Insulin dependent diabetes mellitus (IDDM) also known as Type l diabetes is an autoimmune disease of unknown etiology is manifested as destruction of beta cells in the pancreatic islets of Langerhans. T cells are implicated in the pathogenesis of this multigenic inflammatory disease. From an immunological point of view, two hypotheses (at least) can be suggested for the development of human IDDM. The first states that beta cell destruction is an autoantigen targeted process; the second that beta cell destruction is the result of an inflammatory process that is not specifically directed to those cells but results in their destruction because of their susceptibility to cytokines produced by infiltrating cells. Transgenic mice will be used to evaluate these hypotheses and to study mechanisms of inflammation. The long term goal of this project is to evaluate the role of tumor necrosis factor-alpha (cachectin) and beta (lymphotoxin) in the pathogenesis of IDDM. Mice transgenic for the rat insulin promoter II (RIP) driving TNF-alpha or TNF-beta express the transgene in their islets. Both types of RIP-TNF mice exhibit periinsulitis and insulitis, but no beta cell destruction, insulin reduction, or diabetes. These animals appear to be locked in the first stages of IDDM.
The specific aims and methods to evaluate the cells and mechanisms of inflammation and pathogenesis in a transgenic model of IDDM are: A) To determine the requirements for progression from periinsulitis and insulitis to diabetes in TNF transgenic mice by testing whether TNF under the control of the glucagon promoter also induces inflammation and then analyze the response of RIP-TNF and GLU-TNF mice to activation signs (anti-CD3, anti-CD 28, superantigens) delivered in vivo or in vitro. TNF transgenic mice will be compared to NOD mice, a well established model of human IDDM and crossed to mice that possess the NOD but lack the background genes to determine if TNF expression in the islets can substitute for these genes; B)To determine the role of T cells specific or not for beta antigens in inflammation and beta cell destruction in TNF transgenic mice by analyzing T cells specific for GAD, BSA, and additional islet antigens or highly purified homogeneous populations of cells activated to cytochrome c or ovalbumin; C)To determine the mechanism of inflammation and beta cell destruction in TNF transgenic mice by analyzing the role of T and B cells, adhesion molecules, MHC antigens, cytokines, and chemokines. Transgenic mice that express TNF at inappropriate levels in islet tissue represent an interesting model system to test the mechanism of inflammation and beta cell destruction in IDDM and the role of particular immunologic cells in this process. They provide a unique opportunity to investigate the effect of targeted expression of a single cytokine gene on autoimmune disease pathogenesis.
