T cell induction by MBP and MBP peptides will be compared. In this way, the dominant determinants sin each strain that can activate responses, when MBP is the immunogen, will be learned. T cell clones will be raised to suitable determinants to be used to accomplish the other specific aims. The specificity of these clones for Class II MHC proteins will be studied, and the clones will be used to establish which portions of proteins will be studied, and the clones will be used to establish which portions of MBP determinants bind to Class II MHC in antigen presentation. Chimeric peptides employing dominant and subdominant determinants will be used to study mechanisms responsible for immunodominance hierarchies. The plasticity of the T cell repertoire will be examined by studying parent-- F1 chimeras (C57L-- (B10.PL x C57BL/6)F1); (SJL- (B10.PL x SJL)F1) in which each of these donors has a genetically truncated repertoire missing several V-beta genes. In the MBP response to the dominant, aminoterminal determinant in B10.PL mice, the V-beta genes used in the T cell response are highly restricted. These V- beta genes are missing in C57L and SJL mice: the question is whether the remainder of the V-beta genes in the truncated repertoires of C57L and SJL animals suffice to produce a response? The induction of T cell clonal inactivation tolerance to both dominant and subdominant peptides (either encephalitogenic or non encephalitogenic) will be studied in the 3 strains, in particular to determine the effect on the response and induction of disease to MBP. Furthermore, we will attempt to induce tolerance to MBP at birth or in adulthood and determine whether tolerance is only induced to dominant determinants. T suppressor cell-inducing determinants (SD) on MBP will be identified SD on lysozyme will be """"""""grafted"""""""" onto MBP peptides capable of inducing EAE in an effort to prevent the T cell response to the latter peptides. The specificity of clonal """"""""vaccination"""""""" experiments will be studied in the 3 mouse strains as well as in vitro. The protection afforded by this vaccination has been attributed to idiotype-specific interactions and we will attempt to define whether the idiotypes recognized are related to specific T cell idiotypic structure for antigen or MHC recognition.
Showing the most recent 10 out of 21 publications
