RECOMBINANT T-CELL RECEPTOR MOLECULES CAN PREVENT AND REVERSE EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS - DOSE EFFECTS AND INVOLVEMENT OF BOTH CD4 AND CD8 T-CELLS

Autoimmune diseases are often characterized by spontaneous remission f ollowed by relapses, Although the mechanism(s) controlling pathogenic self-reactive T cells are not fully understood, recent data in experim ental autoimmune encephalomyelitis (EAE), a prototype for CD4 T cell-m ediated autoimmune diseases, indicate that spontaneous recovery is med iated by regulatory T cells (Treg) specific for peptides derived from the beta-chain of the TCR, Here we have tested whether recombinant sin gle-chain TCRs (scTCRs) containing V beta domains can be used as vacci nes for efficient priming of Treg, A single injection of mice with the se recombinant proteins leads to efficient in vivo priming of Treg and almost complete protection from Ag-induced EAE, Significantly, admini stration of scTCRs during ongoing disease at a 10-fold lower dose than that required for prophylactic treatment also reverses established EA E. However, if a higher dose of scTCR is administered during ongoing d isease, paralytic symptoms become exacerbated and the majority of trea ted animals die from severe and chronic EAE, Furthermore, we demonstra te that regulatory determinants are processed and presented from scTCR s resulting in the recruitment of both CD4 and CD8 regulatory T cells which are required for efficient regulation induced by scTCR, Reversal of established disease following an optimum dose of recombinant TCRs suggests that proteins expressing appropriate V beta domains could be used for the treatment of a variety of T cell-mediated pathologic cond itions.