The Journal of Experimental Medicine
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Published online 4 June 2001.
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© The Rockefeller University Press, 0022-1007/2001/6/1261/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 11, June 4, 2001 1261-1268

Original Article

Adjuvant Immunotherapy Is Dependent on Inducible Nitric Oxide Synthase

Daniel A. Kahna, D. Clay Archerb, Daniel P. Goldc, and Carolyn J. Kellya,b,d

a Biomedical Sciences Graduate Program, University of California at San Diego, San Diego, California 92093
b Department of Medicine, University of California at San Diego, San Diego, California 92093
c Sidney Kimmel Cancer Center, San Diego, California 92121
d Department of Veterans Affairs, San Diego Healthcare System, San Diego, California 92161
UCSD and VASDHS, 111-H, 3350 La Jolla Village Dr., San Diego, CA 92161.858-642-6243858-552-8585 ext. 2522

ckelly{at}ucsd.edu

Rodents immunized with complete Freund's adjuvant (CFA) are resistant to subsequent attempts to induce autoimmune disease, while animals immunized with incomplete Freund's adjuvant (IFA) remain susceptible. Mycobacterial extracts can stimulate inducible nitric oxide synthase (NOS2) gene transcription. Robust expression of NOS2 has been linked to suppression of T cell proliferation and alterations in immune responses. Our studies investigated the hypothesis that the immunoprotective effect of CFA before immunization requires functional NOS2. NOS2 gene expression is chronically elevated in lymph nodes and spleens of CFA-immunized mice. Maximal expression of NOS2 after CFA immunization requires the presence of functional type I tumor necrosis factor {alpha} receptor (TNFR1) and interferon {gamma}. Groups of nontreated and CFA-preimmunized male C57BL/6J or C57BL/6NOS2–/– mice were immunized with myelin oligodendrocyte glycoprotein (MOG) peptide 35–55 in CFA to induce experimental allergic encephalomyelitis (EAE). Wild-type C57BL/6J mice were protected from the development of symptoms of EAE, while the NOS2–/– mice failed to be protected. NOS2-dependent effects of CFA included an augmentation of the MOG-specific IgG1 response, a decrease in interleukin 6 production by MOG-reactive lymphocytes, and a marked decrease in mononuclear cell infiltrates in the central nervous system. These studies support the hypothesis that CFA immunization modulates immune responses through a nitric oxide–dependent mechanism.

Key Words: experimental allergic encephalomyelitis • Freund's adjuvant • immunosuppression • interleukin 6 • tumor necrosis factor {alpha}

Abbreviations used in this paper: CNS, central nervous system; EAE, experimental allergic encephalomyelitis; MOG, myelin oligodendrocyte glycoprotein; NOD, nonobese diabetic.

© 2001 The Rockefeller University Press


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