The overall goals of this application are to determine the potential coordinate effects of LT-mediated microenvironment and LIGHT-mediated costimulation in the development of IDDM. Insulin-dependent diabetes mellitus (IDDM) is an autoimmune-mediated destruction of pancreatic islet cells after prolonged insulitis (inflammation and formation of lymphoid structures in the islets). The mechanisms by which the lymphoid structures are formed and their roles in IDDM are undefined. We have recently shown that signaling via lymphotoxin receptor (LTR) by membrane LT (mLT) is essential for the localization of immune cells and the formation of lymphoid structure in the spleen. To explore the potential role of mLT in the development of lymphoid structures in IDDM, LTR-Ig was administered to adult NOD mice and CD28-/-NOD mice. Such treatment dramatically prevents the development of IDDM. Since LTR-Ig blocks the binding of both mLT and LIGHT (a strong T cell costimulating molecule) to their receptors, it is necessary to assess carefully the relative contribution of LT and/or LIGHT in the development of IDDM in NOD mice. We hypothesize that both LT-mediated microenvironment and LIGHT-mediated costimulation in local microenvironment are essential for the development of autoimmune diabetes. Our research has three aims.
The first aim i s to explore whether LT regulates the microenvironment in islets and/or draining lymph nodes (LN) required for the development and maintenance of insulitis and IDDM.
The second aim i s to define the relative contribution of LIGHT in the development of insulitis and IDDM by altering expression of LIGHT. Antibodies and receptor fusion proteins that specifically block LIGHT or transgenic mice that express LIGHT in the pancreas will be generated to study the potential role of LIGHT in priming autoreactive T cells and in forming lymphoid structures. In a search for alternative and complementary treatments for the human IDDM, the third aim is to explore the effectiveness of multiple preventive and therapeutic protocols on NOD mice by the administration of LTR-Ig before and/or after the onset of disease. It is likely that careful use of LTR-Ig will be an effective way to treat the disease. Together, these studies will enhance our ability to understand the role of local microenvironment and LT/LIGHT in the development of autoimmune disorders, which may open a new avenue to treat such diseases.
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