ORAL TOLERANCE AS THERAPY FOR EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS AND MULTIPLE-SCLEROSIS - DEMONSTRATION OF T-CELL ANERGY

Experimental autoimmune encephalomyelitis (EAE) is an important model for developing therapies for multiple sclerosis (MS). The oral adminis tration of the central nervous system antigen, myelin basic protein (M BP), to Lewis rats and susceptible mouse strains prior to MBP immuniza tion prevents the induction of EAE. Clinical trials administering myel in orally to MS patients have met with only partial success, and thus require that oral tolerance be further studied to improve this treatme nt strategy. Clonal anergy, clonal deletion, immune deviation from Th1 to Th2 T cell subsets, and active suppression by TGF-beta-secreting T cells have all been implicated as possible mechanisms in oral toleran ce. Which mechanism predominates depends on antigen dosage, frequency of feeding, and timing of antigen administration. In this study, we ha ve characterized T cells derived from MBP-fed rats and determined the level of their unresponsiveness. Myelin basic protein-specific T cells are indeed present although in reduced numbers in lymphoid tissue of orally tolerized animals. Following several cell divisions in the pres ence of IL-2, these MBP-specific T cells undergo a dramatic reversal o f unresponsiveness, proliferate in response to MBP and are capable of transferring EAE. These results support clonal anergy as an important mechanism for oral tolerance. Recent developments in clinical trials o f oral tolerance are described.