MONOCYTE CHEMOTACTIC PROTEIN-1 REGULATES ORAL TOLERANCE INDUCTION BY INHIBITION OF T-HELPER CELL 1-RELATED CYTOKINES

Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated a utoimmune demyelinating disease of the central nervous system that ser ves as an animal model for multiple sclerosis. Antigen-specific tolera nce regimens, including oral tolerance, have been used prophylacticall y to prevent development of acute EAE as well as a number of other aut oimmune diseases. Two mechanisms have been proposed to explain the imm unologic basis for disease inhibition: bystander immune suppression an d clonal anergy/deletion. This report demonstrates a novel mechanism f or monocyte chemotactic protein (MCP)-1 as a regulatory factor of oral tolerance. Oral administration of proteolipid protein peptide (PLP139 -151) increased MCP-1 expression in the intestinal mucosa, Peyer's pat ch, and mesenteric lymph nodes. Increase in MCP-1 expression resulted in downregulation of mucosal interleukin (IL)-12 expression with conco mitant increase in mucosal IL-4 expression. Functionally, MCP-1 upregu lation was shown to regulate oral tolerance induction by the ability o f antibodies to MCP-1 to inhibit tolerance induction. The anti-MCP-1 a brogation of oral tolerance induction also resulted in restoration of mucosal IL-12 expression as well as peripheral antigen-specific T help er cell 1 responses. These results demonstrate a novel and important r ole for MCP-1 in the regulation or oral tolerance for the prevention a nd treatment of autoimmune disease.