MECHANISMS OF TOLERANCE IN AUTOIMMUNE ARTHRITIS

University Of Tennessee Health Sci Ctr, Memphis TN

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Abstract

DESCRIPTION (provided by applicant): Collagen-induced arthritis (CIA) is a murine model of autoimmune arthritis that has been widely used to determine how autoimmune reactions to type II Collagen (CII) cause arthritis. We have developed a mouse transgenic for a T cell receptor that recognizes the immunodominant epitope of CII. Greater than 95% of the alpha/beta T cells in this mouse express the transgene. As might be expected, it is highly susceptible to CIA and develops an accelerated disease with greater severity than non-transgenic control animals. In spite of the fact that this animal seems poised to develop autoimmunity to CII, it does not develop spontaneous arthritis. However, CIA can be effectively prevented by iv administration of CII. We propose to use this model to study the mechanism by which iv administration of CII prevents the development of arthritis. Our hypothesis is that when CII is administered iv, it induces a state of immune deviation. This immune deviation may be manifested by expression of a unique combination of cell surface markers and by an altered response to CII such that the Th2 cytokines IL-4 and IL-10 are produced rather than the Thl cytokines IFNgamma and IL-2.that characterize an inflammatory response. Our transgenic (Tg) mouse presents us with a unique opportunity to directly address this hypothesis using a quantifiable biological endpoint, the inflammation associated with CIA. We will identify the phenotypic and functional changes that occur in the CII-specific T cells following iv exposure to CII and subsequent challenge with CII to induce autoimmunity. We will analyze the cytokine production by the CII specific T cells; identify the tolerized cells by changes in cell surface markers; and by cell sorting and passive transfer, determine if the tolerance is an "active" process; and verify the identity of the tolerogenic T cells. In addition, we will analyze the molecular interactions that trigger the phenotypic changes observed in the tolerized Tg lymphocytes.