Suarez-Pinzon W, Korbutt G S, Power R, Hooton J, Rajotte R V, Rabinovitch A
Department of Medicine, University of Alberta, Edmonton, Canada.
Diabetes. 2000 Nov;49(11):1810-8. doi: 10.2337/diabetes.49.11.1810.
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.
睾丸支持细胞可保护胰岛移植免受同种异体和自身免疫性破坏；然而，保护机制尚不清楚。本研究的目的是确定支持细胞产生的免疫调节蛋白——Fas配体（FasL）和/或转化生长因子（TGF）-β是否可能介导这些细胞对胰岛β细胞自身免疫性破坏的保护作用。从非肥胖糖尿病（NOD）小鼠的睾丸中纯化支持细胞，并将其植入糖尿病NOD小鼠的右肾包膜下，而将NOD胰岛植入左肾包膜下。接受胰岛和支持细胞移植的小鼠中，64%（14只中的9只）在移植后60天仍保持正常血糖水平，而仅接受胰岛移植的小鼠中这一比例为0%（6只中的0只）。对血糖正常小鼠的支持细胞移植进行免疫组织化学检查发现，支持细胞的TGF-β1表达保持较高水平，而支持细胞的FasL表达在移植后逐渐降低。此外，接受支持细胞和胰岛移植的小鼠血浆中TGF-β1水平显著升高，给予抗TGF-β1抗体完全消除了支持细胞对胰岛移植存活的保护作用，而抗FasL抗体则没有。抗TGF-β1处理的小鼠中胰岛移植破坏与胰岛移植中产生干扰素（IFN）-γ的细胞增加以及产生白细胞介素（IL）-4的细胞减少有关。我们得出结论：1）支持细胞产生的TGF-β1而非FasL可保护胰岛β细胞免受自身免疫性破坏；2）TGF-β1将浸润胰岛的细胞从β细胞破坏性（IFN-γ+）表型转变为非破坏性（IL-4+）表型。
