Kägi D, Odermatt B, Seiler P, Zinkernagel R M, Mak T W, Hengartner H
Ontario Cancer Institute, Toronto M5G2M9, Canada.
J Exp Med. 1997 Oct 6;186(7):989-97. doi: 10.1084/jem.186.7.989.
To investigate the role of T cell-mediated, perforin-dependent cytotoxicity in autoimmune diabetes, perforin-deficient mice were backcrossed with the nonobese diabetes mouse strain. It was found that the incidence of spontaneous diabetes over a 1 yr period was reduced from 77% in perforin +/+ control to 16% in perforin-deficient mice. Also, the disease onset was markedly delayed (median onset of 39.5 versus 19 wk) in the latter. Insulitis with infiltration of CD4(+) and CD8(+) T cells occurred similarly in both groups of animals. Lower incidence and delayed disease onset were also evident in perforin-deficient mice when diabetes was induced by cyclophosphamide injection. Thus, perforin-dependent cytotoxicity is a crucial effector mechanism for beta cell elimination by cytotoxic T cells in autoimmune diabetes. However, in the absence of perforin chronic inflammation of the islets can lead to diabetogenic beta cell loss by less efficient secondary effector mechanisms.
为了研究T细胞介导的、穿孔素依赖性细胞毒性在自身免疫性糖尿病中的作用，将穿孔素缺陷小鼠与非肥胖糖尿病小鼠品系进行回交。结果发现，在1年的时间里，自发性糖尿病的发生率从穿孔素+/+对照组的77%降至穿孔素缺陷小鼠的16%。此外，后者的疾病发病明显延迟（中位发病时间为39.5周对19周）。两组动物中CD4(+)和CD8(+) T细胞浸润的胰岛炎情况相似。当通过注射环磷酰胺诱导糖尿病时，穿孔素缺陷小鼠的发病率较低且疾病发病延迟也很明显。因此，穿孔素依赖性细胞毒性是自身免疫性糖尿病中细胞毒性T细胞消除β细胞的关键效应机制。然而，在没有穿孔素的情况下，胰岛的慢性炎症可通过效率较低的次级效应机制导致致糖尿病的β细胞丢失。
