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.

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.

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.

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.

scholarly journals The Wnt agonist R-spondin1 regulates systemic graft-versus-host disease by protecting intestinal stem cells

2011 ◽  
Vol 208 (2) ◽  
pp. 285-294 ◽  
Author(s):  
Shuichiro Takashima ◽  
Masanori Kadowaki ◽  
Kazutoshi Aoyama ◽  
Motoko Koyama ◽  
Takeshi Oshima ◽  
...  
Keyword(s):  
Stem Cells ◽  
Graft Versus Host Disease ◽  
Intestinal Epithelium ◽  
Critical Role ◽  
Intestinal Stem Cells ◽  
Allogeneic Bone ◽  
Gi Tract ◽  
Host Disease ◽  
Graft Versus Host ◽  
Allogeneic Bmt

Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation (BMT), and damage to the gastrointestinal (GI) tract plays a critical role in amplifying systemic disease. Intestinal stem cells (ISCs) play a pivotal role not only in physiological tissue renewal but also in regeneration of the intestinal epithelium after injury. In this study, we have discovered that pretransplant conditioning regimen damaged ISCs; however, the ISCs rapidly recovered and restored the normal architecture of the intestine. ISCs are targets of GVHD, and this process of ISC recovery was markedly inhibited with the development of GVHD. Injection of Wnt agonist R-spondin1 (R-Spo1) protected against ISC damage, enhanced restoration of injured intestinal epithelium, and inhibited subsequent inflammatory cytokine cascades. R-Spo1 ameliorated systemic GVHD after allogeneic BMT by a mechanism dependent on repair of conditioning-induced GI tract injury. Our results demonstrate for the first time that ISC damage plays a central role in amplifying systemic GVHD; therefore, we propose ISC protection by R-Spo1 as a novel strategy to improve the outcome of allogeneic BMT.

scholarly journals Recombinant human interleukin-1 receptor antagonist in the treatment of steroid-resistant graft-versus-host disease

Blood ◽  
1994 ◽  
Vol 84 (4) ◽  
pp. 1342-1348 ◽  
Author(s):  
JH Antin ◽  
HJ Weinstein ◽  
EC Guinan ◽  
P McCarthy ◽  
BE Bierer ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Mononuclear Cells ◽  
Interleukin 1 ◽  
Response To Therapy ◽  
Mrna Levels ◽  
Steroid Resistant ◽  
Host Disease ◽  
Graft Versus Host

Abstract Acute graft-versus-host disease (GVHD) that is resistant to therapy is a highly lethal complication of marrow transplantation. Inflammatory cytokines such as interleukin-1 (IL-1) may be critical mediators of this process. If so, specific inhibition of IL-1 activity with recombinant human IL-1 receptor antagonist (IL-1Ra), a naturally occurring competitive inhibitor of IL-1, may ameliorate acute GVHD. We performed an open-label, phase I/II trial to evaluate the safety and efficacy of IL-1Ra in 17 patients with steroid-resistant GVHD. The IL- 1Ra was administered as a 24-hour continuous infusion over 7 days. The dose was escalated in cohorts of patients from 400 to 3,200 mg/d. Acute GVHD was evaluated in each affected organ and as an overall grade. Stage-specific improvement of acute GVHD occurred in the skin (8 of 14, 57%), gut (9 of 11, 82%), and liver (2 of 11, 18%). Overall, acute GVHD improved by at least one grade in 10 of 16 (63%) patients. Response to therapy was associated with a reduction of tumor necrosis factor-alpha (TNF-alpha) mRNA levels in blood mononuclear cells (P = .001). The only toxicity attributable to IL-1Ra was reversible transaminase elevation in two patients. Inhibition of IL-1 activity with IL-1Ra is safe and has demonstrable efficacy in acute GVHD that failed to respond to conventional treatment. These data provide further evidence that IL-1 is a mediator of GVHD.

scholarly journals Dynamic regulation of effector IFN-γ-producing and IL-17-producing T cell subsets in the development of acute graft-versus-host disease

2015 ◽  
Vol 13 (2) ◽  
pp. 1395-1403 ◽  
Author(s):  
KAI ZHAO ◽  
SUHONG RUAN ◽  
LINGLING YIN ◽  
DONGMEI ZHAO ◽  
CHONG CHEN ◽  
...  
Keyword(s):  
T Cell ◽  
Graft Versus Host Disease ◽  
T Cell Subsets ◽  
Dynamic Regulation ◽  
Host Disease ◽  
Graft Versus Host ◽  
Ifn Γ ◽  
Acute Graft

scholarly journals Critical role for CCR5 in the function of donor CD4+CD25+ regulatory T cells during acute graft-versus-host disease

Blood ◽  
2005 ◽  
Vol 106 (9) ◽  
pp. 3300-3307 ◽  
Author(s):  
Christian A. Wysocki ◽  
Qi Jiang ◽  
Angela Panoskaltsis-Mortari ◽  
Patricia A. Taylor ◽  
Karen P. McKinnon ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Graft Versus Host Disease ◽  
Critical Role ◽  
Allogeneic Bone Marrow Transplantation ◽  
Lymphoid Tissues ◽  
Allogeneic Bone ◽  
Host Disease ◽  
Graft Versus Host

AbstractCD4+CD25+ regulatory T cells (Tregs) have been shown to inhibit graft-versus-host disease (GVHD) in murine models, and this suppression was mediated by Tregs expressing the lymphoid homing molecule l-selectin. Here, we demonstrate that Tregs lacking expression of the chemokine receptor CCR5 were far less effective in preventing lethality from GVHD. Survival of irradiated recipient animals given transplants supplemented with CCR5-/- Tregs was significantly decreased, and GVHD scores were enhanced compared with animals receiving wild-type (WT) Tregs. CCR5-/- Tregs were functional in suppressing T-cell proliferation in vitro and ex vivo. However, although the accumulation of Tregs within lymphoid tissues during the first week after transplantation was not dependent on CCR5, the lack of function of CCR5-/- Tregs correlated with impaired accumulation of these cells in the liver, lung, spleen, and mesenteric lymph node, more than one week after transplantation. These data are the first to definitively demonstrate a requirement for CCR5 in Treg function, and indicate that in addition to their previously defined role in inhibiting effector T-cell expansion in lymphoid tissues during GVHD, later recruitment of Tregs to both lymphoid tissues and GVHD target organs is important in their ability to prolong survival after allogeneic bone marrow transplantation.

Tryptophan Metabolites Analogue, N-(3,4-dimethoxycinnamonyl) Anthranilic Acid, Ameliorates Acute Graft-Versus-Host Disease Through Inhibiting Th1 Responses

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5421-5421
Author(s):  
Jinhuan Xu ◽  
Yicheng Zhang
Keyword(s):  
T Lymphocytes ◽  
Graft Versus Host Disease ◽  
Anthranilic Acid ◽  
Allogeneic Bone Marrow Transplantation ◽  
Enzyme Linked Immunosorbent Assay ◽  
Allogeneic Bone ◽  
Host Disease ◽  
Graft Versus Host ◽  
Ifn Γ ◽  
Acute Graft

Abstract Local catabolism of tryptophan (Trp) by indoleamine 2,3-dioxygenase (IDO) is considered an important mechanism of regulating T cell immunity. N-(3,4-dimethoxycinnamonyl) anthranilic acid (3,4-DAA) is an active synthetic anthranilic acid derivative which was proved to be effective to treat type±helper T lymphocytes (Th1) mediated autoimmune diseases such as multiple sclerosis. In this report, we investigated the effects of 3,4-DAA on the acute graft versus host disease (aGVHD) following allogeneic bone marrow transplantation (allo-BMT) and its potential mechanism of action. we established a murine aGVHD model, 3,4-DAA was injected intraperitoneally at 200 mg/kg/day per mouse immediately after allo-BMT or at the onset of aGVHD for 14 consecutive days; the signs of aGVHD and the survival were recorded periodically; the histological changes of target organs were evaluated with hematoxylin-eosin staining; the IDO activity and cytokine levels in plasma were measured by reverse-phase high-performance liquid chromatography (HPLC) and enzyme linked immunosorbent assay (ELISA), respectively. We revealed that administration of 3,4-DAA after allo-BMT significantly reduced the severity and the histological score of aGVHD; The survival for mice receiving 3,4-DAA prophylaxis and treatment were prolonged in comparison to the vehicle control mice. The plasma levels of IFN-γ, TNF-α, IL-12 and IL-2 in 3,4-DAA treatment group were found to be decreased, while the IDO activity, the IL-10, IL-5 and IL-4 levels elevated in these mice. In consistent with the in vivo results, 3,4-DAA also inhibited IFN-γ and IL-2 production of spleen T lymphocytes in vitro. Our findings suggest that 3,4-DAA can diminish the murine experimental aGVHD through inhibition of Th1 response; this property makes it a potential alternative agent for prevention and treatment of GVHD in the clinic. Disclosures: No relevant conflicts of interest to declare.

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