Journal articles: 'Graft vs Host Reaction'

1

Goltz, Robert W. "The Graft-vs-Host Reaction." Archives of Dermatology 124, no. 12 (December 1, 1988): 1849. http://dx.doi.org/10.1001/archderm.1988.01670120065012.

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Friedman, Kenneth J. "Acute Follicular Graft-vs-Host Reaction." Archives of Dermatology 124, no. 5 (May 1, 1988): 688. http://dx.doi.org/10.1001/archderm.1988.01670050032014.

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Murphy, William J., Michael Bennett, Miriam R. Anver, Michael Baseler, and Dan L. Longo. "Human-mouse lymphoid chimeras: host-vs.-graft and graft-vs.-host reactions." European Journal of Immunology 22, no. 6 (June 1992): 1421–27. http://dx.doi.org/10.1002/eji.1830220614.

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4

Jones, D. C., and N. T. Young. "Natural killer receptors and graft-vs.-host/ graft-vs.-leukaemia reactions." Vox Sanguinis 87, s2 (July 2004): 15–17. http://dx.doi.org/10.1111/j.1741-6892.2004.00446.x.

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5

Hill, Wolfgang, Karl Sotlar, Heinz Diem, Andreas Hausmann, and Hans Jochem Kolb. "Bone Marrow Reaction in Chronic Graft-Versus-Host Disease." Blood 112, no. 11 (November 16, 2008): 1166. http://dx.doi.org/10.1182/blood.v112.11.1166.1166.

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Abstract Hematopoiesis of the host is a primary target organ of the graft-versus-host reaction. However histological analyses of the bone marrow are rarely reported. Here we report histological changes in the bone marrow of patients (pts) with and without chronic graft-versus-host disease (cGvHD). Bone marrow biopsies were obtained between 101 days and 4623 days (median:419 days) after transplantation as part of a controlled prospective phase ll study of patients with osteopenia/osteoporosis after allogeneic hematopoietic stem cell transplantation (HCT). Previously we reported an increased density of microvessels using an antibody against v. Willebrand factor (vW) (Hill W. et al Blood110, abstract No 1963; 2007). Here we report additional immunohistological and immunocytological findings in marrow and blood. We analyzed the number of CD34+ and vW+ microvessels as well as CD8+ suppressor/cytotoxic T-cells/mm² (T-S) in sequential biopsies of pts with (n=9) or without (n=6) cGvHD after median 2 years apart. Biopsies of 3 pts without HCT and without lymphoma involvement served as controls. Simultaneously lymphocyte subpopulations were evaluated in peripheral blood samples of pts with (n=16) or without (n=8) cGvHD. The pts were divided in 5 groups: neither aGvHD nor cGvHD; no cGvHD but acute GvHD before entry; cGvHD limited; cGvHD extensive without immunosuppression; cGvHD extensive with immunosuppression. Results: In the first biopsies the content of CD34+, vW+ microvessels and T-S cells were significantly higher in pts with cGvHD (group 3–5) than in those without cGvHD (group 1–2) (21,3 vs 8,2 p=0,03; 22,0 vs 9,2 p=0,002 respectively 106,2 vs 32,1 p=0,04). In the second biopsies these parameters were also increased in cGvHD: CD34+ (18,3 vs 11,2 p=0,02), vW+ (17,3 vs 9,0 p=0,08) microvessels and T-S cells (63,2 vs 37,8 p=0,27). The increased density of CD34+ and vW+ microvessels correlated with the number of T-S cells (p=0,05). As compared to normal controls we observed a significantly higher content of vW+ microvessels in all groups of transplanted pts (16,9 vs 4,2 p=0,03). In pts with cGvHD (group 3–5) CD34+ and vW+ microvessels were further increased (p=0,02 respectively p=0,002). At the time of the first biopsy the absolute T-S cell content in peripheral blood was moderately increased in group 5 (1124/ul) and minimally increased in group 2 (993/ul) (normal 270 – 880), whereas the overall T cell (CD3) content was normal in all groups. The percentage of activated T-S (HLA-DR+) cells was increased in all groups of transplanted pts (61,8% vs normal =33%; p=0,05). After two years T-S cells content was reduced in pts under immunosuppressive therapy (group 5) (1415 vs 900/ul; p=0.000) but remained increased over the norm. In group 4 T-S cell content was increased over the norm (800 vs 920/ul; p=0,043). In conclusion, sequential immunohistology and immunocytology analyses on bone marrow biopsies and peripheral blood provide evidence for the existence of a chronic graft-versus-host reaction of the bone marrow in pts with cGvHD. This is characterized by an increased content of CD34+ and vW+ microvessels and an increased content of T-S cells at least initially. However this reaction does not lead to a generalized hematopoietic insufficiency.

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Friedman, K. J. "Acute follicular graft-vs-host reaction. A distinct clinicopathologic presentation." Archives of Dermatology 124, no. 5 (May 1, 1988): 688–91. http://dx.doi.org/10.1001/archderm.124.5.688.

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7

Bril, Herman, Robbert Benner, and J. Wayne Streilein. "Graft-Vs.-Host Reactions: Mechanisms and Contemporary Theories." CRC Critical Reviews in Clinical Laboratory Sciences 22, no. 1 (January 1985): 43–95. http://dx.doi.org/10.1080/10408368509176815.

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Johnson, Bryon D., Emily E. Becker, and Robert L. Truitt. "Graft-vs.-host and graft-vs.-leukemia reactions after delayed infusions of donor T-subsets." Biology of Blood and Marrow Transplantation 5, no. 3 (June 1999): 123–32. http://dx.doi.org/10.1053/bbmt.1999.v5.pm10392958.

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9

Horn, Thomas D. "Lichen Planus—Like Histopathologic Characteristics in the Cutaneous Graft-vs-Host Reaction." Archives of Dermatology 133, no. 8 (August 1, 1997): 961. http://dx.doi.org/10.1001/archderm.1997.03890440027003.

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10

Kupers, Rudolf C., Tobias Suiter, Ernst Gleichmann, and Noel R. Rose. "The induction of organ-specific antibodies during the graft-vs. -host reaction." European Journal of Immunology 18, no. 1 (January 1988): 161–66. http://dx.doi.org/10.1002/eji.1830180124.

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11

Rees, Michael A., Andrew J. Butler, Hugh Davis, Eleanor Bolton, Derek G. J. Wight, David J. G. White, and Peter J. Friend. "GRAFT VS. HOST REACTION GENERATED BY PORCINE LIVERS PERFUSED WITH HUMAN BLOOD." Transplantation 67, no. 7 (April 1999): S222. http://dx.doi.org/10.1097/00007890-199904150-00885.

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12

Goltz, R. W. "The graft-vs-host reaction. An iatrogenic model for a number of skin disorders." Archives of Dermatology 124, no. 12 (December 1, 1988): 1849–50. http://dx.doi.org/10.1001/archderm.124.12.1849.

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13

Bauer, Diane J. "Histologic Comparison of Autologous Graft-vs-Host Reaction and Cutaneous Eruption of Lymphocyte Recovery." Archives of Dermatology 129, no. 7 (July 1, 1993): 855. http://dx.doi.org/10.1001/archderm.1993.01680280043007.

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14

Chisholm, Patricia M., Mark T. Drayson, Josephine H. Cox, and William L. Ford. "The effects of cyclosporin on lymphocyte activation in a systemic graft-vs.-host reaction." European Journal of Immunology 15, no. 10 (1985): 1054–59. http://dx.doi.org/10.1002/eji.1830151018.

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15

Bauer, D. J. "Histologic comparison of autologous graft-vs-host reaction and cutaneous eruption of lymphocyte recovery." Archives of Dermatology 129, no. 7 (July 1, 1993): 855–58. http://dx.doi.org/10.1001/archderm.129.7.855.

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16

Theofilopoulos, A. N., R. S. Balderas, Y. Gozes, M. T. Aguado, L. M. Hang, P. R. Morrow, and F. J. Dixon. "Association of lpr gene with graft-vs.-host disease-like syndrome." Journal of Experimental Medicine 162, no. 1 (July 1, 1985): 1–18. http://dx.doi.org/10.1084/jem.162.1.1.

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Hemopoietic cells have been reciprocally transferred between two lines of mice (MRL lpr/lpr and MRL +/+) that are congenic, differing only at the lpr (lymphoproliferation) and possibly closely linked genes. The lpr strain develops a significantly more severe and fast-paced lupus-like syndrome than +/+ strain, along with a substantially larger lymphoid mass. The results showed that: (a) hemopoietic cells of such mice were sufficient to induce the respective disease phenotypes in lethally irradiated syngeneic recipients; (b) cells of MRL +/+ mice maturing in an MRL lpr/lpr environment essentially retained the disease-producing characteristics of the donor, i.e., they induced late-life lupus without lymphadenopathy; but (c) MRL lpr/lpr cells transferred into irradiated MRL +/+ recipients unexpectedly failed to induce the early-life severe lupus and lymphoid hyperplasia of the donor, instead they caused a severe wasting syndrome resembling, in many respects, graft-vs.-host disease (GVHD). This GVHD-like syndrome developed after transfer of MRL lpr/lpr fetal liver, bone marrow, or spleen cells, and was not abrogated by elimination of T cells from the inocula. Thymectomy of the MRL +/+ recipients retarded, but did not prevent, the wasting disease. The unidirectional nature of this disease suggests that the lpr mutation conferred either a structural or regulatory defect that interfered, blocked, or altered the expression or structure of certain lymphocyte antigen(s). As a result, the MRL +/+ cells that did express this antigen(s) were recognized as foreign, and stimulated a graft-vs.-host reaction. These findings may allow definition of a new kind of rejection phenomenon caused by non-H-2 products, and may extend our understanding of the means by which the lpr gene adversely affects lymphocyte regulation and homeostasis.

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17

DE BONAPARTE, YOLANDA P., LUCAS L. COLOMBO, SLOBODANKA KLEIN, ISABEL S. D'ELIA, and MIRIAM DIAMENT. "Graft-vs-Host Reaction Induced by Para-aortic Lymph Nodes During Estrous and Diestrous Stages." American Journal of Reproductive Immunology and Microbiology 12, no. 2 (October 1986): 45–47. http://dx.doi.org/10.1111/j.1600-0897.1986.tb00061.x.

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18

Du, Jing, Ryan P. Flynn, Katelyn Paz, Ante Vulic, Tara M. Robinson, Katie E. Lineburg, Kelli P. A. Macdonald, et al. "Pirfenidone Reverses Murine Chronic Graft Versus Host Disease." Blood 128, no. 22 (December 2, 2016): 1158. http://dx.doi.org/10.1182/blood.v128.22.1158.1158.

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Abstract Allogeneic hematopoietic stem cell transplantation (aHSCT) is hampered by chronic graft-versus-host disease (cGVHD), which results in multi-organ fibrosis and loss of function. In particular, bronchiolitis obliterans (BO) and scleroderma resulting from fibrotic bronchiolar and cutaneous response, respectively, are two devastating outcomes for cGVHD patients. Fibrotic manifestations often are considered irreversible and progressive. Therefore, new therapies targeting fibrosis are urgently needed. Pirfenidone (5-methyl-1-phenyl-2- (1H)-pyridone) exhibits a well-documented anti-inflammatory and anti-fibrosis function in multiple pre-clinical models and is the first and only FDA-approved drug for idiopathic pulmonary fibrosis. For this study, Pirfenidone was synthesized as a crystalline solid and found to be pure both by melting point and NMR spectroscopy. We evaluated Pirfenidone's anti-fibrosis function in 2 pathophysiologically distinct cGVHD murine models: 1. a major mismatched multi-organ system model (C57BL/6 to B10.BR) that induces BO as a result of a cGVHD-induced germinal center (GC) reaction, antibody deposition and fibrosis in the lung; and 2. a minor antigen mismatched model (B10.D2 to BALB/c) in which severe scleroderma is the major disease manifestation. In the BO model, pulmonary function loss in cGVHD mice (as reflected by increased resistance, elastance and decreased compliance of the lung) was restored by Pirfenidone treatment (400mg/kg) during both the early (day28-56) (Fig A, representative of 3 experiments with 5-8 mice per group) and late stages (day56-84) of the disease. Pathologic changes in the lung, such as collagen deposition and narrowing of bronchioles, were significantly reduced by Pirfenidone. The size and frequency of GCs in the spleen, and the frequency of GC B cells (Fig B, representative of 2 experiments with 5-8 mice per group) and T follicular helper cells were all significantly reduced in Pirfenidone- treated groups. To determine whether GCs were directly affected by Pirfenidone, we evaluated Pirfenidone in C57BL/6 mice immunized with sheep red blood cells (SRBC) to induce GCs. Interestingly, Pirfenidone did not reduce the SRBC-induced GC reaction (Fig C) (comparable frequencies of splenic GC B cells, T follicular helper cells and serum IgG levels were seen between Pirfenidone and vehicle-treated groups). These results suggested that Pirfenidone suppresses the GC reaction through a cGVHD-specific mechanism, rather than through immune regulation. Mechanistically, Pirfenidone administration attenuated the sequestration of pro-fibrogenic F4/80+ macrophages (Fig D, representative of 2 experiments) and TGF-β (Fig E, representative of 2 experiments) production within the lung. These results have led us to elucidate a potential mechanism of cGVHD: antibody deposition in the lung results in the activation of macrophages and TGF-β that drive fibrotic change and tissue damage, resulting in the exposure of auto- and allo- antigens to the immune system that support and sustain pathologic GC reactions. In the B10.D2 to BALB/c sclerodermatous cGVHD model, Pirfenidone treatment (400mg/kg, day21-55) improved clinical signs of scleroderma and reduced macrophage infiltration in the skin (Fig F). In summary, this is the first study evaluating a commercially available anti-fibrosis drug on pathologically distinct pre-clinical cGVHD models. Our data suggests Prifenidone reversed cGVHD in the BO model and, to a lesser extent, in the scleroderma model. Thus, Pirfenidone is a novel therapeutic agent for treating cGVHD patients with fibrosis that have been typically refractory to therapies. A. Resistance of lungs was measured on day56 of transplantation; Elastance and compliance correlated with resistance but were not shown here. B. Flow cytometry analysis of GC B cells of no cGVHD vs cGVHD mice treated with Pirfenidone or vehicle; C. Flow cytometry analysis of GC B cells from SRBC-immunized mice treated with Pirfenidone or vehicle; D and E. Macrophage F4/80 and TGF-β quantification of day56 lungs of no cGVHD vs cGVHD mice treated as indicated; F. Skin GVHD scores were recorded on indicated dates of irradiated BALB/c mice transplanted with B10.D2 donor BM alone or with T cells and treated as indicated. Unpaired student T test was used for statistical analysis. ****:P<0.0001; ***: P<0.001; **: P<0.01; *: P<0.05; ns: not significant. Figure Figure. Disclosures No relevant conflicts of interest to declare.

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19

Pelot, Michele R., Denise A. Pearson, Kirsten Swenson, Guiling Zhao, Jessica Sachs, Yong-Guang Yang, and Megan Sykes. "Lymphohematopoietic graft-vs.-host reactions can be induced without graft-vs.-host disease in murine mixed chimeras established with a cyclophosphamide-based nonmyeloablative conditioning regimen." Biology of Blood and Marrow Transplantation 5, no. 3 (June 1999): 133–43. http://dx.doi.org/10.1053/bbmt.1999.v5.pm10392959.

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20

Rieker, Theresa, Josef Penninger, Karel Hala, Max D. Cooper, and Georg Wick. "In situ analyses of in ovo graft-vs.-host reaction induced by thymic nurse cell lymphocytes." European Journal of Immunology 23, no. 4 (April 1993): 904–10. http://dx.doi.org/10.1002/eji.1830230421.

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21

Pereira, Andre Domingues, Vinicius Campos de Molla, Ana Rita Da Fonseca, Yana Novis, Marcela Souza Pires, Ana Popi, and Celso Arrais-Rodrigues. "Ikaros Expression in the Graft Is Associated with Chronic Graft Versus Host Disease." Blood 136, Supplement 1 (November 5, 2020): 1–2. http://dx.doi.org/10.1182/blood-2020-138981.

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Introduction: Hematopoietic stem cell transplantation (HSCT) is the only potentially curative treatment for several diseases. Immune reconstitution post HSCT is a complex and extremely variable process. Ikaros transcription factor has an important role in hematopoiesis of several cell lines, especially in the lymphoid compartment. We hypothesized that Ikaros expression, both in the graft and in the recipient after transplant, might influence immune reconstitution and, consequently, the risk of opportunistic infections, relapse, and graft versus host disease (GVHD). Objectives: To correlate Ikaros expression both in the graft and in the recipient's peripheral blood (PB) after engraftment with the risk of GVHD after allogeneic HSCT outcomes. Patients and methods: 51 patients were included. Median age was 51 years (19-80), 53% of patients were male, and 57% of them had acute leukemia. Donor were haploidentical in 45% of cases, related identical in 29% and unrelated identical in 26%. Most patients (82%) received reduced-intensity conditioning regimens. Median follow-up was 20 months (10-40 months). Samples were collected from the graft and from the PB of the recipient 3 weeks after neutrophil recovery. Real time polymerase chain reaction (RT-PCR) was performed for analysis of absolute and relative Ikaros expression. Results: There was no association between Ikaros expression and the risk of acute GVHD, relapse or mortality. However, a significant association was observed in the risk of chronic GVHD. Cumulative incidence (CI) of chronic GVHD and of moderate / severe chronic GVHD (according to National Institute of Health - NIH classification) in two years were 49% and 28%, respectively. Higher Ikaros expression in the graft was associated with a significantly higher risk of moderate/severe chronic GVHD (54% vs. 15%, respectively, P=0.01). Higher Ikaros expression in the recipient's PB after engraftment was also associated with a significantly higher risk of moderate/severe chronic GVHD (65% vs. 11%, respectively, P=0.01). Conclusions: Ikaros expression in the graft and in the PB of the recipient after transplant seems to be correlated with a higher risk of moderate/severe chronic GVHD and might be evaluated in larger and prospective trials as a potential biomarker. Disclosures No relevant conflicts of interest to declare.

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22

Maeda, Yoshinobu, Pavan Reddy, Chen Liu, D. Keith Bishop, and James L. M. Ferrara. "Host γd T cells Exacerbate Experimental Acute Graft-Versus-Host Disease through Activation of Host Antigen Presenting Cells." Blood 104, no. 11 (November 16, 2004): 3045. http://dx.doi.org/10.1182/blood.v104.11.3045.3045.

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Abstract Large numbers of T cells bearing γd T cell receptors are present in graft-versus-host disease (GVHD) target tissues. We investigated the potential role of host γd T cells during acute GVHD in a well-characterized GVHD model following full intensity conditioning (11 Gy TBI). BM and spleen T cells from BALB/c (H2d) donors were transplanted into wild type (wt) B6, aß T cell deficient B6 (aß −/−) or γd T cell deficient B6 (γd −/−) hosts. γd −/− hosts demonstrated significantly better day 35 survival (85%) than wt (40%) or aß−/− hosts (18%) (P<0.05). Reconstitution of γd −/− B6 hosts with B6 type γd T cells 24 hr prior to BMT restored lethal GVHD (50 % day 35 survival). In vivo, γd −/− B6 hosts demonstrated at least a five fold reduction in donor T cell expansion and cytokine production. In vitro, T cells proliferated less when co-cultured with allogeneic γd −/− dendritic cells (DCs) than with wt DCs (40,127 ± 1634 vs. 72,503 ± 1296, P<0.05). BM-derived DCs cultured with γd T cells caused greater proliferation of allogeneic T cells than DCs cultured with aß T cells (15.1 ± 21 x 104 vs. 5.1 ± 1.2 x 104, P<0.05). We next tested the effect of γd T cells on host DCs in vivo using a model system in which only the DCs injected prior to BMT expressed the alloantigen that stimulated the GVHD reaction. MHC Class II −/− B6 mice that had been depleted of γd T cells were given 11 Gy TBI and injected one day prior to BMT with B6 DCs that had been co-cultured either with γd T cells or with medium. On day 0 both groups of recipient mice were injected with BM plus splenic T cells from allogeneic bm12 donors. On day +5, CD4+ donor T cells expanded four times more in recipients of DCs co-cultured with γd T cells than in recipients of control DCs and serum levels of TNF-a were significantly higher (36.7 + 6.8 vs. 21.3 + 3.7 pg/ml, P<0.05). Together these data demonstrate that γd T cells amplify the stimulatory function of host DCs and increase the severity of GVHD, suggesting that a new therapeutic target for the prevention of the major BMT toxicity.

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23

Mann, Steven, and Matthew Kuhar. "284 Hypertrophic Variant of Cutaneous Graft Vs Host Disease Clinically Mimicking a Drug Reaction: A Case Report." American Journal of Clinical Pathology 149, suppl_1 (January 2018): S120—S121. http://dx.doi.org/10.1093/ajcp/aqx123.283.

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24

Truitt, Robert L., Bryon D. Johnson, Nancy Eisenberg, and Cathleen McCabe. "USE OF T-CELL SPECIFIC MONOCLONAL ANTIBODIES TO MANIPULATE GRAFT-VS-HOST (GVH) and GRAFT-VS-LEUKEMIA (GVL) REACTIONS AFTER BMT IN MICE." Journal of Immunotherapy 14, no. 4 (November 1993): 369. http://dx.doi.org/10.1097/00002371-199311000-00065.

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25

Ma, Hui-Hui, Jing Fu, Suzanne Lentzsch, and Markus Y. Mapara. "Role of MMP-13 in Graft-Versus-Host Disease." Blood 134, Supplement_1 (November 13, 2019): 1928. http://dx.doi.org/10.1182/blood-2019-127703.

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Matrix metalloproteinases (MMPs) have been initially recognized for their role in degradation of extracellular matrix (ECM) and collagen remodeling. However, MMPs have been shown to play a crucial role in inflammation, tumor cell invasion, adaptive and innate immunity. Acute and chronic Graft versus Host Disease (GVHD) are characterized by distinctive histopathological features involving tissue infiltration with donor cells, tissue damage and remodeling. We therefore hypothesized that GVHD-associated organ damage may involve MMPs. We have now identified a novel immunomodulatory function for MMP-13 (alternatively called collagenase-3)and have uncovered a previously unknown role of MMP-13 in regulating GVHD.To address the function of MMP-13 in GVHD we first assesed the effect of MMP-13 on alloresponses in vitro. Using fully Major Histocompatibility Complex (MHC)-mismatched standard mixed lymphocyte reaction we demonstated that antigen presentig cells (APC) from B6.MMP-13-/-(H2b) mice led to signifcantly enhanced antigen-driven activation and proliferation of Carboxyfluorescein succinimidyl ester (CFSE)-labeled Balb/c responder splenocytes. Thus, MMP-13 deficiency in either splenocytes or bone marrow-derived dendritic cells used as stimulators resulted in enhanced proliferation, activation and IFN-gproduction in the allo-reactive lymphocyte responders. Similarly, exogenous MMP13 reduced proliferation of responder T cells as determined tested by CFSEdilution (CFSEloof CD4+T cells from 62.3% decreased to 40.6%, CFSEloof CD8+T cells from 74.1% down to 47.9%). We next assessed the impact of MMP-13 in vivousing fully MHC-mismatched rodent acute GVHD models. To study the role of host-derived MMP-13 we induced GVHD in B6.MMP-13-/-or B6.WT recipient mice following lethal TBI (1075 rad) using splenic T cells from Balb/cdonors. We observed signifcantly accelerated GVHD-related mortality (Median Survival Time 7 vs. 47 days post-transplant, p<0.05) in MMP-13-deficient recipients. Most importantly, donor T cells expanded more vigorously in the secondary lymphoid organs (Spleen and mesenteric lymphnoodes) of MMP13-/-compared to wildtype recipient mice (e.g. spleen: absolute donor CD4+Tcells 1.5x104± 7.3 x 103 (WT) vs. 5.83 x104±1.65 x104[MMP-13-/-] and CD8+5.5 x104± 3.8 x104(WT) vs 3.4 x105±1.4 x105[MMP-13-/-], p<0.01). Enhanced donor lymphocyte expansion was further confirmed by bioluminescence imaging. To further delineate the underlying mechanisms, we analyzed the effects of MMP-13deficiency and exogenous MMP-13 on maturation of mouse bone marrow derived-dendritic cells (BMDC) and macrophages in vitro. We noted decreased expression of inhibitory molecules PD-L1 and PD-1H on GM-CSF/LPS cultured BMDC. Similarly, bone marrow-derived MMP-13-/-macrophages also showed reduced PD-L1 and PD-1H expression upon LPS stimulation when compared to their WT counterparts. In summary we posit that recipient myeloid cell-derived MMP-13 mitigates GVHD and limits donor T cell expansion. Further studies are warranted to determine how MMP-13 suppresses expansion of donor T cells and impacts Graft-versus-Leukemia responses. Disclosures Lentzsch: Caelum Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Abbvie: Consultancy; Clinical Care Options: Speakers Bureau; Sanofi: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Honoraria; International Myeloma Foundation: Honoraria; Karyopharm: Research Funding; Columbia University: Patents & Royalties: 11-1F4mAb as anti-amyloid strategy; Proclara: Consultancy; BMS: Consultancy.

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Kawakami, Tamihiro, Madoka Takimoto, and Yoshinao Soma. "Late appearance of an acute graft-vs.-host disease reaction subsequent to a graft-vs.-tumor effect induced by bone marrow transplantation in a refractory ovarian carcinoma patient." International Journal of Dermatology 49, no. 3 (March 2010): 308–10. http://dx.doi.org/10.1111/j.1365-4632.2009.04261.x.

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27

Lindemann, Monika, Hellmut D. Ottinger, Ahmet H. Elmaagacli, Rudolf Trenschel, Vera Rebmann, Dietrich W. Beelen, and Hans Grosse-Wilde. "Donor cell reaction to OKT3 as predictor of chronic graft-vs-host disease in hematopoietic stem cell recipients." Experimental Hematology 34, no. 12 (December 2006): 1753–58. http://dx.doi.org/10.1016/j.exphem.2006.08.003.

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28

Rolink, A. G., T. Radaszkiewicz, and F. Melchers. "The autoantigen-binding B cell repertoires of normal and of chronically graft-versus-host-diseased mice." Journal of Experimental Medicine 165, no. 6 (June 1, 1987): 1675–87. http://dx.doi.org/10.1084/jem.165.6.1675.

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A quantitative analysis of the frequencies of autoantibody-producing B cells in GVHD and in normal mice has been undertaken by generating collections of hybridomas of activated B cells. These hybridomas secreted sufficient quantities of Ig to allow binding analyses on a panel of autoantigens. B cells have been activated in a variety of ways. In vivo they were activated by injection of alloreactive T cells of one parent, leading to GVHD by a foreign antigen, sheep erythrocytes, in a secondary response, or by the polyclonal activator LPS. B cells from an experimentally unstimulated animal were used for an analysis of the normal background. In vitro B cells were activated by alloreactive T cells or by LPS. The frequencies of hybridomas and, therefore, of activated B cells producing autoantibodies to DNA or to kidney were not significantly different in mice activated by a graft-vs.-host T cell response as compared with B cell populations activated by any of the other procedures. They were found to compose 7.1-17.1% of the total repertoire of activated B cells. Moreover, the frequencies of autoantibody-producing activated B cells does not change with time after induction of the graft-vs.-host reaction. The pattern and frequencies of autoantigen-binding specificities to cytoskeleton, smooth muscle, nuclei, mitochondria, and DNA were not found to be different in any of the groups of hybridomas. The single notable exception, found in GVHD mice, were hybridomas producing autoantibodies to kidney proximal tubular brush border. These results allow the conclusion that autoantigen-binding B cells exist in an activated state in GVHD mice, as well as in mice activated by a foreign antigen or by a polyclonal activator, in B cell populations activated in vitro either by alloreactive T cells or by a polyclonal activator, and even in the background of experimentally unstimulated animals. T cell-mediated graft-vs.-host activation, in large part, does not lead to a selective expansion of autoantigen-binding B cells. The main difference between the graft-vs.-host-activated B cell repertoire and all others is that approximately 90% of teh autoantibodies were of the IgG class, whereas al autoantibodies found in the other groups were IgM.

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Lehmann, P. V., G. Schumm, D. Moon, U. Hurtenbach, F. Falcioni, S. Muller, and Z. A. Nagy. "Acute lethal graft-versus-host reaction induced by major histocompatibility complex class II-reactive T helper cell clones." Journal of Experimental Medicine 171, no. 5 (May 1, 1990): 1485–96. http://dx.doi.org/10.1084/jem.171.5.1485.

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T cell clones isolated from class II MHC-disparate MLR combinations, and specific for I-Ak and I-Ek molecules, respectively, are shown to induce acute lethal graft-vs-host disease in unirradiated recipients. Cytolytic and noncytolytic clones are equally efficient in this respect. The lethal disease is dependent on recognition of the stimulatory class II molecules in the host. The clones home to lungs and liver, and become activated in these organs as demonstrated by an in vivo thymidine incorporation assay. After activation, a severe vascular leak syndrome develops causing death of the recipients within 5 d after the injection of 5 x 10(6) to 10(7) cloned cells. The disease develops without the participation of secondary host-derived inflammatory mechanisms, such as mast cell degranulation, complement activation, and the release of prostaglandins, oxygen radicals, or proteolytic enzymes. The results raise the possibility that Th cells can directly influence vascular permeability, and control, thereby, the acute inflammatory reaction of blood vessels.

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Rozendaal, Lawrence, Steven T. Pals, Marco Schilham, Cornelis J. M. Melief, and Ernst Gleichmann. "Allosuppression of B cellsin vitro by graft-vs.-host reaction-derived T cells is caused by cytotoxic T lymphocytes." European Journal of Immunology 19, no. 9 (September 1989): 1669–75. http://dx.doi.org/10.1002/eji.1830190922.

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Piguet, P. F., G. E. Grau, B. Allet, and P. Vassalli. "Tumor necrosis factor/cachectin is an effector of skin and gut lesions of the acute phase of graft-vs.-host disease." Journal of Experimental Medicine 166, no. 5 (November 1, 1987): 1280–89. http://dx.doi.org/10.1084/jem.166.5.1280.

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Lethally irradiated mice were injected with semiallogeneic, T-depleted bone marrow cells and an amount of peripheral T lymphocytes sufficient to induce graft-vs.-host disease (GVHD) becoming apparent on the second week after the graft and leading to an increasing mortality rate within the following weeks (greater than 90% mortality within 80 d). Mice receiving bone marrow cells alone had no GVHD and were used as controls. Beginning on day 8, mice with GVHD were injected weekly with 2 mg of either rabbit anti-mouse recombinant tumor necrosis factor/cachectin (TNF-alpha) IgG, or normal rabbit IgG. On the 16-18th d, mice were killed to examine the skin and intestinal lesions of the acute phase of GVHD. The anti-TNF treatment resulted in an almost complete prevention of the severe lesions seen in the mice treated with normal rabbit IgG, i.e., the skin epidermal cell necrosis, foci of lichenoid hyperplastic reactions, and loss of the hypodermic fat; in the gut dilatation with marked flattening of the villi and elevation of the crypts, with increased numbers of mitoses and isolated crypt cell necrosis. In addition to preventing these acute lesions, anti-TNF treatment resulted in a significantly decreased mortality (approximately 70% survival at 80 d). These results suggest that during acute GVHD, the activation of grafted lymphocytes leads to a local release of TNF in the cutaneous and intestinal mucosae, which induces epithelial cell alterations and increases the inflammatory reaction.

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Zeng, Ke, Hongbing Ma, Uday Popat, Yago Nieto, Stefan O. Ciurea, Amanda L. Olson, Mi-Ae Lyu, et al. "Allogeneic Cord Blood Regulatory T Cells Can Prevent Graft Vs. Host Disease and Preserve Graft Vs Leukemia Effect: Update on Phase I/II Clinical Trial." Blood 134, Supplement_1 (November 13, 2019): 4547. http://dx.doi.org/10.1182/blood-2019-127726.

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Previously, we presented the results of a phase I trial of using cord blood (CB) derived regulatory T cells (Tregs) at a dose of 1x106 cells/kg in the prevention of graft vs. host disease (GVHD) in five patients undergoing allogeneic stem cell transplant (SCT). We now present an update of those patients and also the outcome of a single patient treated with CB Tregs at higher dose of 1x107 cells/kg. At the last follow up of 3.5 years, 5 of 6 patients are alive, in complete remission, without GVHD and off immune-suppression (table 1). One patient died of head injury at day 45 post-transplant without GVHD. None of the patients relapsed in spite of having high risk disease including Flt3+ acute myeloid leukemia (AML) (pt#1); refractory mycosis fungoides/ sezary syndrome (pt#2); relapsed refractory multiple myeloma including two autologous SCT (pt#3); myeloid sarcoma (pt#4); AML with complex cytogenetics (pt#5). Specifically, the sixth patient (treated at CB Tregs cell dose of 1x107 cells/kg) had a diagnosis of lymphoid blast crisis of chronic myelogenous leukemia (CML) and underwent allogeneic peripheral blood (PB) matched unrelated donor (MUD) SCT in second chronic phase with the conditioning regimen of fludarabine (40 mg/m2/d on day -5 to -2) and melphalan (140mg/m2 on day -2) and received CB Tregs at a dose of 1x107 cells/kg on day -1. The CB Tregs were manufactured at the MD Anderson GMP facility. Tregs were isolated from 4 out of 6 HLA matched CB unit with a post-thaw total nucleated cell (TNC) count of 1295 x 106 cells with 90% recovery. Enrichment of CD25+ Treg cells was accomplished with directly conjugated anti-CD25 magnetic microbeads and the LS column (Miltenyl) based selection. After selection, the total no. of isolated CB Tregs was 17.6 x 106 cells. These cells were ex-vivo expanded in culture for a total of 14 days in the continued presence of CD3/28 microbeads and interleukin-2. On the day of harvest, a total of 1359 x 106 Treg cells were generated with 96% viability. Based on patient's weight of 67 kg, a total of 67x107 CB Treg cells were infused. The expanded CB Tregs were also evaluated for functionality by using an in vitro suppression assay, where the stimulated CD4+ Tcon cells stained with CellTrace Violet and Tregs were added into a 96-well plate at a 1:1 and 1:2 ratio and incubated for three days at 37oC. As shown in figure 1A, the clinically manufactured CB Tregs were functional and exerted 98% suppression of the proliferating Tcon cells. Subsequently, the patient received PB MUD graft on day 0. The graft had a TNC count of 1900 x106 cells where the CD3+ T cells were at a dose of 400 x106 cells/kg resulting in a Treg: Tcon ratio of 1:40, a significantly lower number of Tregs compared to other published clinical trials using Treg prophylaxis for GVHD. There was no infusion reaction related to the CB Treg infusion, the patient engrafted on day+12 with 100% donor chimerism on day +30. The patient did not develop any grade II-IV GVHD and was off immune suppression by +6 months. At the time of last follow up of 2 years and 4 months, the patient remains alive, in complete remission and without GVHD. We compared the inflammatory cytokine profile as well as GVHD biomarkers for pt #6 to the rest of the five patients who received the lower dose of CB Tregs at 1x106 cells/kg (with up to 400 times Tcon cells in the graft), where 4 patients had developed acute GVHD. The inflammatory biomarkers of IL-6 (fig 1B) and IL-8 (fig 1C) for pt#6 were low to undetectable compared to the other patients. Similarly, the GVHD biomarkers of ST2 (fig 1D); MIG/ CXCL9 (fig 1E) and follistatin (fig 1F) were also low to undetectable in pt#6 compared to the rest. At the time of last follow up, all patients had resolved acute GVHD and were off-immune suppression and in complete remission. Based on these data, we conclude that CB Treg dose of 1x107 cells/kg may be able to prevent GVHD without alleviating the graft vs leukemia effect. Disclosures Popat: Jazz: Consultancy; Incyte: Research Funding; Bayer: Research Funding. Nieto:Affimed: Consultancy; Astra-Zeneca: Research Funding; Novartis: Research Funding; Affimed: Research Funding. Ciurea:Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees, Other: stock holder; MolMed: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Miltenyi: Research Funding. Qazilbash:Amgen: Consultancy, Other: Advisory Board; Genzyme: Other: Speaker; Bioclinical: Consultancy; Autolus: Consultancy. Champlin:Actinium: Consultancy; Johnson and Johnson: Consultancy; Sanofi-Genzyme: Research Funding. Parmar:Cellenkos Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Verner, Jan, Jitka Kabathova, Boris Tichy, Zbynek Zdrahal, Alexandra Tomancova, Yvona Brychtova, Michael Doubek, et al. "Gene-Expression Profiling of Graft-Versus-Host Disease by Oligonucleotide Microarrays." Blood 114, no. 22 (November 20, 2009): 4645. http://dx.doi.org/10.1182/blood.v114.22.4645.4645.

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Abstract Abstract 4645 Background Graft-versus-host disease (GvHD) is the life-threatening complication of allogeneic hematopoietic stem cells transplantation (allo-HSCT). GvHD is mediated by an immune reaction of donor T lymphocytes against recipient's tissues/cells. Acute GvHD (aGvHD) appearing within the first 100 days post transplantation is the most frequent cause of recipient's death and characterization of biomarkers for early prediction of aGvHD or resistance to corticoid treatment could be of great clinical relevance. Biomarker panels for aGvHD are currently extensively studied by proteomic and gene expression based approaches but so far very few markers were described and validated (Kaiser et al., 2004; Baron et al., 2007; Weissinger et al., 2007; Paczesny et al., 2009). Aim In this study, we performed microarray gene expression analysis (whole genome Human OneArray, Phalanx) of 43 leukemia patients who received allo-HSCT. Mononuclear cells isolated from peripheral blood samples (Ficoll-Paque) were collected at i) 14 days before transplantation, ii) 20 and iii) 30 days after transplantation and iv) at the time of aGvHD manifestation. We also performed gene-expression analysis for corticoid-resistant vs. corticoid-sensitive aGvHD cases. Results The SAM supervised analysis of samples collected at day +20 post transplantation revealed set of differentially expressed genes between groups of patients that developed aGvHD vs. aGvHD-free recipients. Among others, genes CASP1 (encoding caspase 1, protein implicated in apoptosis), HLA-DRA (member of MHC class II family) and LILRA3 (leukocyte immunoglobulin-like receptor, subfamily A member 3) showed the highest difference in expression. Gene expression with regard to corticoid response was analyzed at the time of first aGvHD manifestation. The SAM supervised analysis of gene expression between patients with corticoid-sensitive aGvHD (n=10) or aGvHD resistant to corticoid treatment (n=4) revealed a set of significantly differentially expressed genes including NR4A2 (nuclear receptor subfamily 4; member of the steroid-thyroid hormone-retinoid receptor superfamily), DEDD2 (death effector domain containing 2), TREM1 (triggering receptor expressed on myeloid cells 1), TPK1 (thiamin pyrophosphokinase 1) and HBEGF (heparin-binding EGF-like growth factor). Conclusion Oligonucleotide microarrays proved to be a useful tool for expression studies of hematological malignancies and our work shows that they may help to identify markers for early diagnosis/treatment of aGvHD. The limited patients' cohort and their heterogeneity complicate such studies. Our future effort will be focused on experimental group extension, cohort uniformity and verification of the obtained data. This work is supported by the grant NS9683-4/2008 provided by the IGA MH of the Czech Republic, and MSM0021622430 provided by MEYS of Czech Republic Disclosures: No relevant conflicts of interest to declare.

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Harper, S. E., J. R. Roubinian, and W. E. Seaman. "Regulation of autoimmunity and donor cell engraftment by recipient Lyt-2+ cells during the graft-versus-host reaction." Journal of Experimental Medicine 166, no. 3 (September 1, 1987): 657–67. http://dx.doi.org/10.1084/jem.166.3.657.

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When lymphocytes from DBA/2 mice are transferred to (C57BL X DBA/2)F1 (BDF1) mice, the ensuing graft-vs.-host reaction (GVHR) causes an autoimmune illness resembling human SLE. To examine the role of recipient T cells in this process, BDF1 mice were depleted of L3T4+ or Lyt-2+ cells by thymectomy followed by treatment with mAbs to L3T4 or Lyt-2. This produced sustained depletion of these T cell subsets. Subsequent grafting with parental DBA/2 lymphocytes produced autoimmune disease in mice depleted of L3T4+ cells and controls but not in mice depleted of Lyt-2+ cells. Analysis of blood lymphocytes 4 wk after donor cell transfer demonstrated that BDF1 recipients depleted of Lyt-2+ cells were virtually repopulated with donor T lymphocytes, compared with less than or equal to 35% donor cell engraftment in all other groups. Thus, recipient Lyt-2+ cells influence both host cell engraftment and autoimmunity during the parent-into-F1 GVHR.

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Eckert, R., J. Maciejewski, H. Weber, H. D. Volk, W. Diezel, K. Forner, and R. v. Baehr. "Splenopentin (DAc-SP5) - Influence on Engraftment and Graft-vs-Host Reaction after Non-H-2 Bone Marrow Transplantation in Mice." Experimental and Clinical Endocrinology & Diabetes 96, no. 06 (July 16, 2009): 307–13. http://dx.doi.org/10.1055/s-0029-1211024.

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Guéry, Jean-Charles, Hervé Tournade, Lucette Pelletier, Elvira Druet, and Philippe Druet. "Rat anti-glomerular basement membrane antibodies in toxin-induced autoimmunity and in chronic graft-vs.-host reaction share recurrent idiotypes." European Journal of Immunology 20, no. 1 (January 1990): 101–5. http://dx.doi.org/10.1002/eji.1830200115.

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Fu, Chengcheng, Shiqiang Qu, Wu Depei, Aining Sun, Zhengming Jin, Huiying Qiu, Weirong Chang, et al. "Effect Analysis of Antithymocyte Globulin Versus Antilymphocyte Globulin for Graft Versus Host Disease Prophylaxis in 102 Cases of Allogeneic Hematopoitic Stem Cell." Blood 114, no. 22 (November 20, 2009): 4325. http://dx.doi.org/10.1182/blood.v114.22.4325.4325.

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Abstract Abstract 4325 Objective Retrospective analysis the therapeutic and side effect of the rabbit antithymocyte (ATG) versus swine ALG within the preparative regimen of allogeneic hematopoietic transplantation (allo-HSCT) for graft versus host disease (GVHD) prophylaxis. Methods Totally 102 patients who had admitted to our hospital and been treated by allo-HSCT with the preparative regimen including ATG/ALG were followed up from June 2002 to June 2008. They were divided into ATG group and ALG group. The allergic reaction, effect of GVHD prophylaxis, transplantation related mortality (TRM), disease free survival (DFS) and relapse rate (RR) of these groups were retrospectively analyzed. Cumulative rate were analyzed by the Kaplan-Meier method and the factors associated with the III?‘‡W AGVHD were analyzed with the COX regression model. Results ALG group had more allergic reaction than ATG, but ATG group had more bacteremia and cytomegalovirus (CMV) antigenaemia. The haematopoiesis reconstitution was comparable in two groups. The III?‘‡W AGVHD, two-year TRM,DFS and RR were (40% vs 21%,p=0.028),(54% vs 29%,p=0.039),(41% vs 53%,p=0.174),(10% vs 24%,p=0.306),respectively in ATG/ALG groups. In multivariate analysis,10mg/kg ATG as a protective variable to III?‘‡W AGVHD occurrence(RR=0.53 ;95%CI, 0.38?‘0.71),The CD3+ cell counts of administration was associated with an increased risk for III?‘‡W GVHD(RR=4.43 ;95%CI, 3.87?‘4.95). Conclusion 10mg/kg ATG significantly decreased the risks for III?‘‡W AGVHD and extensive chronic GVHD(ecGVHD); The lethal infections became the most important cause of death in the ATG group, but the increased risk for infection did not neutralize the reduction of TRM induced by the decrease of severe GVHD. Disclosures: No relevant conflicts of interest to declare.

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Chen, Bao-An, Wei-Min Dong, Jia-Hua Ding, Xiao-Jing Deng, Gang Zhao, Chong Gao, Yun-Yu Sun, et al. "Experimental Study on Prevention of GVHD by Selective Elimination of Alloreactive Donor Lymphocytes Prior to Stem Cell Transplantation." Blood 108, no. 11 (November 16, 2006): 5161. http://dx.doi.org/10.1182/blood.v108.11.5161.5161.

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Abstract Objective: To investigate a new concept aiming for induction of graft-vs-leukemia (GVL) effect prior to stem cell transplantation (SCT). Mismatched lymphocytes given pre-SCT will be followed by selective elimination of alloreactive donor lymphocytes, thus avoiding lethal graft-vs-host disease (GVHD). Methods: Female (BALB/c×C57BL/6)F1 mice (H-2d/b) as recipients received sublethal total body irradiation (TBI) of 4 Gy (60Coγ-ray) on day 0 followed by being inoculated with 0.5×107 P388D1 leukemia cell line on day 1, injection of 1.5×107 allogeneic splenocytes supplied by C57BL/6 male mice(H-2b)for induction of GVHD, intraperitoneally injection of cyclophosphamide (Cy) (200 mg/kg) or TBI (9 Gy) were given on day 7, one day later, treated mice were rescued with 3×107 syngeneic bone marrow cells supplied by (BALB/c×C57BL/6)F1 male mice(H-2d/b). Recipients were observed clinical manifestation, phenotype, re-establishment of haematogenesis, histopathologic changes of internal organs suffered from GVHD and investigated donor chimerism by the semi-quantitate analyses of polymerase chain reaction (PCR). Data was analyzed by SPSS 10.0 software and expressed as mean ± SD. Results: Recipients had no occurrence of leukemia and GVHD by selective elimination of alloreactive donor lymphocytes by Cy and TBI, survived more than 210 days, to become complete-donor chimerism on day +21. The ratio of chimerism descended subsequently, but still displayed mixed-chimerism on day +90. Control mice died of evident GVHD, leukemia or other death-related-transplantation within 20 to 36 days(p<0.01). Attempting to induce GVL effects by mismatched lymphocytes given before stem cell transplantation followed by selective elimination of alloreactive donor lymphocytes, thus avoiding graft-vs-host disease (GVHD) was feasible.

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Volk, Hans-Dieter, Stefan Brocke, Hisao Osawa, and Tibor Diamantstein. "Suppression of the local graft-vs.-host reaction in ratsby treatment with a monoclonal antibody specific for the interleukin 2 receptor." European Journal of Immunology 16, no. 10 (1986): 1309–12. http://dx.doi.org/10.1002/eji.1830161020.

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Okuyama, Harue, Seiichi Kobayashi, Hiroyuki Harada, Yoshinori Kawaguchi, and Isao Sekikawa. "Treatment of donor cells with l-leucyl-l-leucine methyl ester prevents induction of graft-vs-host-like reaction in [] chimera." Clinical Immunology and Immunopathology 54, no. 1 (January 1990): 26–39. http://dx.doi.org/10.1016/0090-1229(90)90003-9.

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Feinman, Rena, Iriana Colorado, Keyi Wang, Eugenia Dziopa, Michael A. Flynn, Kevin Peters, Andrew L. Pecora, and Robert Korngold. "Inhibition of HIF Prolyl Hydroxylases Mitigate Gut Graft-Versus-Host Disease." Blood 128, no. 22 (December 2, 2016): 3349. http://dx.doi.org/10.1182/blood.v128.22.3349.3349.

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Abstract The etiology of graft-versus-host disease (GVHD) is rooted in the alloreactive response of donor T cells present in the hematopoietic graft resulting in the destruction of the patient's tissues, particularly the gastrointestinal tract. Gut GVHD affects up to 50% of patients, is a leading cause of death, and has overlapping features with inflammatory bowel disease (IBD). Increased gut permeability, alterations of the gut microbiome and intestinal stem cell niche damage predispose the gut to the local and systemic effects of GVHD, and is exacerbated by the inability of the gut to adequately regenerate. Severe shifts in metabolism and reduced oxygen (O2) availability in the inflamed gut are major underlying factors in the pathogenesis of IBD. Two related transcription factors, hypoxia-inducible factor-1 (HIF-1) and HIF-2, originally discovered as master regulators of the adaptive response to hypoxia, have been recently shown to be gut protective and promote mucosal healing in response to injury. Using a MHC mismatched B10.BR→B6 bone marrow transplant (BMT) model, we previously found that loss of intestinal epithelial (IE) HIF-1α or HIF-2α worsened survival compared to wild-type mice and exhibited increased GVHD-induced-histopathology. Thus, we hypothesized that HIF-1 and HIF-2 protects and repairs the gut from conditioning and GVHD-related damage. HIF-1 and HIF-2 are heterodimers consisting of an O2-labile HIF-1α or HIF-2α subunit respectively and a constitutively expressed HIF-1β subunit. The recent discovery that iron-dependent prolyl hydroxylase enzymes (PHD1-3) can trigger the O2-dependent proteasomal degradation of the HIF-1α subunit has led to the development of pan-PHD inhibitors (PHDi) that activate HIF-1 and HIF-2. PHDi such as dimethyloxallyl glycine (DMOG) and AKB-4924 have been shown to attenuate colitis and radiation-induced gut toxicity in animal models. We thus sought to determine whether PHDi could also ameliorate gut GVHD in the B10.BR→B6 BMT model. B6 mice were lethally irradiated (10Gy, split dose) and transplanted with 5x106 T-cell depleted bone marrow (BM) cells from B10.BR donors with 2x106 enriched T cells from spleens and lymph nodes (BM+T). B6 mice transplanted with only T cell depleted BM cells served as our non-GVHD control group. B6 mice were treated with AKB-4924 (AKB, 5 mg/kg) or vehicle (β-cyclodextrin) via intraperitoneal delivery, beginning 1 day prior to BMT and for 6 consecutive days post-BMT. Treatment with AKB prevented significant weight loss, compared to vehicle-treated mice, 7 days post-BMT (n=6, p<.002). Histopathologic assessment of the jejunum of AKB treated mice after 7 days revealed fewer apoptotic cells and an increased number of Paneth and goblet cells compared to vehicle-treated mice. Immunohistochemical staining for lysozyme showed that AKB prevented GVHD-induced Paneth cell ablation compared to their vehicle BMT counterpart (2.8 Lyz+ cells/crypt vs 0.84 Lyz+ cells/crypt, n=3, p<.003). Additionally, we evaluated the effects of AKB on T cell alloreactivity. In mixed lymphocyte reaction Elispot assays, AKB and DMOG, reduced the alloreactive interferon (IFN)-γ response in B10.BR anti-B6 (p<0.001) and MHC matched, minor antigen-mismatched B6 anti-BALB.B cultures (p<0.05). Furthermore, AKB reduced the number of gut-infiltrating CD3+ T cells compared to vehicle-treated BMT mice (39 vs 155.1 CD3+ cells/high-power field, n=3, p<.0003). Our results provide the framework to validate the therapeutic potential of PHDi as an intestinal regenerative strategy in mitigating GVHD. Disclosures Peters: Aerpio Therapeutics: Employment, Equity Ownership.

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Xu, Jinhuan, and Yicheng Zhang. "Increased Plasma Indoleamine 2,3-Dioxygenase Activity Correlates with the Severity of Acute Graft-Versus-Host Disease." Blood 118, no. 21 (November 18, 2011): 1985. http://dx.doi.org/10.1182/blood.v118.21.1985.1985.

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Abstract Abstract 1985 Indoleamine 2,3-dioxygenase (IDO) is a rate-limiting enzyme for the tryptophan catabolism, which plays an important role in the induction of immune tolerance. To evaluate the expression level of IDO in the patients receiving hematopoietic stem cell transplantation (HSCT) and to identify the possible correlation between IDO activity and acute graft-versus-host disease (aGVHD), we collected blood samples from 96 patients before and after HSCT and 10 healthy volunteers served as controls. The expression of IDO mRNA was detected by reverse transcription-polymerase chain reaction (RT-PCR) in peripheral blood mononuclear cells of the patients and healthy controls. Reverse-phase high-performance liquid chromatography (HPLC) was performed to analyze the level of kynurenine (Kyn) and tryptophan (Trp) in plasma. The IDO activity was calculated as the ratio of kyn to trp. Plasma IFNgama was measured by standard ELISA. RT-PCR showed that IDO mRNA was detected in 65 of 85(65/85, 76.5%) patients with aGVHD; in patients without aGVHD, only 1 of them express IDO mRNA (1/11, 9.1%); none of 10 healthy volunteers was positive for the IDO expression. The plasma IDO activity was much higher in aGVHD group than those without aGVHD(4.49¡À0.46 vs. 1.69¡À0.9, respectively; p < 0.0001) or the healthy controls(4.49¡À0.46 vs. 1.77¡À0.22, respectively; p < 0.0001). Patients with severe aGVHD (grade III/IV) had significantly higher IDO activity than those with mild aGVHD (grade I/II) (6.74¡À0.58 vs. 2.17¡À0.79, respectively; p < 0.0001). IDO activity was decreased following effective treatment of aGVHD, while fluctuation of plasma IDO was also observed upon the recurrence of aGVHD. The plasma IDO activity was correlated with the IFNgama level(r=0.8816). Conclusion: The IDO mRNA was expressed in blood mononuclear cells from patients with aGVHD. The plasma IDO activity was elevated in aGVHD and correlated with severity of aGVHD. In combination with plasma IFNgama, IDO may serve as a potential biomarker for the diagnosis and evaluation of aGVHD following HSCT; intervention of IDO pathway may also provide an alternative way to overcome the steroids resistant aGVHD. Keywords: acute graft-versus-host disease, Indoleamine 2,3-dioxygenase, hematopoietic stem cell transplantation Disclosures: No relevant conflicts of interest to declare.

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Veys, Paul. "Reduced intensity transplantation for primary immunodeficiency disorders." Pediatric Reports 3, no. 2s (June 17, 2011): 11. http://dx.doi.org/10.4081/pr.2011.s2.e11.

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Studies so far indicate that reduced intensity transplantation (RIT) may have an important role in treating patients with primary immunodeficiency disease (PID). Unlike more standard approaches, such regimens can be used without severe toxicity in patients with severe pulmonary or hepatic disease. RIT also offers the advantage that long-term sequelae such as infertility or growth retardation may be avoided or reduced. RIT appears to be most appropriate for those patients with significant co-morbidities (eg T cell deficiencies) and those undergoing unrelated donor haematopoietic cell transplantation. More studies are required using pharmacokinetic monitoring (eg busulphan, treosulfan and alemtuzumab) and varying stem cell sources to optimise graft vs marrow reactions and minimise graft vs host disease. In certain PID patients RIT will be the “first step” towards establishing donor cell engraftment; second infusions of donor stem cells, donor lymphocyte infusions, or a second myeloablative HCT, which appears to be well tolerated, may be required in some patients with low level donor chimerism or graft rejection.

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Llull, R., N. Murase, Q. Ye, A. J. Demetris, and T. E. Starzl. "Chimerism, graft-vs-host disease, rejection, and their association with reciprocal donor-host immune reactions after cell, organ, and composite tissue transplantation." Transplantation Proceedings 29, no. 1-2 (February 1997): 1203–4. http://dx.doi.org/10.1016/s0041-1345(96)00550-7.

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Dickinson, Anne M., L. Sviland, G. Jackson, J. Dunn, S. Stephens, and S. J. Proctor. "Monoclonal anti-TNF-α suppresses graft vs host disease reactions in an in vitro human skin model." Cytokine 6, no. 2 (March 1994): 141–46. http://dx.doi.org/10.1016/1043-4666(94)90035-3.

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Avni, Batia Ronit, Joycelynne Palmer, Tracey Stiller, and Stephen J. Forman. "Eosinophilia As a Biomarker Predicting the Occurrence of Chronic Graft Versus Host Disease,." Blood 118, no. 21 (November 18, 2011): 4084. http://dx.doi.org/10.1182/blood.v118.21.4084.4084.

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Abstract Abstract 4084 Introduction: Chronic graft-versus-host disease (cGVHD) is a major complication after allogeneic hematopoietic stem cell transplantation (HSCT) known to impair quality of life and functional status and adversely affects long-term survival. Given its impact on outcomes post HSCT, biological markers predicting cGVHD appearance could be useful. Eosinophilia has been reported to occur in the setting of both acute and cGVHD. Even though many physicians refer to eosinophilia as a predictor of GVHD, it is unclear whether eosinophilia can serve as a biomarker predicting occurrence of cGVHD in the general HSCT population. Objectives: In order to evaluate whether eosinophilia can predict the development of cGVHD, we have chosen to study a cohort of HSCT patients who developed eosinophilia while being tapered off their immunosuppressive drugs. Methods: From 01/2000 to 12/2009, a matched series of 112 patients who underwent allogeneic HSCT at City of Hope was identified. Of those, 56 patients presented with eosinophilia (>0.5×10^9 /L on two consecutive visits within 4 weeks, not related to relapse or documented allergy, drug reaction or parasitic infection) after day 120, while being tapered from their immunosuppressive drugs (case group). A control group (with no eosinophilia present on two consecutive visits within 4 weeks after day 120) was matched for the following criteria: age (±10 years), transplant year (± 2 years), HSC source (peripheral blood versus bone marrow), donor type (related vs. unrelated), female donor to male recipient, occurrence of acute GVHD and type of GVHD prophylaxis(tacrolimus/sirolimus vs. other). Results: A total of 112 patients were included in the analysis (Table no. 1). The most prevalent indication for HSCT was acute leukemia. Fifty seven percent of patients underwent myeloablative HSCT. There was no statistically significant difference between the case and control group for the matching criteria: age (p=0.88), HSC source, donor type, female donor to male recipient, occurrence of acute GVHD and type of GVHD prophylaxis (p=1). There was also no statistically significant difference between the groups for the different disease risk category (i.e. low risk, intermediate risk, high risk and non malignant) (p=0.4581). In the group of patients presenting with eosinophilia, 89% (50 out of 56) developed cGVHD, as opposed to 59% (33 out of 56) in the control group (p=0.0002, Chi square test). In this setting, eosinophilia was found to have a positive predictive value of 89%. In a multivariate logistic regression model, looking at the mentioned above known cGVHD risk factors, patients with eosinophilia were nearly 7 times more likely to develop cGVHD compared to those without eosinophila (p=0.0003, 95% CI 2.41–20.13). The median time from the development of eosinophilia to first GVHD sign was 20 days. Eighty four percent of patients both in the eosinophilia and the control groups presented with extensive GVHD grading, with skin, mouth and liver being the most prevalent sites for cGVHD occurrence. With a median follow up of 51 month for the entire cohort (range 5.5–132m) 80% of patients were alive in the eosinophilia group vs. 87% in the control group. Conclusions: The development of eosinophilia in the setting of tapering or discontinuation of immunosuppression may serve as a good predictor of cGVHD. Eosinophilia in this setting may be an indicator for early intervention. Disclosures: No relevant conflicts of interest to declare.

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Forcade, Edouard, Haesook T. Kim, Corey S. Cutler, Kathy S. Wang, Vincent T. Ho, John Koreth, Philippe Armand, et al. "Activated Circulating T Follicular Helper Cells with Increased Function during Chronic Graft Versus Host Disease after Allogeneic Stem Cell Transplantation." Blood 126, no. 23 (December 3, 2015): 924. http://dx.doi.org/10.1182/blood.v126.23.924.924.

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Abstract T follicular helper cells (TFH) interact with B cells in the germinal center to support B cell proliferation, differentiation and immunoglobulin class switch. Previous studies have demonstrated that donor B cells contribute to the immune pathology of chronic GVHD (cGVHD) and studies in murine models of cGVHD have suggested that TFH play a central role in this process. Although TFH are located primarily within germinal centers of secondary lymphoid organs, TFH can also be found in the peripheral blood and are identified as a subset of memory CD4 T cells expressing CXCR5. Circulating TFH (cTFH) share functional and phenotypic characteristics of TFH including the ability to interact with B cells and provide helper signals. To examine the potential role of cTFH in the pathogenesis of cGVHD we monitored the reconstitution of cTFH (CD4+CD45RA-CXCR5+ T cells) in fresh blood samples obtained at different times after allogeneic HSCT. Recovery of cTFH mirrored the recovery of CD4 T cells and absolute numbers of cTFH gradually increased over time, reaching a plateau at 24 months post-HSCT in the range of normal values. Within the CD4 T cell population, the frequency of cTFH was low initially, but reached normal levels 6-9 months post-HSCT. Detailed phenotypic and functional analysis of cTFH was undertaken in a cohort of 66 adult patients (>9 months post-HSCT): 16 had no cGVHD, 12 had resolved cGVHD, and 38 had active cGVHD (mild = 15, moderate = 14, severe = 9). Results were compared to 22 healthy donors (HD). Overall, the frequency of cTFH was significantly reduced in HSCT patients compared to HD (median: 9.87 vs. 13.65 % of CD4+ T-cells, respectively, p =0.0003). cTFH frequency was lower in active cGVHD compared to no cGVHD patients (median: 9.44 vs. 11.65 % of CD4+ T-cells, p = 0.029); while cTFH in patients with resolved cGVHD was similar to patients without cGVHD (Figure 1). CXCL13 chemokine facilitates T-B interaction, thus promoting the GC reaction. CXCL13 levels were increased in active cGVHD compared to no cGVHD (137.7 pg/mL vs. 33.74 pg/mL, p < 10-4) suggesting that trafficking of cTFH to lymphoid organs was promoted in cGVHD. cTFH activation results in increased surface expression of ICOS and PD1 and increased proliferation. ICOShi PD1hi cTFH were increased in active cGVHD compared to no cGVHD (2.035 % vs 1.065 %, p = 0.016) in association with high proliferative activity (Ki67) (3.38 % vs. 2.31 % respectively, p = 0.0086). Functional cTFH subsets are also characterized by expression of CXCR3 and CCR6 as follows: Th1 (CXCR3+CCR6-), Th2 (CXCR3-CCR6-), Th17 (CXCR3-CCR6+). Within these subsets, Th2 and Th17 cTFH provide greater levels of B cell help measured by in vitro co-cultureassays (plasmablast generation and IgG production). Although not statistically significant, Th1 cTFH frequency was decreased during active cGVHD (33.95 vs 37.6 for no cGVHD) and Th2 and Th17 cTFH frequencies were increased in the moderate-severe cGVHD group (31.1 and 30.5, respectively) compared to no cGVHD (27.05 and 24.45, respectively). Within active cGVHD patients, the frequencies of Th1 and Th17 were associated with clinical grade of cGVHD (Th1: 40, 34, 19, p=0.008; Th17: 21, 26, 37, p=0.02; for mild, moderate, severe, respectively). We used the ratio (Th2+Th17)/Th1 cTFH to normalize B cell help capacity, and found a higher ratio in severe cGVHD compared to no cGVHD (3.59 vs 1.36, p = 0.0006). To measure cTFH functional activity, cTFH and naive B cells were purified from patient samples by cell sorting and co-cultured for 6 days. cTFH from patients with active cGVHD induced greater plasmablast generation (CD27hi CD38hi B cells) compared to cTFH from non-active cGVHD (Fig. 2). Increased functional activity of cTFH was confirmed when patient cTFH were purified and cocultured with naive B cells from a normal allogeneic donor (Fig. 2). In patients with cGVHD, there was also a significant correlation between the proliferative activity of cTFH and the generation of CD27hi CD38hi B cells (r = 0.48, p = 0.0029). These results indicate that active cGVHD is characterized by phenotypic and functional abnormalities of cTFH. In cGVHD, cTFH show high levels of activation, proliferation and switch toward Th2 and Th17 phenotype. These changes enhance cTFH function, promoting GC reactions and B cell differentiation. These data support the involvement of cTFH in the immune pathology of human cGVHD, suggesting the investigation of novel therapies targeting the GC reaction. Disclosures Armand: Merck: Consultancy, Research Funding; Infinity Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Research Funding. Antin:Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

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Fanning, L. R., Y. Hegerfeldt, M. Tary-Lehmann, M. Lesniewski, J. Maciejewski, R. P. Weitzel, M. Kozik, et al. "Allogeneic transplantation of multiple umbilical cord blood units in adults: role of pretransplant-mixed lymphocyte reaction to predict host-vs-graft rejection." Leukemia 22, no. 9 (March 20, 2008): 1786–90. http://dx.doi.org/10.1038/leu.2008.55.

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49

Tajima, Nobuyuki, Katsunari Tezuka, Atsuo Tanimoto, Atsuko Miyai, Minako Tanimoto, Junji Maruhashi, and Yoshihiro Watanabe. "JTA–009, a fully human antibody against human AILIM/ICOS, ameliorates graft–vs–host reaction in SCID mice grafted with human PBMCs." Experimental Hematology 36, no. 11 (November 2008): 1514–23. http://dx.doi.org/10.1016/j.exphem.2008.06.004.

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Lei, Jun-xia, Shu-nong Li, Xiu-ming Zhang, Xin Du, and Peng Xiang. "Rat Bone Marrow Mesenchymal Stem Cells Cotransplanted with BM Improve Hematopietic Reconstitution and Immunoreconstitution with Alleviating Graft-versus-Host Disease." Blood 104, no. 11 (November 16, 2004): 4248. http://dx.doi.org/10.1182/blood.v104.11.4248.4248.

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Abstract Prolonged immunodeficiency after allogeneic bone marrow transplantation (BMT) causes significant morbidity and mortality from infection, while graft versus host disease (GVHD) after allogeneic BMT and immunosuppression therapies against GVHD further deteriorate this process. Adult bone marrow mesenchymal stem cells (MSC) have recently been shown to inhibit T-cell proliferation and reduce GVHD after allo-BMT. In this study, we characterized the effect of MSC on immunoreconstitution and hematopoietic-reconstitution after bone marrow transplantation. BMT model from Fischer344 rats (RT-1Al) to WF rats (RT-1Au) was established for this experiment. Effects of MSCs on hematopoietic reconstitution, immunoreconstitution and GVHD were studied by survival rate, peripheral blood counts, histological analysis and FACS at day +30 after transplantation. Immune function recovery were assessed by lymphocyte proliferation reaction stimulated with ConA and LPS and allogeneic mixed-lymphocyte reaction. At day 30 postransplant, compared with BMT groups, we observed that cotransplantation of MSC and bone marrow promoted the recovery of peripheral blood white blood cells (5.47±1.11x109/L vs7.12±1.70x109/L, p<0.05), lymphocytes and platelets. Accordingly, it was noticed that cotransplantation of MSC with BM not only improved recovery of bone marrow cellularity, but also enhanced B lymphopoiesis (4.66±1.03x109/L vs 6.05±1.39x109/L, p<0.05) and megakaryocytopoiesis (402.50±63.70 x109/L vs 594.33±121.09x109/L, p<0.05). MSC was also shown to improve thymic and spenic architecture reconstitution. Histological analysis showed that near normal thymus architecture and normal spenic architecture, with well-developed red and white pulp and intact lymphoid follicles in the cotransplantation group, while loss of demarcation between cortex and medulla in the thymus and lymphocytic depletion of spenic arteriolar sheaths in BM transplantation rats.The total number of thymus cells and spleen cells were also increased in cotransplantation group compared to only BM transplantation group. Most notable, the higher percentage of CD3+CD4+ was observed in the spleens of cotransplantation group (11.47±3.68% vs 19.14±4.03%, respectively), while no difference in the percentage of CD3+CD8+ between two groups (10.61±3.37% vs 12.13±2.27%, respectively). So the ratio of CD4+/CD8+ cells increased and inclined to normal in cotransplantation groups compared to only BM transplantation group.There are no difference in the percentage of natural killer (NK) cells and monocytes between BMT group and BMT with MSC group. The immuno-inhibitory effect of MSC on reducing GVHD in recipients of an MHC-mismatched BMT was also evident in our study, nonetheless, splenic cells from recipients of MSC cotransplantation group displayed improved non-specific proliferation capability (against ConA LPS stimulation) and alloreactivity (against the third party splenocytes) compared to BM transplantation group. In conclusion, rat bone marrow mesenchymal stem cells cotransplanted with BM improves hematopietic reconstitution and immunoreconstitution with alleviating graft-versus-host disease.

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Journal articles on the topic 'Graft vs Host Reaction'

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