Selective immunotherapy of iddm: a discussion based on new findings from the RIP-LCMV model for autoimmune diabetes ☆

THE USE of animal models to define and test novel immunotherapeutic approaches for type I autoimmune diabetes (IDDM) has elicited increasing interest. The goal is to selectively influence the autoimmune process in the islets of Langerhans by dampening or increasing certain immune functions without significantly affecting the overall immune competence of the host. In contrast to generalized systemic immunosuppression using chemotherapeutic drug regimens, this novel strategy attempts to identify and then modulate key molecules and regulators that are specific only for the pathogenesis of IDDM. The appealing aspect is that side effects can be kept to a minimum, and therefore a large collective of individuals at risk for developing IDDM could be treated. For testing such approaches quickly, small animal models are the best tools. The focus of this article is to describe more recent findings using a transgenic mouse model, the RIP-LCMV mice, and discuss their relevance for pointing out strengths and pitfalls in future immunotherapy of human IDDM. The pathogenesis of IDDM is a multifactorial process that is influenced by genetic host factors as well as environmental influences, for example viral infections. It involves a chain of immunologic events that have to occur before enough insulin-producing b cells are destroyed to generate clinical symptoms. Many steps of this process have been defined through studies on animal models or humans. The key events are displayed in Fig 1 and numbered 1 through 10. Most of the stages allow selective immunologic interventions and could form the basis for efficient immunotherapy. The purpose of this article is to identify the key stages that are suited for immunomodulatory approaches (Fig 1) and discuss the supporting evidence from the rat insulin promoter-lymphocytic choriomeningitis (RIP-LCMV) and other models, including the relevance for potential therapeutic approaches. In this way, I hope to shine more light on the multiple facets of immunotherapy for IDDM and provide some ideas and guidelines for future drug development and clinical testing in prediabetic or recently diabetic individuals. The RIP-LCMV model for autoimmune diabetes that will form the basis for the discussions in this article was developed in 1991 independently by Michael Oldstone and Rolf Zinkernagel and Hans Hengartner. These transgenic mice express proteins from LCMV under control of the RIP in their b cells. Expression of the proteins as target self-antigens does not lead to disease or islet cell dysfunction. However, the animals are not tolerant to the viral proteins because infection with LCMV induces IDDM in 90 to 100% of the transgenic mice but never in nontransgenic controls. IDDM is characterized by lymphocytic infiltration of islets by CD4 and CD8 cytotoxic T lymphocytes (CTL) resulting in their destruction and does not occur in the absence of CTL. Animals from lines that develop IDDM more slowly require participation of CD4 and CD8 lymphocytes for disease development and some also exhibit auto-antibodies to GAD and insulin (M.G. von Herrath, T. Dyrberg, W. Hagopian, and M.B.A. Oldstone, unpublished results), which indicate that the autoimmune process spreads from the initial target LCMV antigen. The advantage of this diabetes model is that the initiating self-antigen is known, autoreactive lymphocytes can be precisely tracked, and the time-point for induction of autoimmunity can be experimentally chosen. It exhibits most features that have been found or postulated for human IDDM and offers a suitable therapeutic window between triggering of disease (LCMV infection) and clinical IDDM (2 weeks to 6 months).