Testicular Sertoli Cells Protect Islet -Cells From Autoimmune Destruction in NOD Mice by a Transforming Growth Factor- 1–Dependent Mechanism

Testicular Sertoli cells protect pancreatic islet grafts from alloand autoimmune destruction; however, the mechanism(s) of protection is unclear. The aim of this study was to determine whether Fas ligand (FasL) and/ or transforming growth factor (TGF), immunoregulatory proteins produced by Sertoli cells, might mediate the protective effects of these cells against autoimmune destruction of islet -cells. Sertoli cells were purified from testes of NOD mice and implanted under the right renal capsule of diabetic NOD mice, whereas NOD islets were implanted under the left renal capsule. Of the mice that received islet and Sertoli cells grafts, 64% (9 of 14) remained normoglycemic at 60 days posttransplantation compared with 0% (0 of 6) of the mice that received islet grafts alone. Immunohistochemical examination of Sertoli cell grafts in normoglycemic mice revealed that TGF1 expression by Sertoli cells remained high, whereas FasL expression by Sertoli cells decreased progressively posttransplantation. Also, plasma levels of TGF1 were significantly elevated in mice that received Sertoli cells and islet grafts, and anti–TGF1 antibody administration completely abrogated the protective effect of Sertoli cells on islet graft survival, whereas anti-FasL antibody did not. Islet graft destruction in anti–TGF1–treated mice was associated with increases in interferon (IFN)–producing cells and decreases in interleukin (IL)-4–producing cells in the islet grafts. We conclude that 1) Sertoli cell production of TGF1, not FasL, protects islet -cells from autoimmune destruction and 2) TGF1 diverts islet-infiltrating cells from a -cell–destructive (IFN) phenotype to a nondestructive (IL-4) phenotype. Diabetes 49:1810–1818, 2000 Certain tissues such as brain, anterior chamber of the eye, and testis have been termed immunologically privileged because immune responses to “non-self” antigens are reduced at these sites (1). For example, allogeneic (2) and xenogeneic (3) pancreatic islets survive transplantation in the testis with little immunosuppression. Sertoli cells have been identified as the component in testicular tissue that confers immune privilege to tissue allografts (4), including islet allografts transplanted into chemically diabetic rats (5–8) and islet isografts transplanted into NOD mice with autoimmune diabetes (9). The mechanism(s) of Sertoli cell–induced protection of -cells from immunological destruction, however, have not been fully elucidated. Sertoli cells produce a wide variety of proteins, including immunoregulatory factors such as Fas ligand (FasL) and transforming growth factor (TGF)(10,11). FasL expression by testicular tissue has been reported to protect mouse testicular (12) and islet (13) allografts from rejection. In other studies, however, FasL expression by mouse -cells, achieved transgenically (14,15) or by gene transfection (15,16), failed to protect islet allografts, or even isografts, from destruction. TGF1 is a potent suppressor of inflammatory and immune responses, including autoimmune diabetes (17–22); however, this cytokine has not been examined as a possible mediator of the protective effects of Sertoli cells against immunological destruction of islet -cells. Therefore, the aim of the present study was to determine whether FasL and/or TGF1 might mediate the protective effect of Sertoli cells against autoimmune -cell destruction. To address this question, we used the model of syngeneic islet transplantation in NOD mice. We implanted syngeneic Sertoli cells into diabetic NOD mice at the time of syngeneic islet transplantation; then we studied FasL and TGF1 expression by the implanted Sertoli cells and the effects of anti-FasL and anti–TGF1 monoclonal antibody administration on islet graft survival. Our findings demonstrate that TGF1, not FasL, is a mediator of the protective effect of Sertoli cells against autoimmune destruction of islet -cells.