Overexpression of Galectin-9 in Islets Prolongs Grafts Survival via Downregulation of Th1 Responses
Abstract:The differential activation of T helper (Th) cells and production of cytokines contribute to graft rejection or tolerance. In general, the Th1-type cytokines and cytotoxic T-cells are detected consistently in a host who is undergoing rejection, whereas Th2 responses are linked to a tolerance condition. Galectin-9 modulates Th1 cell immunity by binding to the T-cell immunoglobulin mucin-3 (Tim-3) molecule expressed on the Th1 cells. We investigate whether overexpression of galectin-9 in islets prolongs grafts survival in diabetic recipients. Islets were transduced with lentiviruses carrying galectin-9 and were then transplanted to streptozotocin-induced diabetic NOD/SCID recipients. The normoglycemic recipients then received splenocytes from diabetic NOD mice. Blood glucose concentration was monitored daily after adoptive transfer. The histology of the islet grafts and flow cytometric analyses were assessed at the end of the study. Overexpression of galectin-9 in islets prolonged graft survival in NOD/SCID mice after challenge with diabetogenic splenocytes (mean graft survival, 38.5 vs. 26.0 days, n=10, respectively; p=0.0096). The galectin-9-overexpressed grafts showed decreased infiltration of IFN-γ-producing CD4+ and CD8+ T-cells, but not of IL-17-producing CD4+ T-cells. Strikingly, this islet-specific genetic manipulation did not affect the systemic lymphocyte composition, indicating that galectin-9 may regulate T-cell-mediated inflammation in situ. We demonstrate that galectin-9 protects grafts from Th1 and Tc1 cell-mediated rejections, suggesting that galectin-9 has preventive and/or therapeutic benefit in transplant therapy for autoimmune diabetes and may be applied further to the transplantation of other organs or tissues.
Document Type: Research Article
Publication date: 2013-11-05
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