| In addition to their clearly essential role in the induction and maintenance of effective immune responses that eradicate foreign pathogens, Th cells have also been implicated as the initiators of autoimmunity. One well-studied model of CD4+ T-cell mediated autoimmunity is experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. The main goal of this dissertation is to investigate novel methods of controlling unwanted anti-self immune responses in EAE.; To more uniformly control polyclonal antigen-specific CD4+ T cell responses, we have designed peptide analogs containing substitutions at MHC anchor residues. Stimulation with an MHC anchor substituted peptide of MOG 35--55 possessing a 200-fold lower affinity for I-Ab resulted in anergy in several MOG 35--55-specific T cell clones as well as polyclonal populations. In contrast, a classic altered peptide ligand possessing affinity for I-A b similar to that of wild-type MOG 35--55 resulted in anergy in one MOG 35--55-specific T cell clone but did not anergize polyclonal MOG 35--55-specific T cells. These results provide evidence that MHC anchor substituted peptides have utility in mitigating the functionality of polyclonal populations of encephalitogenic T cells. While we describe the application of this principle in an EAE model, the approach may have general applicability in modulating other aberrant immune responses where the target antigen is known.; We identified a prominent positive regulatory role for CD43, both during the initial activation and differentiation as well as the homing of potentially encephalitogenic precursors in EAE. CD43-deficient animals developed EAE with decreased severity and delayed kinetics relative to wild-type controls, and CD43-/- CD4+ T cells were less encephalitogenic upon adoptive transfer. Our results suggest that anti-CD43 mAbs may be useful as therapeutic agents for the treatment of MS.; Our study, along with the results of others, reveals an important role for CD8+ effectors during EAE. We identified CD8+ T cells that were specific for MOG 37--50 by intracellular cytokine and tetramer staining, and demonstrate that they induce EAE upon adoptive transfer into naive recipients. Importantly, these studies suggest that future therapies should endeavor to control the CD8+ T cell response in EAE and MS. |
