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William J. Karpus^*, Kevin J. Kennedy^*, Steven L. Kunkel, and Nicholas W. Lukacs

From the ^* Department of Pathology, Immunobiology Center, Robert H. Lurie Cancer Center, and Institute for Neuroscience, Northwestern University Medical School, Chicago, Illinois 60611; and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109

Experimental autoimmune encephalomyelitis (EAE) is a T cell–mediated autoimmune demyelinating disease of the central nervous system that serves as an animal model for multiple sclerosis. Antigen-specific tolerance regimens, including oral tolerance, have been used prophylactically to prevent development of acute EAE as well as a number of other autoimmune diseases. Two mechanisms have been proposed to explain the immunologic basis for disease inhibition: bystander immune suppression and clonal anergy/deletion. This report demonstrates a novel mechanism for 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 patch, and mesenteric lymph nodes. Increase in MCP-1 expression resulted in downregulation of mucosal interleukin (IL)-12 expression with concomitant increase in mucosal IL-4 expression. Functionally, MCP-1 upregulation was shown to regulate oral tolerance induction by the ability of antibodies to MCP-1 to inhibit tolerance induction. The anti–MCP-1 abrogation of oral tolerance induction also resulted in restoration of mucosal IL-12 expression as well as peripheral antigen-specific T helper cell 1 responses. These results demonstrate a novel and important role for MCP-1 in the regulation or oral tolerance for the prevention and treatment of autoimmune disease.

Address correspondence to William J. Karpus, Department of Pathology, Northwestern University Medical School, 303 E. Chicago Ave., W127, Chicago, IL 60611. Phone: 312-503-1005; Fax: 312-503-8240; E-mail: w-karpus{at}nwu.edu

¹ Abbreviations used in this paper: CNS, central nervous system; EAE, experimental autoimmune encephalomyelitis; MCP, monocyte chemotactic protein; MIP, macrophage inflammatory protein; MLN, mesenteric lymph node; MS, multiple sclerosis; NRS, normal rabbit serum; PLP, proteolipid protein; RANTES, regulated on activation normal T cell expressed and secreted; RT, reverse transcriptase.

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