Galectin-9 Significantly Prolongs the Survival of Fully Mismatched Cardiac Allografts in Mice

Wang, He; Fang, Zemin; Wang, Feng; Wu, Ke; Xu, Yi; Zhou, Hongmin; Du, Dunfeng; Gao, Ying; Zhang, Weina; Niki, Toshiro; Hirashima, Mitsuomi; Yuan, Jing; Chen, Zhonghua Klaus

doi:10.1097/tp.0b013e3181b47f25

Cited by 75 publications

(55 citation statements)

References 33 publications

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“…We now show that treatment with rGal-9 activated TIM-3 expression, diminished IR-triggered TLR4 activation and mitigated proinflammatory cytokine programs, ultimately leading to OLT cytoprotection. These beneficial effects are in agreement with the ability of Gal-9 to ameliorate diet-induced liver steatosis by modulating NKT cell function (31); prolong survival of fully allogeneic cardiac allografts by suppressing Th1/Th17 immune responses (32); or protect corneal allografts from destruction by allo-reactive T cells (33). …”

Section: Discussionsupporting

confidence: 71%

Negative CD4 + TIM-3 Signaling Confers Resistance Against Cold Preservation Damage in Mouse Liver Transplantation

Liu

Zhang

et al. 2015

American Journal of Transplantation

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Ischemia-reperfusion injury (IRI), an innate immunity-driven local inflammation, remains the major problem in clinical organ transplantation. T cell immunoglobulin and mucin domain (TIM-3) – Galectin-9 (Gal-9) signaling regulates CD4+ Th1 immune responses. Here, we explored TIM-3 – Gal-9 function in a clinically relevant murine model of hepatic cold storage and orthotopic liver transplantation (OLT). C57BL/6 livers, preserved for 20h at 4°C in UW solution, were transplanted to syngeneic mouse recipients. Up-regulation of TIM-3 on OLT-infiltrating activated CD4+ T cells was observed in the early IRI phase (1h). By 6h of reperfusion, OLTs in recipients treated with a blocking anti-TIM-3 Ab were characterized by: 1/ enhanced hepatocellular damage (sALT levels, liver Suzuki's histological score); 2/ polarized cell infiltrate towards Th1/Th17-type phenotype; 3/ depressed T cell exhaustion markers (PD-1, LAG3); and 4/ elevated neutrophil and macrophage infiltration/activation. In parallel studies, adoptive transfer of CD4+ T cells from naïve WT, but not from TIM-3 Tg donors, readily recreated OLT damage in otherwise IR-resistant RAG−/− test recipients. Furthermore, pre-treatment of mice with rGal-9 promoted hepatoprotection against preservation-association liver damage, accompanied by enhanced TIM-3 expression in OLTs. Thus, CD4+ T cell-dependent “negative” TIM-3 costimulation is essential for hepatic homeostasis and resistance against IR stress in OLTs.

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Section: Discussionsupporting

confidence: 71%

Negative CD4 + TIM-3 Signaling Confers Resistance Against Cold Preservation Damage in Mouse Liver Transplantation

Liu

Zhang

et al. 2015

American Journal of Transplantation

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“…Systemic administration of recombinant galectin-9 (rgal-9) has been shown to improve allogeneic cardiac as well as skin grafts. 30,31 Increased allograft survival was consistent with deletion of CD4 ϩ Tim-3 ϩ Th1 cells. Because of these promising findings, it may be possible to develop the use of reagents, such as rgal-9, for use in the clinic.…”

mentioning

confidence: 81%

Contrasting acute graft-versus-host disease effects of Tim-3/galectin-9 pathway blockade dependent upon the presence of donor regulatory T cells

Veenstra

Taylor

Zhou

et al. 2012

Blood

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T-cell immunoglobulin mucin-3 (Tim-3) is expressed on pathogenic T cells, and its ligand galectin-9 (gal-9) is up-regulated in inflamed tissues. When Tim-3 ؉ T cells encounter high gal-9 levels, they are deleted. Tim-3 is up-regulated on activated T cells during GVHD. Inhibition of Tim-3/ gal-9 binding by infusion of a Tim-3-Ig fusion protein or Tim-3 ؊/؊ donor T cells increased T-cell proliferation and GVHD lethality. When the Tim-3/gal-9 pathway engagement was augmented using gal-9 transgenic recipients, GVHD lethality was slowed. Together, these data indicate a potential for modulating this pathway to reduce disease by increasing Tim-3 or gal-9 engagement. Paradoxically, when Tim-3/gal-9 was inhibited in the absence of donor T-regulatory cells (Tregs), GVHD was inhibited. GVHD reduction was associated with decreased colonic inflammatory cytokines as well as epithelial barrier destruction. CD25-depleted Tim-3 ؊/؊ donor T cells underwent increased activationinduced cell death because of increased IFN-␥ production. To our knowledge, these studies are the first to show that although the absence of Tim-3/gal-9 pathway interactions augments systemic GVHD, concurrent donor Treg depletion paradoxically and surprisingly inhibits GVHD. Thus, although donor Tregs typically inhibit GVHD, under some conditions, such Tregs actually may contribute to GVHD by reducing activation-induced T-cell death. (Blood. 2012;120(3):682-690) IntroductionGVHD remains the leading cause of morbidity and mortality after bone marrow transplantation (BMT). Patients are given immune suppressive therapy to prevent or diminish the severity of GVHD after allogeneic BMT that in turn increases the risk of infection and disease recurrence. Novel GVHD strategies remain a high priority.The T-cell immunoglobulin mucin (TIM) family consists of 3 proteins (TIM-1, -3, and -4), homologous in mouse and human. 1 Tim-3 was the first described member 2 and has been the most well studied. Differentiated T-effector cells (Teffs) express Tim-3 with the highest density on T-helper (Th)1, lower density on Th17, and no expression on Th2 cells. 3,4 The expression of galectin-9 (gal-9), identified as a ligand for Tim-3, is up-regulated in inflamed tissues. [5][6][7][8] When Tim-3 ϩ Teffs encounter high gal-9 levels, they are deleted. 5,9-11 A major function of the Tim-3/gal-9 pathway is to limit immune responses under conditions of tissue inflammation and injury. In vivo blockade of Tim-3/gal-9 interaction or the use of Tim-3 knockout (Ϫ/Ϫ) mice increases Th1 cells within inflamed tissues. 2,12,13 When Tim-3 binds with gal-9, Th1 responses are inhibited and peripheral tolerance is induced. 5,12,13 In vivo blocking strategies relying on monoclonal anti-Tim-3 antibody and Tim-3-Ig fusion protein showed exacerbation of experimental autoimmune encephalomyelitis and autoimmune diabetes. 2,12 Transplant tolerance induced by donor-specific transfusion and anti-CD154 treatment was impaired. 13 Thus, Tim-3/gal-9 signaling acts to dampen a Th1 immune response, whereas signaling ...

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“…In a number of studies, Gal-9 has been administered to experimental autoimmune disease models and displayed therapeutic effects, including for experimental allergic encephalomyelitis, experimental autoimmune arthritis, and autoimmune diabetes (23,35,37). Our previous studies also revealed that Gal-9 prolongs the survival of allografts through inhibition of the activation of CD8 ϩ T cells and Th17 cells (8,32).…”

mentioning

confidence: 95%

Galectin-9 ameliorates anti-GBM glomerulonephritis by inhibiting Th1 and Th17 immune responses in mice

Zhang

Luan

Wang

et al. 2014

American Journal of Physiology-Renal Physiology

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Antiglomerular basement membrane glomerulonephritis (anti-GBM GN) is a Th1- and Th17-predominant autoimmune disease. Galectin-9 (Gal-9), identified as the ligand of Tim-3, functions in diverse biological processes and leads to the apoptosis of CD4(+)Tim-3(+) T cells. It is still unclear how Gal-9 regulates the functions of Th1 and Th17 cells and prevents renal injury in anti-GBM GN. In this study, Gal-9 was administered to anti-GBM GN mice for 7 days. We found that Gal-9 retarded the increase of Scr, ameliorated renal tubular injury, and reduced the formation of crescents. The infiltration of Th1 and Th17 cells into the spleen and kidneys significantly decreased in Gal-9-treated nephritic mice. The reduced infiltration of Th1 and Th17 cells might be associated with the downregulation of CCL-20, CXCL-9, and CXCL-10 mRNAs in the kidney. In parallel, the blood levels of IFN-γ and IL-17A declined in Gal-9-treated nephritic mice at days 21 and 28. In addition, an enhanced Th2 cell-mediated immune response was observed in the kidneys of nephritic mice after a 7-day injection of Gal-9. In conclusion, the protective role of Gal-9 in anti-GBM GN is associated with the inhibition of Th1 and Th17 cell-mediated immune responses and enhanced Th2 immunity in the kidney.

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Galectin-9 Significantly Prolongs the Survival of Fully Mismatched Cardiac Allografts in Mice

Abstract: A short-course administration of galectin-9 significantly prolonged the survival of fully allogeneic cardiac allografts, which was associated with the suppression of Th1 and Th17 immune responses.

Cited by 75 publications

References 33 publications

Negative CD4 + TIM-3 Signaling Confers Resistance Against Cold Preservation Damage in Mouse Liver Transplantation

Negative CD4 + TIM-3 Signaling Confers Resistance Against Cold Preservation Damage in Mouse Liver Transplantation

Contrasting acute graft-versus-host disease effects of Tim-3/galectin-9 pathway blockade dependent upon the presence of donor regulatory T cells

Galectin-9 ameliorates anti-GBM glomerulonephritis by inhibiting Th1 and Th17 immune responses in mice

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