The long-term objective of this proposal is to understand the mechanisms which control the induction and maintenance of self tolerance. Such information might ultimately enable one to manipulate the immune response, e.g. to dampen the anti-host response in autoimmunity or enhance the response in malignancy. The proposal focuses on tolerance to Mlsa determinants, a class of cell surface antigens which is highly immunogenic for T cells. Three broad groups of experiments are proposed. First, information will be sought on the distribution of Mlsa determinants in the thymus, the main site of tolerance induction. Using T hybridoma cells to measure responsiveness, purified populations of various cell types in the thymus will be tested for Mlsa expression. Second, various approaches will be used to study the mechanism of intrathymic tolerance induction to Mlsa determinants vs. H-2 determinants. The broad aim here is to determine which particular cell types control tolerance induction. This question will be addressed with the aid of thymus-grafted mice and bone marrow chimeras, using primary mixed-lymphocyte reactions and antibodies to T cell receptor molecules to assess tolerance. The third group of experiments concerns tolerance induction at the level of mature post-thymic T cells. Detailed information will be sought on a form of T cell anergy which develops in adult mice after injection of Mlsa-positive lymphoid cells.
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