MONOCLONAL ITP AUTOANTIBODIES--PARADIGM FOR AUTOIMMUNITY

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The study of autoimmune disease is greatly facilitated by focusing on disorders in which the autoantibodies clearly contribute to the pathogenic process. Because anti-platelet antibodies directly lead to the manifestation of the disease, ITP serves as an excellent model for understanding the pathogenesis of autoimmunity. Clinically, ITP is the most common autoimmune hematologic disorder. It can occur idiopathically or in the context of other disorders of the immune system such as HIV infection, SLE, AIHA and CLL. Therapies aimed directly at modifying the humoral immune response are most frequently utilized, such as steroids and chemotherapy, IVIG, splenectomy and, more experimentally, Staph protein A columns. Despite significant advances in our understanding of ITP, fundamental questions remain unanswered: What causes the breakdown in self-tolerance? Why is ITP associated with those other forms of impaired humoral immune response? Why is there such variability in the natural history and responsiveness to treatment among patient groups? Does IVIG and Rh(D) immune globulin have an antigene-specific mechanism, and why does immunoadsorption on Staph A columns appear effective when plasmapheresis is not? Ultimately, can more specific and reliable forms of therapy be developed? We believe that these clinical observations may be a result of the genetic restriction of these antigen-specific autoantibodies. By determining the spectrum of antigenic specificities and genetic properties of the autoantibody repertoire, one can ask questions regarding the molecular basis for pathogenicity. Earlier technologies were insufficient to determine these relationships. We propose to utilize a powerful new technology known as Fab/phage display to rapidly clone and characterize human platelet autoantibodies and test this hypothesis. The information derived from these studies will provide insight into the role that immune repertoire composition plays in the natural history and therapeutic responsiveness of ITP. This knowledge is critical for the design for future experiments that investigate the regulation of autoimmune responses. A better molecular understanding of the Ig repertoire will comprise the essential first step for the creation of novel approaches for antigen-specific modulation such as tolerance induction, peptide-based inhibitors, and DNA vaccination that induces regulatory T-cell responses. Ultimately, the proposed approach may be applied to the understanding of other autoimmune disorders.