoxic T lymphocyte percursors (pCTL) reactive with host-type alloantigens. To determine whether the presence of tolerizing alloantigens is essential for maintenance of unresponsiveness, lymphohematopoietic cells obtained from such tolerant chimeras were transferred into supralethally irradiated recipients of two different genotypes: in one case the adoptive recipients were syngeneic with host-type cells, and in the other they were syngeneic with donor-type cells of the original chimeras, thus providing the chimeric cells with a tolerogen-free environment. After "parking" for 4 d in syngeneic donor-type mice, the transferred cells displayed a marked increase in the frequency of pCTL directed against tolerizing alloantigens, whereas a low pCTL frequency directed against the same H-2 target cells was maintained in allogeneic tolerizing-type adoptive recipients. Multiple injections of adoptive donor-type mice with tolerizing-type cells of the original chimera reestablished a low level of cytotoxic precursors. Cytotoxic activity against unrelated alloantigens was independent of the presence of tolerogen-presenting cells in the adoptively transferred mice. Our experimental model suggests that persistence of cells bearing tolerizing alloantigens is an essential requirement for maintenance of previously established tolerance.