FUNCTIONAL ANALYSIS OF HUMAN IA

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The goals of the proposed studies are to analyze the role of HLA class II diversity in the development of immune responses in man. The epitopes of the tetanus toxin (ttox) antigen which are immunodominant in the context of different class II molecules will be determined. The following questions will be addressed using L cell and B cell transfectants expressing high levels of individual HLA class II molecules: 1)Do the immunodominant epitopes differ in individuals of different DR and DQ type? 2)What is the relative contribution of DQ restricted responses to the total response? 3)In heterogygous individuals, what is the contribution of "hybrid" DQ molecules to the total DQ response? Are different epitopes immunodominant? 4)What is the role of the DQomicron( chain in DQ-restricted responses? 5)Is there any evidence of ttox responses restricted to mixed isotypes and which epitopes are used by such molecules? 6)Are there differences in the DR-restricted response in the context of different DR4 subtypes and will antigen-specific and DR4-restricted T cell be able to distinguish the various DR4 subtypes and to what extent? 7)What is the role of the third hypervariable (HV) region of DR molecules in determining which epitopes are immunodominant in DR restricted responses? T cell responses will be analyzed by measuring both a) bulk proliferative responses and b) the frequency of precursor T cells directed against peptide fragments of the ttox antigen presented by different class II transfectants. In addition, class II-restricted ttox-specific T cell clones will be generated in order to study the effects of structural variation in class II molecules on T cell recognition.