Interferon-gamma is essential for destruction of beta cells and development of insulin-dependent diabetes mellitus

Abstract

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.

Figure 1

Incidence of IDDM (blood glucose >300 mg/dl) in RIP LCMV (NP or GP) IFN-γ– deficient or –competent tg mice. Blood glucose levels were measured at 2-wk intervals as described in Materials and Methods, 10 mice per group were analyzed. LCMV-treated mice were challenged with 2 × 10³ PFU LCMV intraperitoneally.

Figure 2

Histopathology and immunochemical analysis of islets of Langerhans in LCMV-infected RIP LCMV (NP) IFN-γ–deficient or –competent tg mice. Immunohistochemical staining of consecutive 5-6 micron sections of islets was carried out as described in Materials and Methods. At least three different areas were surveyed per mouse. 10 mice were studied from each experimental group. Representative sections are shown that were similar for each mouse in that particular group. Sections shown were processed and stained at the same time. Original magnification is 200. Panels A–F indicate tg mouse strain, time after infection, and staining method applied.