ABO ANTIBODIES--PARADIGM FOR HUMAN REPERTOIRE EVOLUTION

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DESCRIPTION (Adapted from applicants' abstract) This application comprises a five-year plan for the candidate to develop the skills and experience necessary to combine basic science research with the teaching and practice of Transfusion Medicine. The candidate has completed three years of formal residency training, is board certified in Clinical Pathology, and has been working in his co-sponsors' laboratories acquiring preliminary data for the proposed studies. The candidate's basic research interests lie in antigenicity and the development of humoral immune responses, particularly in antibody diversity and the development of specificity. The immune response to the human ABO blood group system is ubiquitous and is the most important determinant in Transfusion Medicine and allogeneic transplantation. Despite its discovery nearly a century ago, essentially nothing is known about the structure and diversity of anti-ABO antibodies on a molecular level. This is in large part due to the difficulty in producing human monoclonal anti-ABO antibodies in vitro. The proposed research will utilize a recently-described bacteriophage display system for isolating- and expressing recombinant human anti-ABO antibodies. The antibody molecules thus produced will be used to ask basic questions relating to the structure and fine specificity of ABO antibodies produced by individuals of blood groups A, B, and 0. This information will provide an understanding of the repertoires of anti-ABO antibodies at a molecular level which may eventually lead to novel methods for immunomodulating this response in the clinical settings of blood transfusion, hemolytic disease of the newborn, and solid organ, bone marrow, and xeno-transplantation. The laboratories of the sponsors, Drs. Don Siegel and Steven Spitalnik, provide a unique and ideal environment in which to undertake the proposed research project. Dr. Siegel has been instrumental in introducing bacteriophage display technology into the field of Transfusion Medicine. Dr. Spitalnik is a well-recognized expert in the characterization of red cell carbohydrate antigen/antibody interactions. Together, Dr. Chang's sponsors are part of a Transfusion Medicine section led by Dr. Les Silberstein, a member of the candidate's proposed advisory committee, which has recently established an NHLBI-funded Specialized Center of Research in transfusion Medicine and Biology. Along with the candidate's proposed consultants in the areas of molecular modeling and surface plasmon resonance, Dr. Chang will gain the technical and professional expertise to make future contributions to the field of immunohematology as an independent clinical scientist. (End of Abstract)