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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL061844-01
Application #
2751779
Study Section
Special Emphasis Panel (ZHL1-CSR-K (S1))
Project Start
1998-09-30
Project End
2003-08-31
Budget Start
1998-09-30
Budget End
1999-08-31
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Siegel, Don L (2008) Translational applications of antibody phage display. Immunol Res 42:118-31
Siegel, Don L (2005) Developing phage display tools for use in transfusion medicine. Transfusion 45:100S-108S
Silverman, Gregg J; Goodyear, Carl S; Siegel, Don L (2005) On the mechanism of staphylococcal protein A immunomodulation. Transfusion 45:274-80
Abrams, Charles S; Cines, Douglas B (2004) Thrombocytopenia after treatment with platelet glycoprotein IIb/IIIa inhibitors. Curr Hematol Rep 3:143-7
Roark, Jessica H; Bussel, James B; Cines, Douglas B et al. (2002) Genetic analysis of autoantibodies in idiopathic thrombocytopenic purpura reveals evidence of clonal expansion and somatic mutation. Blood 100:1388-98
Cines, Douglas B; Blanchette, Victor S (2002) Immune thrombocytopenic purpura. N Engl J Med 346:995-1008
Siegel, D L (2002) Recombinant monoclonal antibody technology. Transfus Clin Biol 9:15-22
Siegel, D L (2001) Research and clinical applications of antibody phage display in transfusion medicine. Transfus Med Rev 15:35-52
Tagaya, M; Haring, H P; Stuiver, I et al. (2001) Rapid loss of microvascular integrin expression during focal brain ischemia reflects neuron injury. J Cereb Blood Flow Metab 21:835-46
Arepally, G M; Kamei, S; Park, K S et al. (2000) Characterization of a murine monoclonal antibody that mimics heparin-induced thrombocytopenia antibodies. Blood 95:1533-40