TOLERANCE INDUCTION AND AUTOIMMUNE ENCEPHALOMYELITIS AMELIORATION AFTER ADMINISTRATION OF MYELIN BASIC PROTEIN-DERIVED PEPTIDE

Experimental autoimmune encephalomyelitis (EAE), a demyelinating disea se of the central nervous system, is an animal model of paralyzing hum an disease, multiple sclerosis. EAE is readily induced by immunization with myelin basic protein (MBP) in mice transgenic for an alpha beta T cell receptor (TCR) that is specific for MBP. Subcutaneous injection of p17 (a peptide consisting of 17 NH2-terminal aminoacids of MBP) in complete Freund's adjuvant (CFA) causes paralysis. Induction of paral ysis is inhibited by prior intraperitoneal injection of the same pepti de in incomplete Freund's adjuvant (IFA). In addition, ongoing paralys is is ameliorated by subsequent intraperitoneal injection of p17 in IF A. Tolerance induction is equally efficient in Fas-deficient and IL-4- deficient TCR-transgenic mice, suggesting that neither activation-indu ced cell death nor differentiation into Th2 type cells plays a role in the tolerance induction. Tolerance induction by p17 seems to be based on reduction in the responsiveness of anti-MBP T cells, as documented by lower overall antigen-induced lymphokine production and proliferat ion, as well as diminished upregulation of early activation marker CD6 9 by tolerized T cells. We propose that continuous encounters of MBP-s pecific T cells with p17 play a critical role in the induction and mai ntenance of tolerance.