Chronic intravenous injections of antigen induce and maintain tolerance inT cell receptor-transgenic mice

Antigen-specific T cell tolerance can be induced by systemic injection of h igh-dose antigen. In particular, a single intravenous (i.v.) injection of i nfluenza virus hemagglutinin peptide in HNT-TCR transgenic mice induces T c ell tolerance through thymocyte apoptosis as well as anergy and deletion of peripheral CD4(+) T cells. We now show that this tolerance is reversed aft er 8 weeks probably due to the short in vivo half-life of the peptide. Sinc e durable tolerance is required for this strategy to be of therapeutic valu e, we tested whether weekly i.v. injections of peptide (up to 12 weeks) cou ld maintain the CD4(+) T cell tolerance. Each injection induces a profound deletion of thymocytes, although their level recovers before the next injec tion. Therefore, during the treatment period, the thymus undergoes cycles o f contraction/expansion. In the periphery, the number of CD4(+) T cells is stably decreased and the persisting CD4(+) T cells are hyporeactive both in vitro and in vivo. This tolerance is essentially peripheral since comparab le results were obtained in thymectomized HNT-TCR mice injected weekly. Our data show that stable antigen-specific tolerance can be induced by repeate d i.v, injections of antigen. These findings might have implications for th e treatment of T cell-mediated autoimmune diseases.