Graft-versus-host disease causes failure of donor hematopoiesis and lymphopoiesis in interferon-γ receptor-deficient hosts

Blood ◽  
2008 ◽  
Vol 112 (5) ◽  
pp. 2111-2119 ◽  
Author(s):  
Jean-Sébastien Delisle ◽  
Louis Gaboury ◽  
Marie-Pier Bélanger ◽  
Éliane Tassé ◽  
Hideo Yagita ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Hematopoietic Cells ◽  
Interferon Γ ◽  
Host Cells ◽  
Type I ◽  
Host Disease ◽  
Graft Versus Host ◽  
Donor Cells ◽  
Ifn Γ ◽  
The Impact

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.

Donor-derived interferon γ separates graft-versus-leukemia effects and graft-versus-host disease induced by donor CD8 T cells

Blood ◽  
2002 ◽  
Vol 99 (11) ◽  
pp. 4207-4215 ◽  
Author(s):  
Yong-Guang Yang ◽  
Jin Qi ◽  
Min-Guang Wang ◽  
Megan Sykes
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Cd8 T Cells ◽  
Interferon Γ ◽  
Host Disease ◽  
Graft Versus Host ◽  
Graft Versus Leukemia ◽  
Donor Cells ◽  
Ifn Γ ◽  
First Time

The graft-versus-leukemia (GVL) effects and graft-versus-host disease (GVHD)–inducing activity of CD8 T cells was compared in murine recipients of wild-type (WT) or interferon γ (IFN-γ)–deficient (GKO) allogeneic donor cells. CD8 T cells (or CD4-depleted splenocytes) from GKO donor mice induced more severe GVHD in lethally irradiated allogeneic recipients compared to the same cell populations from WT donors. Consistent with GVHD severity, donor CD8 T-cell expansion in allogeneic recipients was augmented in the absence of IFN-γ. These results demonstrate that IFN-γ does not stimulate but instead down-modulates GVHD induced by donor CD8 T cells. Remarkably, antihost lymphohematopoietic reactions, including GVL effects against host leukemia/lymphoma cells, of CD8 T cells correlated inversely with their GVHD-inducing activity, and those of GKO donors were markedly weaker than those mediated by WT donor CD8 T cells. These data show for the first time that GVHD-inducing activity and GVL effects of allogeneic CD8 T cells can be separated by a single cytokine, IFN-γ.

scholarly journals Paradoxical effects of IFN-γ in graft-versus-host disease reflect promotion of lymphohematopoietic graft-versus-host reactions and inhibition of epithelial tissue injury

Blood ◽  
2009 ◽  
Vol 113 (15) ◽  
pp. 3612-3619 ◽  
Author(s):  
Hui Wang ◽  
Wannee Asavaroengchai ◽  
Beow Yong Yeap ◽  
Min-Guang Wang ◽  
Shumei Wang ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Tissue Injury ◽  
Hematopoietic Cells ◽  
Graft Versus Host Reaction ◽  
Epithelial Tissue ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Ifn Γ

Abstract Interferon-γ (IFN-γ) inhibits graft-versus-host disease (GVHD) in lethally irradiated mice receiving allogeneic hematopoietic cell transplantation (allo-HCT) but promotes lethality in unirradiated and sublethally irradiated recipients. We investigated the role of IFN-γ in GVHD in sublethally irradiated B6D2F1 recipients of B6 allo-HCT. B6D2F1 mice receiving wild-type B6 splenocytes alone died rapidly, whereas those receiving wild-type B6 splenocytes plus marrow survived long-term. Mice in both groups showed rapid elimination of host hematopoietic cells but minimal parenchymal tissue injury. However, mice receiving allo-HCT from IFN-γ–deficient donors died rapidly regardless of whether donor marrow was given, and they exhibited severe parenchymal injury but prolonged survival of host hematopoietic cells. IFN-γ plays a similar role in another model involving delayed B6 donor leukocyte infusion (DLI) to established mixed allogeneic (B6→BALB/c) chimeras. IFN-γ promotes DLI-mediated conversion from mixed to full donor chimerism while attenuating GVHD. Importantly, IFN-γ enhances graft-versus-leukemia (GVL) effects in both models. Our data indicate that previously reported IFN-γ–induced early mortality in allo-HCT recipients is due to augmentation of lymphohematopoietic graft-versus-host reaction (LGVHR) and can be avoided by providing an adequate source of donor hematopoietic stem/progenitor cells. Furthermore, the magnitude of GVL is correlated with the strength of LGVHR, and IFN-γ reduces the potential of this alloreactivity to cause epithelial tissue GVHD.

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
Keyword(s):  
Graft Versus Host Disease ◽  
Host Cells ◽  
Host Disease ◽  
Graft Versus Host ◽  
Donor Cells ◽  
Cells Cultured

Expansion of cytolytic CD8+ natural killer T cells with limited capacity for graft-versus-host disease induction due to interferon γ production

Blood ◽  
2001 ◽  
Vol 97 (10) ◽  
pp. 2923-2931 ◽  
Author(s):  
Jeanette Baker ◽  
Michael R. Verneris ◽  
Maki Ito ◽  
Judith A. Shizuru ◽  
Robert S. Negrin
Keyword(s):  
T Cells ◽  
Natural Killer ◽  
Graft Versus Host Disease ◽  
Nkt Cells ◽  
Interferon Γ ◽  
Lytic Activity ◽  
Cell Phenotype ◽  
Host Disease ◽  
Graft Versus Host ◽  
Ifn Γ

Abstract T cells with natural killer cell phenotype and function (NKT cells) have been described in both human and murine tissues. In this study, culture conditions were developed that resulted in the expansion of CD8+ NKT cells from bone marrow, thymus, and spleen by the timed addition of interferon-γ (IFN-γ), interleukin 2 (IL-2), and anti-CD3 monoclonal antibody. After 14 to 21 days in culture, dramatic expansion of CD3+, CD8+, αβT-cell receptor+ T cells resulted with approximately 20% to 50% of the cells also expressing the NK markers NK1.1 and DX5. The CD8+ NKT cells demonstrated lytic activity against several tumor target cells with more than 90% lysis by day 14 to day 21 of culture. Cytotoxicity was observed against both syngeneic and allogeneic tumor cell targets with the greatest lytic activity by the cells expressing either NK1.1 or DX5. The expanded CD8+ NKT cells produce TH1-type cytokines with high levels of IFN-γ and tumor necrosis factor α. Expansion of the CD8+ NKT cells was independent of CD1d. Ly49 molecules were expressed on only a minority of cells. A single injection of expanded CD8+ NKT cells was capable of protecting syngeneic animals from an otherwise lethal dose of Bcl1 leukemia cells. Expanded CD8+ NKT cells produced far less graft-versus-host disease (GVHD) than splenocytes across major histocompatibility barriers, even when 10 times the number of CD8+ NKT cells as compared to splenocytes were injected. This reduction in GVHD was related to IFN-γ production since cells expanded from IFN-γ knock-out animals caused acute lethal GVHD, whereas cells expanded from animals defective in fas ligand, fas, IL-2, and perforin did not. These data indicate that CD8+ NKT cells expanded in this fashion could be useful for preserving graft-versus-leukemia activity without causing GVHD.

Cytokine and chemokine profiles in autologous graft-versus-host disease (GVHD): interleukin 10 and interferon γ may be critical mediators for the development of autologous GVHD

Blood ◽  
2002 ◽  
Vol 100 (7) ◽  
pp. 2650-2658 ◽  
Author(s):  
Yuji Miura ◽  
Christopher J. Thoburn ◽  
Emilie C. Bright ◽  
Weiran Chen ◽  
Shinji Nakao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Graft Versus Host Disease ◽  
Promoter Region ◽  
Critical Role ◽  
Interferon Γ ◽  
Mrna Levels ◽  
Healthy Individuals ◽  
Host Disease ◽  
Graft Versus Host ◽  
Ifn Γ

Administration of the immunosuppressive drug cyclosporine A (CsA) following autologous stem cell transplantation paradoxically elicits a systemic autoimmune syndrome resembling graft-versus-host disease (GVHD). This syndrome, termed autologous GVHD, is associated with autoreactive CD8+ T cells that recognize major histocompatibility complex (MHC) class II determinants in association with a peptide from the invariant chain. To investigate the potential role of cytokines and chemokines in autologous GVHD, interleukin 2 (IL-2), IL-4, IL-10, interferon γ (IFN-γ), and macrophage inflammatory protein-1α (MIP-1α) gene expression in peripheral blood mononuclear cells (PBMCs) was determined in 36 patients treated with CsA following transplantation and correlated with the induction of cytolytic activity against autologous phytohemagglutinin-stimulated lymphocytes (PHA-blasts) and the breast cancer cell line (T47D). The determination of gene expression by real-time polymerase chain reaction (PCR) revealed that IL-10 mRNA levels by PBMCs in patients with autologous GVHD were 29-fold higher than in healthy individuals. IFN-γ (4-fold), IL-2 (3-fold), and MIP-1α (44-fold) mRNA levels were also increased in GVHD-induced patients compared with healthy individuals. The ability of PBMCs to lyse autologous PHA-blasts and T47D tumor cells exhibited an identical temporal relationship with expression of IL-10 and IFN-γ during autologous GVHD. Moreover, the susceptibility to autologous GVHD as assessed in 75 patients was significantly associated with the IL-10−1082 G/G polymorphic alleles, allelic variants in the promoter region that govern IL-10 production. These findings indicate that IL-10 may play an unexpected but critical role in autologous GVHD and could be utilized to enhance a graft-versus-tumor effect after transplantation. Interestingly, polymorphisms in the IL-10 promoter region may also explain differences in the susceptibility of patients to autologous GVHD induction.

CCR1 Expression on Donor Leukocytes Is Critical to the Development of Graft Versus Host Disease after Allogeneic SCT.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3067-3067
Author(s):  
Gerhard C. Hildebrandt ◽  
Sung Choi ◽  
Krystyna M. Olkiewicz ◽  
Stephen W. Chensue ◽  
Chen Liu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
T Cell Responses ◽  
Target Organ ◽  
Host Disease ◽  
Graft Versus Host ◽  
Cell Responses ◽  
Donor Cells ◽  
The Impact

Abstract Acute graft versus host disease (aGVHD) is the major complication of allogeneic stem cell transplantation (allo-SCT) and limits the utility of this treatment strategy. The pathophysiology of aGVHD involves injury to host tissues by inflammatory cytokines and donor-derived cellular effectors, the recruitment of which is likely mediated by chemokine receptor: ligand interactions. CCR1 is expressed on various cell types such as T cells, monocytes and macrophages and binds to a group of CC chemokines that includes RANTES (CCL5) and Mip-1a (CCL3). In light of the previously described role for both donor T cells and monocytes in the development of aGVHD, we tested the hypothesis that CCR1 expression on donor leukocytes contributes to systemic and target organ inflammation that occurs in this setting by using a well established murine SCT model (B6→B6D2F1) and mutant mice deficient in CCR1. Lethally (1100cGy) irradiated B6D2F1 mice received SCT either from syngeneic (B6D2F1) or allogeneic (B6) CCR1+/+ or CCR1−/− donors. The severity of GVHD was assessed after SCT by survival and a clinical scoring system that incorporates changes in weight loss, fur texture, skin integrity, mobility and posture. As expected, syngeneic SCT recipients all survived and where indistinguishable from naïve, untransplanted controls, whereas animals receiving allo-SCT from CCR1+/+ donors developed significant GVHD and only 50% of animals survived by day 35. By contrast, allo-SCT with CCR1−/− donor cells resulted in significantly improved survival (92% vs. 50%) and less severe clinical GVHD (1.0±0.3 vs. 3.0±0.5) compared to allo-CCR1+/+ controls. In addition, serum TNFa levels were significantly decreased by day +7 following CCR1−/− SCT (4.7±2.7 vs. 55.3±14.4 pg/ml) and correlated with a significant reduction in intestinal histopathology both on day 7 (16.3±1.0 vs. 21.5±0.9) and on day 14 (15.8±1.8 vs. 23.8±1.0). GVHD injury to liver and skin was mild at these time points and did not differ between allo groups. Next we investigated the impact of CCR1 expression on allo-specific T cell responses in vivo and found that by day +7 after SCT both splenic T cell expansion (3.7±0.4 vs. 9.6±0.9 x 106 cells) and serum IFNγ levels (4561±559 vs. 10028±681 pg/ml) were significantly lower when CCR1 was absent on donor cells. In summary, we describe a heretofore unknown role for CCR1 on donor leukocytes in the development of aGVHD. The improvement in systemic and target organ disease observed after CCR1−/− SCT may be attributed to 1) alterations in leukocyte recruitment to the intestinal tract resulting in improved intestinal integrity, reduced translocation of endotoxin and decreased TNFa production and 2) modulation of donor T cell responses to host allo-antigens. Experiments are ongoing to determine whether strategies targeting CCR1 signalling can be exploited to prevent GVHD but maintain GVL effects and thereby improve overall survival after allo-SCT.

scholarly journals Effect of Early Post-Transplantation Tacrolimus Concentration on the Risk of Acute Graft-Versus-Host Disease in Allogenic Stem Cell Transplantation

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 613
Author(s):  
Nidhi Sharma ◽  
Qiuhong Zhao ◽  
Bin Ni ◽  
Patrick Elder ◽  
Marcin Puto ◽  
...  
Keyword(s):  
Stem Cell ◽  
Graft Versus Host Disease ◽  
Tacrolimus Concentration ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
The Impact ◽  
Risk Of Relapse ◽  
Acute Graft

Acute graft versus host disease (aGVHD) remains a leading cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant (allo-HSCT). Tacrolimus (TAC), a calcineurin inhibitor that prevents T-cell activation, is commonly used as a GVHD prophylaxis. However, there is variability in the serum concentrations of TAC, and little is known on the impact of early TAC levels on aGVHD. We retrospectively analyzed 673 consecutive patients undergoing allo-HSCT at the Ohio State University between 2002 and 2016. Week 1 TAC was associated with a lower risk of aGVHD II–IV at TAC level ≥10.15 ng/mL (p = 0.03) compared to the lowest quartile. The cumulative incidence of relapse at 1, 3 and 5 years was 33%, 38% and 41%, respectively. TAC levels at week 2, ≥11.55 ng/mL, were associated with an increased risk of relapse (p = 0.01) compared to the lowest quartile. Subset analysis with acute myeloid leukemia and myelodysplastic syndrome patients showed significantly reduced aGVHD with TAC level ≥10.15 ng/mL at week 1 and a higher risk of relapse associated with week 2 TAC level ≥11.55 ng/mL (p = 0.02). Hence, achieving ≥10 ng/mL during the first week of HCT may mitigate the risk of aGVHD. However, levels (>11 ng/mL) beyond the first week may be associated with suppressed graft versus tumor effect and higher relapse.

scholarly journals IL-22-dependent dysbiosis and mononuclear phagocyte depletion contribute to steroid-resistant gut graft-versus-host disease in mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Qingxiao Song ◽  
Xiaoning Wang ◽  
Xiwei Wu ◽  
Tae Hyuk Kang ◽  
Hanjun Qin ◽  
...  
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Mononuclear Phagocyte ◽  
Mononuclear Phagocytes ◽  
Dependent Manner ◽  
Steroid Resistant ◽  
Host Disease ◽  
Graft Versus Host ◽  
Potential Efficacy ◽  
Ifn Γ

AbstractEfforts to improve the prognosis of steroid-resistant gut acute graft-versus-host-disease (SR-Gut-aGVHD) have suffered from poor understanding of its pathogenesis. Here we show that the pathogenesis of SR-Gut-aGVHD is associated with reduction of IFN-γ+ Th/Tc1 cells and preferential expansion of IL-17−IL-22+ Th/Tc22 cells. The IL-22 from Th/Tc22 cells causes dysbiosis in a Reg3γ-dependent manner. Transplantation of IFN-γ-deficient donor CD8+ T cells in the absence of CD4+ T cells produces a phenocopy of SR-Gut-aGVHD. IFN-γ deficiency in donor CD8+ T cells also leads to a PD-1-dependent depletion of intestinal protective CX3CR1hi mononuclear phagocytes (MNP), which also augments expansion of Tc22 cells. Supporting the dual regulation, simultaneous dysbiosis induction and depletion of CX3CR1hi MNP results in full-blown Gut-aGVHD. Our results thus provide insights into SR-Gut-aGVHD pathogenesis and suggest the potential efficacy of IL-22 antagonists and IFN-γ agonists in SR-Gut-aGVHD therapy.

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