New approach to immunotherapy against organ-specific autoimmune diseases with T cell receptor and chemokine receptor DNA vaccines.

Abstract

Organ-specific autoimmune diseases are characterized by the presence of relapse and remittance of the clinical signs, and last for a long period of time in most cases without an appropriate treatment. Immunopathologically, T cells that respond to organ-specific autoantigens play an important role in the development of inflammatory lesions in the target organ. These pathogenic T cells that had been activated by various stimuli including preceding infection infiltrate the target organ in an antigen-specific manner and break the homeostasis of the organ. Furthermore, they secrete a large number of pro-inflammatory cytokines and chemokines, which recruit by-stander inflammatory cells in the lesion. Although general immunosuppressive drugs such as corticosteroid and cyclosporine are effective in suppressing clinical signs and inflammation, immunospecific therapy is essential for the establishment of long-lasting remission or complete cure. In order to achieve effective immunospecific therapy, several groups have focused on two key molecules that are deeply involved in pathogenesis of autoimmune diseases. One is the T cell receptor (TCR) expressed on pathogenic T cells and the other is the cytokine and chemokine receptor expressed in the target organ. Another important aspect of this issue is the reagent that is used for the suppression of the function of the key molecules. So far, monoclonal antibodies, peptide vaccines and DNA vaccines are the major reagents used for immunosuppressive therapies. In the present review, I introduce the results of immunotherapy obtained in my laboratory using TCR-based and chemokine receptor (chemoR)-based DNA in experimental autoimmune encephalomyelitis (EAE) and myocarditis (EAC) and discuss its effectiveness and pathomechanisms of immunosuppression. First, we administered DNA vaccines encoding pathogenic TCR Vbeta8.2, 10 (to Lewis rats) and 15 (to DA rats) and observed that these vaccinations protected animals from the development of EAE. Similar results were obtained in EAC. Second, DNAs encoding several chemoRs were prepared and administered after the challenge to neutralize the function of chemokines that are highly upregulated in the lesions. It was demonstrated that these chemoR DNAs suppress the relapse of chronic relapsing EAE and block the progression of EAC to dilated cardiomyopathy (manuscripts submitted for publication). These findings clearly indicate that DNA vaccination can be a powerful tool for treatment of organ-specific autoimmune diseases.