Susceptibility to many autoimmune diseases in linked to class II genes of the major histocompatibility complex (MHC). We have succeeded in treating ongoing paralysis and blocking subsequent relapses of experimental autoimmune encephalomyelitis (EAE) with antibodies to the products of class II MHC genes linked to diseases susceptibility. CD4 positive T cells play a critical role in many autoimmune condition including those where susceptibility is linked to class II MHC genes. Anti-CD4 antibodies can also reverse paralysis in EAE. We have produced highly encephalitogenic CD4 positive T cell clones that recognize peptide fragments of myelin basic protein and that are restricted to class II MHC genes. These clones induce relapsing paralysis and demyelination. We will map the fine specificity of these clones, and clone and sequence the V region genes of their antigen-specific T cell receptors (TcR). We will look for the aberrant and imbalanced expression of Ia products in brain in EAE. We will exploit this information to treat EAE with allele specific anti-Ia antibodies as well as with antibodies to the T cell receptor. We will optimize the therapeutic efficacy of these therapeutic mAb's by producing isotype switch variants. Finally we will test the possible deleterious aspects of immunosuppression with these mAB's by analyzing the effects of immunotherapy directed against either Ia, CD4, or TcR on the response to certain viral, protozoan, and bacterial pathogens.
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