We hypothesize that there are four principal events in the development of SLE: (1) genes predisposing to SLE establish a T-cell repertoire capable of recognizing self peptides intrinsic to the autoimmune process of SLE: (2) previously tolerant autoreactive CD4 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) injurious IgG autoantibodies develop through cognitive T-cell B-cell interactions and in concern with potentially self reactive T-cells induce tissue damage and disease. The overall aim of this grant is to study patients at different stages of SLE activity and to use the opportunity presented by an ongoing clinical trial of a humanized monoclonal antibody (moAb) to CD40L in systemic lupus erythematosis (SLE) to study the immunopathogenesis of SLE and the basic mechanisms of the therapeutic intervention in this disorder. In principle, interruption of the CD40 ligand-dependent pathway could down-modulate SLE activity by acting at the distal level of the cognitive T-B interaction involved in IgG autoantibody production or at the induction and regulation of autoreactive T-cell clones. These more proximal mechanisms for anti-CD40L treatment would diminish the number of autoreactive cells in the T cell repertoire. We propose to test hypotheses relating to both the immunopathogenesis of SLE and the basic mechanism of the therapeutic intervention using anti-CD40L treatment. Specifically our aims are: (1) To identify by PCR based spectratyping techniques and T cell receptor (TCR) sequencing, oligoclonal and putatively autoantigen-driven expansions of the CD4 alphabeta TCR repertoire in SLE patients compared with those treated with moAb to CD40L: (2) Identify changes in the T cell functional response to autoantigens including Ro, La. These functional studies will include assay of T-B interactions in T cell activation, tolerance and help assays and (3) directly study the regulatory interactions of TH1, TH2 cells as well as CD8+T cells in controlling the TCR repertoire in SLE during anti-CD40L treatment. In select patients we will directly study the function and repertoire of T cells at the site of inflammation (kidney) using HVS immortalization techniques.
Showing the most recent 10 out of 32 publications
