| In Part I of this work, the relative efficiency of soluble peptide tolerance and coupled-cell tolerance in both preventing and ameliorating EAE was evaluated by performing side-by-side comparative studies. The results demonstrate the greater capability of peptide-coupled cells to positively impact disease progression after onset of clinical symptoms in mice. In addition, results show that intravenous injection of soluble peptide or peptide oligomer, but not antigen-coupled splenocytes, after the peak of acute disease can lead to antibody- and histamine-dependent anaphylaxis. IgE crosslinking of FcepsilonRI appears to be both necessary and sufficient for this myelin peptide-induced anaphylaxis. Along with the greater therapeutic efficacy, this makes coupled-cell tolerance a much more attractive candidate for clinical use.; It was therefore important to demonstrate that multiple myelin peptides could be coupled to donor cells and efficiently used to simultaneously induce immune tolerance to multiple antigenic specificities during ongoing EAE associated with multiple pathogenic autoreactivities. Part II of this work demonstrates the ability of multiple myelin peptide coupled-cell tolerance to prevent the onset of EAE, to prevent future relapses when administered during ongoing disease, and to effectively ameliorate ongoing EAE in which four separate myelin specificities are simultaneously playing a pathogenic role. Ex vivo and in vitro studies indicate roles for both T cell anergy induction and regulatory T cells in this process, although anergy induction appears to be less of a factor in coupled-cell tolerance induced during ongoing disease.; Part III explores the possible mechanisms by which coupled-cell tolerance could be acting. While deletion was not found to play a major role, it was ascertained that both T cell anergy induction and the induction, activation, and/or expansion of regulatory CD4+CD25+ T cells result from coupled-cell tolerance induction. In addition, it is clear that there is a differential involvement of the splenic and lymph node compartments, evidenced by the facts that there is a disparate pattern of anergy induction in the T cells in the spleen versus lymph nodes and that CD4+ T cells from the spleen, but not from the lymph nodes, of previously tolerized mice are capable of transferring tolerance to naive mice. |
