von Herrath M G, Oldstone M B
Scripps Research Institute, Department of Neuropharmacology, La Jolla, California 92037, USA.
J Exp Med. 1997 Feb 3;185(3):531-9. doi: 10.1084/jem.185.3.531.
Autoimmune mediated destruction of beta cells of the islets of Langerhans leads to insulin-dependent diabetes mellitus (IDDM). Rat insulin promoter (RIP) lymphocytic choriomeningitis virus (LCMV) transgenic mice that express the nucleoprotein (NP) or glycoprotein (GP) of LCMV under control of the RIP in their beta cells develop IDDM after infection with LCMV and serve as a model for virus-induced IDDM. Recently, Kagi et al. (Kagi, D., B. Odermatt, P. Ohashi, R.M. Zinkernagel, and H. Hengartner, 1996, J. Exp. Med. 183:2143-2149) showed, using RIP LCMV perforin-deficient mice, that IDDM does not occur in the absence of perforin. They concluded that perforin-mediated killing by cytotoxic T lymphocytes (CTLs) is the main factor needed for beta cell injury and destruction. Here we provide evidence that killing of beta cells is more complex and multifactorial. By the use of our RIP LCMV model, we show that in perforin competent but interferon-gamma (IFN-gamma)-deficient mice, beta cell injury is limited and IDDM does not occur. For these studies, double transgenic mice were generated that were genetically deficient in the production of IFN-gamma and express LCMV NP or GP in their beta cells. In such mice, IDDM was aborted despite the generation of LCMV-specific antiself CTLs that displayed normal cytolytic activity in vitro and in vivo and entered the pancreas. However, mononuclear infiltration into the islets did not occur, and upregulation of class I and II molecules usually found in islets of RIP LCMV single transgenic mice after LCMV infection preceding the onset of clinical IDDM was not present in these bigenic mice. Our findings indicate that in addition to perforin, beta cell destruction, development of insulitis, and IDDM also depend on the cytokine INF-gamma, presumably through enhancement of major histocompatibility complex expression and antigen presentation.
自身免疫介导的胰岛β细胞破坏会导致胰岛素依赖型糖尿病（IDDM）。大鼠胰岛素启动子（RIP）淋巴细胞性脉络丛脑膜炎病毒（LCMV）转基因小鼠在其β细胞中，在RIP的控制下表达LCMV的核蛋白（NP）或糖蛋白（GP），感染LCMV后会发生IDDM，并作为病毒诱导的IDDM模型。最近，卡吉等人（卡吉，D.，B.奥德马特，P.大岛，R.M.津克纳格尔，和H.亨加特纳，1996年，《实验医学杂志》183:2143 - 2149）使用RIP LCMV穿孔素缺陷小鼠表明，在没有穿孔素的情况下不会发生IDDM。他们得出结论，细胞毒性T淋巴细胞（CTLs）通过穿孔素介导的杀伤是β细胞损伤和破坏所需的主要因素。在这里，我们提供证据表明β细胞的杀伤更为复杂且是多因素的。通过使用我们的RIP LCMV模型，我们表明在具有穿孔素但缺乏干扰素 - γ（IFN - γ）的小鼠中，β细胞损伤是有限的，且不会发生IDDM。对于这些研究，我们构建了双转基因小鼠，这些小鼠在基因上缺乏IFN - γ的产生，并且在其β细胞中表达LCMV NP或GP。在这类小鼠中，尽管产生了LCMV特异性的抗自身CTLs，这些CTLs在体外和体内均表现出正常的溶细胞活性并进入胰腺，但IDDM仍未发生。然而，胰岛中没有单核细胞浸润，并且在临床IDDM发作之前，LCMV感染后通常在RIP LCMV单转基因小鼠胰岛中出现的I类和II类分子上调在这些双转基因小鼠中并未出现。我们的研究结果表明，除了穿孔素之外，β细胞破坏、胰岛炎的发展以及IDDM还依赖于细胞因子INF - γ，大概是通过增强主要组织相容性复合体的表达和抗原呈递来实现的。
