Over the past eight years, this laboratory has studied neonatal tolerance induced to alloantigens encoded by genes within the murine major histocompatibility complex, H-2. During the past 2 1/2 years, we have discovered that (a) clonal deletion of cytotoxic T cells specific for tolerated antigens is incomplete in Class I-tolerant mice; (b) the tolerant environment imposes specific unresponsiveness upon immunocompetent cells directed at tolerated Class II alloantigens; and (c) specific unresponsiveness is achieved in part by a suppression mechanism which is donor I-J dependent. In response to these findings we have reformulated our original hypotheses concerning the induction and maintenance of neonatal transplantation tolerances as follows: Neonatal transplantation tolerance is induced and maintained by two different, but complementary, mechanisms: (1) centrally-achieved clonal deletion/inactivation, resulting in drastically reduced precursor cell frequencies compared to non-tolerant animals (for Class I-recognizing cells, the process operates pre-thymically, while for Class II-recognizing cells, the process operates intrahymically); and (2) peripheral suppression that further reduces the remaining Class II-recognizing activity to background, utilizing an I-J dependent process. To test these hypotheses, we propose the following experimental approaches: (1) Compare and contrast pre- and intrathymic environments as sites at which clonal deletion/inactivation of developing T cells with different functions can occur; (2) characterize the tolerogen-specific T cells that are present within tolerant animals, using in vitro cellular as well as molecular biological approahces, in an effort to identify not only the site(s) at which clonal deletion operates, but to understand its effect upon the T cell repertoire; in addition, to extend this analysis to the B lymphocyte compartment which also appears to contain tolerogen-specific cells in tolerant mice; (3) employ assays of delayed hypersensitivity to measure H-2 specific alloimmunity as an efficient method for the study of the active suppression mechanism that down regulates allo Ia-reactive T cells in Class II tolerant mice; and (4) analyze the mechanisms by which donor I-J determinants dictate the induction and maintenance of tolerance to Class II alloantigens. The results of these proposed experiments will promote our understanding of the relative roles that clonal deletion and active suppression play in tolerance of H-2 alloantigens, and by inference, in tolerance of self antigens.
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