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Infect Immun, August 1998, p. 3510-3518, Vol. 66, No. 8
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Inducible Nitric Oxide Synthase-Deficient Mice Develop Enhanced Type 1 Cytokine-Associated Cellular and Humoral Immune Responses after Vaccination with Attenuated Schistosoma mansoni Cercariae but Display Partially Reduced Resistance

Stephanie L. James,1 Allen W. Cheever,2 Patricia Caspar,1 and Thomas A. Wynn1 *

Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda,1 and Biomedical Research Institute, Rockville,2 Maryland

Received 25 March 1998/Returned for modification 14 April 1998/Accepted 6 May 1998

High levels of nitric oxide (NO) are produced by inducible nitric oxide synthase (iNOS) in response to activating signals from Th1-associated cytokines and play an important role in cytotoxicity and cytostasis against many pathogenic microorganisms. In addition to its direct effector function, NO serves as a potent immunoregulatory factor. NO produced by gamma interferon-activated macrophages immobilizes and kills Schistosoma mansoni larvae, and several studies have indicated a role for this pathway in protective immunity against this parasite. The potential regulatory influence of NO in immunity to S. mansoni is less well understood. In this study, we have used iNOS-deficient mice to determine the role of NO in mice vaccinated with irradiated cercariae of S. mansoni. We show by enzyme-linked immunosorbent assay and reverse transcriptase PCR analysis that vaccinated iNOS-deficient mice develop exacerbated type 1 cytokine responses in the lungs, the site where resistance to infection is primarily manifested. In addition, parasite-specific immunoglobulin G2a (IgG2a) and IgG2b antibody responses were significantly increased in vaccinated iNOS-deficient animals and total IgE antibody levels in serum were decreased relative to those in wild-type controls. Surprisingly, since resistance in this vaccine model is largely Th1 dependent and since Th1-related cellular and humoral immune responses were found to be exacerbated in vaccinated iNOS-deficient mice, vaccine-elicited protective immunity against challenge infection was found to be reduced. These findings demonstrate that iNOS plays a paradoxical role in immunity to S. mansoni, both in the effector mechanism of resistance and in the down regulation of the type 1 cytokine response, which is ultimately required for NO production.

* Corresponding author. Mailing address: National Institutes of Health, Bldg. 4, Room 126, 9000 Rockville Pike, Bethesda, MD 20892-0425. Phone: (301) 496-4758. Fax: (301) 402-0077. E-mail: tw12b{at}nih.gov.

Infect Immun, August 1998, p. 3510-3518, Vol. 66, No. 8
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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