This Program Project brings together a group of investigators in a study of the molecular and cellular origins of determinant recognition by the immune system. The program will capitalize on the availability of a core facility for peptide synthesis and characterization. The research will approach the question of determinant recognition at two levels. In Program I, Dr. Wilson will continue the structural analysis of influenza hemagglutinin (HA), an antigen which will serve as a common denominator throughout all. He will also analyze the structural constraints inherent in the interaction between HA determinants, (peptides), and the combining site of monoclonal antibodies. The basis of determinant recognition of another level, that of the determination of humoral and cellular responses, will be the common purpose of the remaining five programs. In Program II, Dr. Lerner will analyze the recognition of the influenza HA at the peptide level and extend these studies to the recognition of hepatitis B antigens. These studies will address the role of topographic vs. linear determinants in the immunogenicity of biologically relevant proteins. The basis for determinant recognition and non-recognition will be addressed in Program III by Dr. Klinman, using responses of immature (environmentally naive) and mature B cells to peptides representative of self protein determinants. In addition, Dr. Klinman will also investigate the role of environmental selection on the repertoire of B cells which recognize foreign antigens only in the context of self MHC alloantigens. The determination of the T cell repertoire that recognizes MHC alloantigens per se and foreign antigens in the context of MHC alloantigens will be the major preoccupation of Programs IV-VI. In Program IV, Dr. Chiller will investigate th role of macrophage Ia antigen presentation in the positive and negative selection of MHC restricted helper T cells. In Program V, Dr. Sherman will investigate the role of """"""""conformational"""""""" determinants of H-2 in both alloantigen and foreign antigen recognition by cytolytic T lymphocytes (CTL). The potential role of positive selection by the developing environment of CTL will be investigated in Program VI by Dr. Bevan. By maximizing the use of common antigens and peptides such as those representative of HA and H-2, the collaborative interactions which are fostered should greatly enhance each of these approaches.
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