The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/2/537/ $5.00
The Journal of Experimental Medicine, Volume 187, Number 4, February 16, 1998 537-546

Articles

An Interleukin (IL)-10/IL-12 Immunoregulatory Circuit Controls Susceptibility to Autoimmune Disease

Benjamin M. Segal, Bonnie K. Dwyer, and Ethan M. Shevach

From the Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892

Cells of the innate immune system secrete cytokines early in immune responses that guide maturing T helper (Th) cells along appropriate lineages. This study investigates the role of cytokine networks, bridging the innate and acquired immune systems, in the pathogenesis of an organ specific autoimmune disease. Experimental allergic encephalomyelitis (EAE), a demyelinating disease of the central nervous system, is widely used as an animal model for multiple sclerosis. We demonstrate that interleukin (IL)-12 is essential for the generation of the autoreactive Th1 cells that induce EAE, both in the presence and absence of interferon {gamma}. The disease-promoting effects of IL-12 are antagonized by IL-10 produced by an antigen nonspecific CD4+ T cell which, in turn, is regulated by the endogenous production of IL-12. This unique immunoregulatory circuit appears to play a critical role in controlling Th cell differentiation and provides a mechanism by which microbial triggers of the innate immune system can modulate autoimmune disease.

The authors would like to thank D. Presky and M.K. Gately and J. Magram for generously providing anti– IL-12 antiserum and the IL-12–/– mice, respectively, and B. Kelsall (Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases) for critical reading of the manuscript.

B.K. Dwyer is a Research Scholar of the Howard Hughes Medical Institute.

Address correspondence to Dr. Ethan M. Shevach, Laboratory of Immunology, NIAID, NIH, Bldg. 10, Rm. 11N311, 10 Center Dr. MSC 1892, Bethesda, MD 20892-1892. Phone: 301-496-6449; Fax: 301-496-0222; E-mail: ems1{at}box-e.nih.gov

1 Abbreviations used in this paper: CNS, central nervous system; EAE, experimental allergic encephalomyelitis; iNOS, inducible nitric oxide synthase; LT{alpha}, lymphotoxin-{alpha}; MBP, myelin basic protein.


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