EFFECTS OF CTLA-4 ON THE PROGRESSION OF T1D IN NEW ONSET SUBJECTS

$3,640M01FY2009RRNIH

University Of Florida, Gainesville FL

Investigators

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In the well-studied models of diabetes, it is now widely accepted that Type1 diabetes mellitus-T1DM is mediated by beta-cell specific T-cells. Co-stimulatory pathways are critical in T cell activation and play a central role in organ specific autoimmunity. T cell activation is thought to involve a "two-signal" model of which the B7-1/2 CD28/CTLA-4 co-stimulatory pathway has been shown to play a crucial role in T-cell activation/tolerance. CTLA-4, CD152, is a major regulator of T cell activation and an important regulator of peripheral tolerance induction. The B7-CD28 blockade by administration of CTLA-4 Ig inhibits Th1- IL-2, INF-y but spares Th2 cytokines, IL-4 and IL-10, and leads to Th2 type IgG isotype switching- IgG 1 upregulated. In animal transplantation models, it significantly prolongs transplanted organ survival and in autoimmune models, is effective in animal pancreatic islet transplantation models as well as in preventing diabetes in NOD mice. Human CTLA-4 Ig (Abatacept - Bristol-Myers Squibb) has been extensively tested in subjects with rheumatoid arthritis and is now FDA approved and in clinical use in that patient population. The Ig Fc component of the Abatacept molecule has been modified so that it neither fixes complement nor takes part in antibody-dependent cellular cytotoxicity-ADCC. This agent inhibits/regulates T cell function, but does not deplete T cells in humans. Individuals with psoriasis, multiple sclerosis, and juvenile idiopathic arthritis have also been studied.

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