Contributions of Viruses and Immunity as Causes of Diabetes and Development of Strategies for Treatment and Prevention of Autoimmune Disease

Abstract

This chapter introduces and explains the rat insulin promoter (RIP)-lymphocytic choriomeningitis virus (LCMV) model of vitally induced autoimmune diabetes. Special emphasis is given to the issues of molecular mimicry, the potential involvement of several viral infections in inducing or abrogating insulin-dependent diabetes mellitus (IDDM), new therapeutic perspectives, and pathogenically important findings that stem from the use of this model. The chapter discusses these issues, as well as other factors that precipitate or prevent IDDM. The RIP-LCMV transgenic mouse model differs in some important aspects from other established antigen-specific models of autoimmunity as well as from the nonobese diabetic (NOD) mouse model of spontaneous IDDM. The RIP-LCMV transgenic mouse model is ideally suited for the testing of novel approaches to antigen-specific immune therapy. The induction of IDDM by viral infection can be controlled and is directed to a known and well-characterized self-antigen, the LCMV transgene expressed by the B cells. Mice that expressed LCMV-NP as a transgene in their β cells developed IDDM after LCMV infection. Subsequent inoculation of plasmid DNA that encoded the insulin B chain reduced the incidence of this virally induced autoimmune diabetes by 50%. The protection provided by insulin B-chain DNA proceeded through induction of anti-self, regulatory CD4 lymphocytes that reacted with the insulin B chain, secreted IL-4, and locally reduced the activities of LCMV-NP autoreactive cytotoxic lymphocytes (CTLs) in the pancreatic draining lymph nodes.