REDUCTION OF FATAL GRAFT-VERSUS-HOST DISEASE BY 3H-THYMIDINE SUICIDE OF DONOR CELLS CULTURED WITH HOST CELLS

1977 ◽  
Vol 23 (4) ◽  
pp. 299-302 ◽  
Author(s):  
MARTIN A. CHEEVER ◽  
ALBERT B. EINSTEIN ◽  
RAYMOND A. KEMPF ◽  
ALEXANDER FEFER
Blood ◽  
2008 ◽  
Vol 112 (5) ◽  
pp. 2111-2119 ◽  
Author(s):  
Jean-Sébastien Delisle ◽  
Louis Gaboury ◽  
Marie-Pier Bélanger ◽  
Éliane Tassé ◽  
Hideo Yagita ◽  
...  

Abstract The immunopathologic condition known as graft-versus-host disease (GVHD) results from a type I T-cell process. However, a prototypical type I cytokine, interferon-γ (IFN-γ), can protect against several manifestations of GVHD in recipients of major histocompatibility complex (MHC)–mismatched hematopoietic cells. We transplanted hematopoietic cells from C3H.SW donors in wild-type (wt) and IFN-γ-receptor–deficient (IFN-γRKO) MHC-matched C57BL/6 recipients. In IFN-γRKO recipients, host cells were unresponsive to IFN-γ, whereas wt donor cells were exposed to exceptionally high levels of IFN-γ. From an IFN-γ perspective, we could therefore evaluate the impact of a loss-of-function on host cells and gain-of-function on donor cells. We found that lack of IFN-γR prevented up-regulation of MHC proteins on host cells but did not mitigate damage to most target organs. Two salient phenotypes in IFN-γRKO recipients involved donor cells: lymphoid hypoplasia and hematopoietic failure. Lymphopenia was due to FasL-induced apoptosis and decreased cell proliferation. Bone marrow aplasia resulted from a decreased proliferation of hematopoietic stem/progenitor cells that was associated with down-regulation of 2 genes negatively regulated by IFN-γ: Ccnd1 and Myc. We conclude that IFN-γ produced by alloreactive T cells may entail a severe graft-versus-graft reaction and could be responsible for cytopenias that are frequently observed in subjects with GVHD.


2018 ◽  
Vol 201 (10) ◽  
pp. 2910-2922 ◽  
Author(s):  
Yue Li ◽  
Xiaoqun Guan ◽  
Weiren Liu ◽  
Hung-Lin Chen ◽  
Jamie Truscott ◽  
...  

Blood ◽  
1990 ◽  
Vol 75 (3) ◽  
pp. 798-805 ◽  
Author(s):  
BR Blazar ◽  
DL Thiele ◽  
DA Vallera

Abstract Incubation of murine bone marrow and splenocytes with the dipeptide methyl ester, L-leucyl-L-leucine methyl ester (Leu-Leu-OMe), which results in the selective depletion of cytotoxic T cells and their precursors, natural killer cells, and monocytes, completely protected 30 recipients of fully allogeneic donor grafts from lethal graft-versus- host disease (GVHD). These results were comparable with those obtained in 30 recipients of anti-Thy 1.2 plus complement (C')-treated donor marrow. However, in contrast to antibody- and C'-dependent T-cell depletion, which reduces the level of donor cell engraftment in our model system, we did not observe such effects using Leu-Leu-OMe marrow pretreatment. As compared with the 24 H-2 typed recipients of anti-Thy 1.2 + C'-treated donor grafts, the 29 H-2 typed recipients of Leu-Leu- OMe-treated donor grafts had significantly (P less than .001) higher percentages of donor cells (mean = 93% v 74%) and significantly (P less than .001) lower percentages of host cells (mean = 6% v 15%) posttransplantation. In vitro limiting dilution assay (LDA) was performed to assess the comparative efficacy of cytolytic T-lymphocyte (CTL) precursor depletion by Leu-Leu-OMe or anti-Thy 1.2 + C' pretreatment. We observed greater levels of CTL precursor depletion in Leu-Leu-OMe treated as compared with anti-Thy 1.2 + C'-treated bone marrow plus spleen cells (BMS) obtained from nontransplanted mice. This suggests that the in vivo results cannot simply be attributed to a less efficacious functional inactivation of cytolytic T-cell precursors by Leu-Leu-OMe treatment as compared with anti-Thy 1.2 + C' treatment. Immunoreconstitution was similar in recipients of Leu-Leu-OMe-treated grafts and anti-Thy 1.2 + C'-treated grafts 100 days posttransplant. In our opinion, Leu-Leu-OMe marrow pretreatment deserves further investigation as a methodology to achieve GVHD prevention without significantly reducing the propensity toward host cell repopulation.


Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3736-3736
Author(s):  
Sam C Nalle ◽  
Peter A Savage ◽  
Jerrold R Turner

Abstract Abstract 3736 Background Graft-versus-host disease (GVHD) is a potentially fatal complication following allogeneic bone marrow transplantation (BMT). GVHD is characterized by three phases: (1) recipient tissue injury mediated by the conditioning regimen of irradiation and/or chemotherapy; (2) donor cell priming and activation; and (3) effector destruction of target tissue such as the intestine, liver, skin, and lung. There is some evidence to suggest that the second and third phases are dependent on the first, however, this has not been rigorously tested. Therefore, we developed major and minor mismatch models of GVHD and used immunodeficient recipients that readily accept allografts to analyze the requirement of irradiation conditioning on GVHD initiation and development. Experimental Design Wild-type (WT) B6 (H-2b) recipients received major mismatch (Balb/c, H-2d), minor mismatch (129, H-2b), or syngeneic (B6) BMTs. Recipients were lethally irradiated, and 24 hours later received an intravenous infusion of 5 × 106 bone marrow cells and 30 × 106 splenocytes, as a source of mature T cells. In adoptive transfer (AT) experiments, B6 Rag1−/− or B6 Rag2−/−/Pfp−/− (perforin deficient) recipients received 30 × 106 splenocytes. Data are represented as mean ± SEM. Results In lethally irradiated WT recipients, Balb/c→B6 caused severe GVHD that was fatal in all recipients by 24 days after BMT. 129→B6 led to a milder GVHD, where 50% of recipients survived to 35 days after BMT, and a few survived long-term (>100 days). Both major and minor mismatch GVHD were characterized by 15–25% weight loss, clinical symptoms including decreased activity, hunched posture, ruffled fur, and hair loss, and target organ histopathology. To test the requirement of irradiation conditioning in GVHD, we transferred Balb/c splenocytes into unconditioned B6 Rag1−/− recipients. No signs of GVHD developed. However, donor T cells were virtually undetectable 5 weeks after AT, indicating graft rejection. To test if this was due to recipient natural killer (NK) cells, a major mismatch AT was performed into B6 Rag2−/−/Pfp−/− recipients, which lack fully functional NKs. Balb/c→B6 Rag2−/−/Pfp−/− resulted in GVHD, including 10–15% weight loss, clinical symptoms, and target organ histopathology, although the disease was not as severe as that following lethal irradiation of WT recipients, consistent with a facilitative role for conditioning in disease progression. In contrast to the above, a 129 splenocyte AT did not cause GVHD in Rag1−/− or Rag2−/−/Pfp−/− recipients, despite donor T cell engraftment. This suggested that conditioning was required for minor mismatch GVHD. To test this, we sublethally irradiated Rag1−/− recipients prior to 129 AT. This resulted in GVHD, with 10–15% weight loss, clinical symptoms, and histopathology. At day 7 after AT, serum IFNγ, TNF, and IL-6 were significantly greater in mice that received irradiation and AT (compared to AT alone, p<0.05). Donor cells within spleens of mice that received irradiation and AT had a reduced fraction of Foxp3+/CD4+ (9.5%±2.3) compared to AT alone (16.8%±1.6, p=0.06), and increased intracellular CD8+ IFNγ expression (%IFNγ+:47.7±2.4 vs. 41.6±1.8, p<0.05; MFI:15722±2003 vs. MFI:8025±319, p<0.05). To determine whether more alloreactive donor cells were primed after irradiation, an in vivo killing assay was performed with recipient-specific targets. Combined irradiation and AT resulted in 66.3±13.5% killing efficiency while AT only had an 18.9±11.7% killing efficiency. Conclusions We conclude that irradiation conditioning is required for minor, but not major mismatch GVHD. The conditioning regimen creates the necessary proinflammatory milieu to prime sufficient numbers of alloreactive cells for GVHD. While this milieu can enhance development of major mismatch GVHD, it is not required for development of disease. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2006 ◽  
Vol 109 (9) ◽  
pp. 4097-4104 ◽  
Author(s):  
Yanhui Xu ◽  
Andrew S. Flies ◽  
Dallas B. Flies ◽  
Gefeng Zhu ◽  
Sudarshan Anand ◽  
...  

Abstract Decoy lymphotoxin β receptor (LTβR) has potent immune inhibitory activities and thus represents a promising biologic for the treatment of inflammation, autoimmune diseases, and graft-versus-host disease (GVHD). As this reagent interrupts multiple molecular interactions, including LTβ-LTβR and LIGHT-HVEM/LTβR, underlying molecular mechanisms have yet to be fully understood. In this study, we demonstrate that blockade of the LIGHT-HVEM pathway is sufficient to induce amelioration of GVHD in mouse models. Anti–host cytotoxic T lymphocyte (CTL) activity following in vivo transfer of allogeneic lymphocytes was completely abrogated when LIGHT- or HVEM-deficient (KO) T cells were used as donor cells. Accordingly, survival of the recipient mice following the transfer of allogeneic bone marrow cells plus LIGHT-KO or HVEM-KO T cells was significantly prolonged. In the absence of LIGHT-HVEM costimulation, alloreactive donor T cells undergo vigorous apoptosis while their proliferative potential remains intact. Furthermore, we prepared a neutralizing monoclonal antibody (mAb) specific to HVEM and showed that administration of anti–HVEM mAb profoundly ameliorated GVHD and led to complete hematopoietic chimerism with donor cells. Collectively, our results demonstrate an indispensable role of LIGHT-HVEM costimulation in the pathogenesis of GVHD and illustrate a novel target for selective immunotherapy in allogeneic bone marrow transplantation.


Blood ◽  
1995 ◽  
Vol 86 (8) ◽  
pp. 3090-3096 ◽  
Author(s):  
LD Fast ◽  
CR Valeri ◽  
JP Crowley

Graft-versus-host disease (GVHD) is currently encountered after bone marrow transplantation and transfusion. GVHD associated with transfusion (TA-GVHD) in apparently immunocompetent recipients has been recently reported with increasing frequency. A consistent finding in many of these cases is that the recipient received blood from a donor homozygous for one of the recipient's HLA haplotypes. However, the observed frequency of TA-GVHD is much lower than the estimated probability of this donor/recipient combination. The potential role of recipient immune responses in controlling TA-GVHD was investigated using an analogous murine model in which GVHD is induced by the injection of parental lymphoid cells into unirradiated F1 hybrid recipients. The effect of various immune manipulations of the recipient of GVHD induction was assessed by determining the number of donor lymphoid cells required to induce GVHD responses. Whereas depletion of recipient CD4+ cells increased the number of donor cells needed to induce GVHD, depletion of recipient CD8+ and natural killer cells resulted in fewer donor cells being needed to induce a GVHD response. These studies suggest a central role for functioning recipient CD8 and natural killer cells in the down-regulation of TA-GVHD development in recipients.


Blood ◽  
1995 ◽  
Vol 86 (8) ◽  
pp. 3090-3096 ◽  
Author(s):  
LD Fast ◽  
CR Valeri ◽  
JP Crowley

Abstract Graft-versus-host disease (GVHD) is currently encountered after bone marrow transplantation and transfusion. GVHD associated with transfusion (TA-GVHD) in apparently immunocompetent recipients has been recently reported with increasing frequency. A consistent finding in many of these cases is that the recipient received blood from a donor homozygous for one of the recipient's HLA haplotypes. However, the observed frequency of TA-GVHD is much lower than the estimated probability of this donor/recipient combination. The potential role of recipient immune responses in controlling TA-GVHD was investigated using an analogous murine model in which GVHD is induced by the injection of parental lymphoid cells into unirradiated F1 hybrid recipients. The effect of various immune manipulations of the recipient of GVHD induction was assessed by determining the number of donor lymphoid cells required to induce GVHD responses. Whereas depletion of recipient CD4+ cells increased the number of donor cells needed to induce GVHD, depletion of recipient CD8+ and natural killer cells resulted in fewer donor cells being needed to induce a GVHD response. These studies suggest a central role for functioning recipient CD8 and natural killer cells in the down-regulation of TA-GVHD development in recipients.


Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4472-4472
Author(s):  
Jennifer Matos ◽  
Zheng Yang ◽  
Eugenia Dziopa ◽  
Leah Dziopa ◽  
Christopher J. Kirk ◽  
...  

Background Proteasome inhibition has been studied and used as a therapeutic target in the treatment of autoimmune disorders and multiple myeloma. Immune system cells, especially antigen-presenting cells, express a higher basal level of immunoproteasomes, which are used to generate peptides that can be processed to fit in the groove of MHC class I molecules. ONX 0914 is a selective inhibitor of the immmunoproteasome that blocks LMP7-specific presentation of MHC-I restricted antigens, whereas PR-825 is a specific inhibitor of the b5 catalytic subunit generated by the constitutive proteasome. In previous work, we found that ONX 0914 administration early after transplantation significantly improved the survival of recipient mice in an MHC-matched minor histocompatibility antigen (miHA)-disparate (B10.BR -> CBA, lethally irradiated) murine model of graft-versus-host disease (GVHD). To further elucidate the mechanism of action, we compared alloreactive responses via IFN-g production in mixed lymphocyte reactions (MLR) in which stimulator cells or responder T cells were pretreated with either ONX 0914 or PR-825. MLR were conducted for the B10.BR anti-C56BL/6y (B6) MHC-mismatched, the CD8+ T cell-mediated B10.BR anti-CBA, and the CD4+ T cell-mediated B6 anti-BALB.B MHC-matched/ miHA-disparate strain combinations. Methods Stimulator splenocytes were treated for one hour with ONX 0914 (300 nM) or PR-825 (125 nM) before or immediately after exposure to irradiation (30 Gy) prior to initiation of the MLR. In addition, to try to optimize putative in vivo drug regimens, we determined the timing of release/degradation of antigenic peptides presented in the context of MHC-I. To this end, the MC57G fibrosarcoma cell line was transiently transfected with a GFP tagged SIINFEKL plasmid, cells were treated with different drug regimens and exposure times of ONX 0914 or PR-825, and monitored over 48 hours for surface expression of MHC-I presented SIINFEKL peptide using flow cytometry. Results ELISpot assays showed a statistically significant decrease in the number of IFN-g producing cells when stimulators (B6 splenocytes) were pretreated with ONX 0914 compared to pretreated responder (B10.BR) cells (60.21% vs. 1.75% respectively, p< 0.01). In the miHA disparate combinations, the percentage decrease in IFN-g+ spots was ∼30% when stimulators were treated with ONX 0914, whereas only a ∼15% decrease was observed with PR-825 pretreatment. Furthermore, IFN-g production was not dependent upon the timing of exposure to irradiation, as ELISpot counts were equally decreased when drug pretreatments were performed before irradiation or just after exposure. Antigenic peptide presentation was maximally decreased in transfected MC57G cells 48 h after treatment (i.e., SIINFEKL % in GFP+ MC57G cells treated with DMSO was equal to 83% vs. 76% when cells were exposed to ONX 0914 [300 nM, for 24 h]. This result suggests that for in vivo application, pretreatment of recipient mice with ONX 0914 to decrease miHA presentation by host cells (24-72 hours prior to bone marrow transplantation) may provide further amelioration of GVHD development. Conclusion Taken together, these data suggest that downregulation of LMP7-mediated presentation of MHC-I restricted antigens by host cells likely modulated stimulation and IFN-g production of donor T cells in vivo, rather than acting on effector cells directly, and accounted in part for the improved survival rate experienced by recipient mice treated with ONX 0914. Disclosures: Matos: Onyx Pharmaceuticals: Research Funding. Dziopa:Onyx Pharmaceuticals: Research Funding. Kirk:Onyx Pharmaceuticals: Employment. Korngold:Onyx Pharmaceuticals: Research Funding. Zilberberg:Onyx Pharmaceuticals: Research Funding.


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