IMMUNIOLOGY OF IMMUNE-MEDIATED THROMBOCYTOPENIAS

University Of Pennsylvania, Philadelphia PA

Investigators

Linked publications & trials

Abstract

Idiopathic thrombocytopenic purpura (ITP), heparin-induced thrombocytopenia (HIT), and thrombotic[unreadable] thrombocytopenic purpura (TTP) are three of the most common antigen-restricted autoantibody-mediated[unreadable] human immunohematological disorders. Yet, the mechanism of autoantibody-induced thrombocytopenia[unreadable] and the natural histories of these disorders differ in ways that suggest fundamental differences in the[unreadable] evolution of autoantibody formation.[unreadable] Children with ITP have a self-limited disease suggesting incitement by an evanescent exogenous antigen[unreadable] with subsequent re-establishment of normal tolerance mechanisms, whereas autoantibody formation persists[unreadable] throughout life in most adults with this disease. Studies of HIT demonstrate that essentially all[unreadable] immunologically "healthy" individuals treated with heparin generate anti-PF4/heparin antibodies suggesting[unreadable] either an anamnestic response to endogenous antigen or polyclonal stimulation by PF4/heparin complexes,[unreadable] e.g. as a superantigen. TTP offers yet a third, ill-studied paradigm in which the clinical disease is transient in[unreadable] 85% of patients, suggesting either a naturally self-limited autoantibody production to ADAMTS13 or a[unreadable] transient enhancement of vWF oligomerization due to vascular injury in the face of persistence of potentially[unreadable] pathogenic antibody.[unreadable] We hypothesize that the fundamental differences in autoantibody production in ITP, HIT and TTP can be[unreadable] explored by determining the genetic restriction and pattern of somatic mutation of the autoantibody[unreadable] repertoire, the role autoantigen plays in the development of the repertoire, the clonality in B-cell response,[unreadable] and the identity of pathogenic B-cell epitopes. This information would provide insight into the molecular basis[unreadable] of pathogenicity and lead to the development of specific and more effective therapies.[unreadable] We propose to utilize several antibody and peptide phage display-based technologies developed in our[unreadable] laboratory to rapidly clone and characterize human monoclonal autoantibodies and test this hypothesis[unreadable] through three interrelated specific aims focused on the autoimmune response in each of these disorders.[unreadable] A comprehensive understanding of the genetic and immunological properties of disease-associated[unreadable] autoantibodies will comprise the essential first step for the creation of novel approaches for antigen-specific[unreadable] modulation such as tolerance induction, peptide-based inhibitors, and DNA vaccination that induces[unreadable] regulatory T-cell responses. Epitope mapping of these antibodies and isolation of peptides based on the[unreadable] antigen-recognition sites will provide valuable reagents for structure/function analysis of the respective[unreadable] autoantigens and the means needed to rationally and specifically modulate their functions in vitro and in vivo.