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

High levels of nitric oxide (NO) are produced by inducible nitric oxid e synthase (iNOS) in response to activating signals from Th1-associate d cytokines and play an important role in cytotoxicity and cytostasis against many pathogenic microorganisms. In addition to its direct effe ctor function, NO serves as a potent immunoregulatory factor, NO produ ced by gamma interferon-activated macrophages immobilizes and kills Sc histosoma mansoni larvae, and several studies have indicated a role fo r this pathway in protective immunity against this parasite. The poten tial regulatory influence of NO in immunity to S. mansoni is less well understood. In this study, we have used iNOS-deficient mice to determ ine the role of NO in mice vaccinated with irradiated cercariae of S, mansoni. We show by enzyme-linked immunosorbent assay and reverse tran scriptase PCR analysis that vaccinated iNOS-deficient mice develop exa cerbated type 1 cytokine responses in the lungs, the site where resist ance to infection is primarily manifested. In addition, parasite-speci fic immunoglobulin G2a (IgG2a) and IgG2b antibody responses were signi ficantly 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 lar gely Th1 dependent and since Th1-related cellular and humoral immune r esponses were found to be exacerbated in vaccinated iNOS-deficient mic e, vaccine-elicited protective immunity against challenge infection wa s found to be reduced, These findings demonstrate that iNOS plays a pa radoxical role in immunity to S, mansoni, both in the effector mechani sm of resistance and in the down regulation of the type 1 cytokine res ponse, which is ultimately required for NO production.