The investigators recently reported that encephalitogenic myelin basic protein (MBP) peptide 63-81 elicits EAE in DA rats when given in incomplete Freund's adjuvant (IFA). The induction of this autoimmune disease without the use of Mycobacteria eliminates one of the more artificial aspects of the EAE model. This protocol elicits tolerance in most susceptible rodents, and our studies suggest that a defect in tolerance induction may exist in DA rats. However, autoimmune diseases do not develop spontaneously in DA rats, which suggests that this strain also possess potent immunoregulatory processes that maintain immunological homeostasis. In recent studies, we have found that DA rats have potent natural killer (NK) cell activity. We also reported in Lewis (LEW) rats, that the aspartic acid residue at position 82 of MBP73-86, the dominant encephalitogenic epitope of guinea pig MBP, is a T cell receptor (TCR) contact residue that is critical for the activation of encephalitogenic V, 88.2+ T cells and induction of EAE. Analogs of MBP73-86 with substitutions at position 82 are not encephalitogenic, but appear to protect against EAE.
Three Specific Aims are proposed:
Aim l. To test the hypothesis that a generalized defect in tolerance induction exists in uniquely EAE-susceptible DA rats. We will evaluate other tolerance induction protocols and ascertain the underlying mechanism.
Aim 2. To determine whether NK cells maintain immunological homeostasis in autoimmune disease-susceptible DA rats.
Aim 3. To determine how Thl cells specific for nonencephalitogenic peptide analogs of MBP suppress EAE in LEW rats. Our objective is to ascertain how the activation of autoreactive encephalitogenic T cells is controlled, and how they evade immunological homeostasis to become activated and elicit autoimmune disease.
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