Testicular sertoli cells protect islet beta-cells from autoimmune destruction in NOD mice by a transforming growth factor-beta1-dependent mechanism.

Abstract

Testicular Sertoli cells protect pancreatic islet grafts from allo- and 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)-beta, immunoregulatory proteins produced by Sertoli cells, might mediate the protective effects of these cells against autoimmune destruction of islet beta-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 TGF-beta1 expression by Sertoli cells remained high, whereas FasL expression by Sertoli cells decreased progressively posttransplantation. Also, plasma levels of TGF-beta1 were significantly elevated in mice that received Sertoli cells and islet grafts, and anti-TGF-beta1 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-TGF-beta1-treated mice was associated with increases in interferon (IFN)-gamma-producing cells and decreases in interleukin (IL)-4-producing cells in the islet grafts. We conclude that 1) Sertoli cell production of TGF-beta1, not FasL, protects islet beta-cells from autoimmune destruction and 2) TGF-beta1 diverts islet-infiltrating cells from a beta-cell-destructive (IFN-gamma+) phenotype to a nondestructive (IL-4+) phenotype.

Genetically engineered Sertoli cells are able to survive allogeneic transplantation

“…In addition to the ability of transplanted SCs to protect themselves in immunologically foreign environments, SCs were shown to protect islets and neuronal cells from immunemediated rejection. 9,10,[14][15][16][17][18][19] The ability of SCs to protect themselves from immunemediated destruction, as well as their ability to produce a variety of proteins, has novel and potentially far-reaching implications for gene therapy. Gene therapy is an emerging field with the goal of replacing defective and deficient proteins to restore function in disease states.…”

“…While the use of SCs to deliver therapeutic proteins has potential applications across numerous clinical situations, the greatest amount of data collected to date have been focused on diabetes and Parkinson's disease (PD). 9,10,[14][15][16][17][18][19] It is not our goal to review these data here; however, it seems intuitively obvious that the consistent ability to graft SCs in animal models of diabetes and PD successfully provides a strong foundation for further exploration of transgenic SCs in these same preclinical systems. For instance, islet transplantation for the treatment of type I diabetes was recently demonstrated to be a viable option.…”

Testicular defense systems: immune privilege and innate immunity

“…24,25 Tissue transplantation studies confirmed that SCs provide immune protection resulting in prolonged survival of grafts after cotransplantation with SCs. 26,27 Most cells undergo apoptosis during spermatogenesis, and the cytoplasmic compartments of sperm form residual bodies that are shed before maturation. Phagocytic removal of the apoptotic germ cells and residual bodies is critical in maintaining testicular homeostasis and normal spermatogenesis.…”

Combination therapy with low dose sirolimus and tacrolimus is synergistic in preventing spontaneous and recurrent autoimmune diabetes in non-obese diabetic mice

“…Also, TGF-b1 somatic gene therapy reduced insulitis and diabetes in cyclophosphamide-accelerated and natural course autoimmune diabetes in NOD mice and pancreatic IL-12 and IFN-g mRNA expression was lower [24]. In addition, we found that TGF-b1 production by testicular Sertoli cells is a mechanism by which these cells protect syngeneic islet grafts transplanted into diabetic NOD mice [25]. Similarly, TGF-b1 has been implicated as a mediator of the diabetes-preventive effects of isletreactive CD4 + T-cell clones [26,27].…”