The overall aim of this center proposal is to establish an interdisciplinary basic and clinical research program at Columbia primarily focused on the evaluation of novel therapeutic approaches to five autoimmune diseases; rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), type one diabetes mellitus (TIDM) and scleroderma. In each of these diseases there are ongoing basic and clinical research programs involving pathophysiologic and/or clinical immunotherapeutic studies. We hypothesize that there are four principal events involved in the immunopathogenesis of these diseases: (1) predisposing genes establish a T-cell repertoire capable of recognizing self peptides intrinsic to the autoimmune process; (2) previously tolerant autoreactive effector T cells; (3) regulatory mechanisms, including the activation of TH1 and TH2 CD4+ T cell subsets as well as those involving CD8 T-cells fail, through processes such as clonal deletion or changes in the cytokine milieu and (4) pathogenic autoantibodies develop through cognitive T- cell B-cell interactions which effect tissue injury. In these diseases, one would predict that reducing the clonal expression of relevant autoreactive T cells by blockade of T cell receptor signaling or interruption of the CD40 ligand-dependent pathway could down-modulate disease activity. Moreover, interruption of the inflammatory effector functions of T cells mediated by TNF or CD40L would similarly reduce disease potential. We propose to test these hypotheses in the above patients during the natural history of disease and during specific immune intervention. In particular, we will study patients with SLE treated with anti-CD40L; MS patients receiving IFN-beta or anti-CD40L; T1DM patients receiving anti-CD3 and RA patients receiving the recombinant TNF receptor inhibitor (Embrel). During these studies we will: (1) identify by PCR based spectratyping techniques and TCR sequencing, oligoclonal and autoantigen-driven expansions in the CD4 alphabeta TCR repertoire; (2) Identify changes in the T cell functional response to autoantigens and (3) directly study the regulatory interactions of TH1, TH2 and CD8+ T cells in controlling the TCR repertoire. In select patients, we will directly study the function and repertoire of T cells at the site of inflammation (CNS, Joints) using HVS immortalization techniques.
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