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Articles |
Induction of Nitric Oxide Synthase 2 (iNOS) Activity: Inhibitors of NO Generation Reveal the Extent of rIL-12 Vaccine Adjuvant Effect
,|| Department of Medicine, Cancer Center, and Institute for Human Gene Therapy, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104; the School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104; and || The Wistar Institute, Philadelphia, Pennsylvania 19104
Recombinant interleukin 12 (IL-12) can profoundly suppress cellular immune responses in mice. To define the underlying mechanism, recombinant murine (rm)IL-12 was given to C57BL/6 mice undergoing alloimmunization and found to transiently but profoundly suppress in vivo and in vitro allogeneic responses and in vitro splenocyte mitogenic responses. Use of neutralizing antibodies and genetically deficient mice showed that IFN-
(but not TNF-
) mediated rmIL-12–induced immune suppression. Splenocyte fractionation studies revealed that adherent cells from rmIL-12–treated mice suppressed the mitogenic response of normal nonadherent cells to concanavalin A and IL-2. Addition of an inhibitor of nitric oxide synthase (NOS) restored mitogenic responses, and inducible (i)NOS–/– mice were not immunosuppressed by rmIL-12. These results support the view that suppression of T cell responses is due to NO produced by macrophages responding to the high levels of IFN- induced by rmIL-12. When a NOS inhibitor was given with rmIL-12 during vaccination of A/J mice with irradiated SCK tumor cells, immunosuppression was averted and the extent of rmIL-12's ability to enhance induction of protective antitumor immunity was revealed. This demonstrates that rmIL-12 is an effective vaccine adjuvant whose efficacy may be masked by its transient immunosuppressive effect.
Key Words: interleukin 12 • immunosuppression • interferon • nitric oxide • nitric oxide synthase 2
Abbreviations used: D-NAME, N-nitro-D-arginine methyl ester; D-NMMA, N-methyl-D-arginine; DTH, delayed-type hypersensitivity; iNOS, inducible nitric oxide synthase; LCMV, lymphocytic choriomeningitis virus; L-NAME, N-nitro-L-arginine methyl ester; L-NMMA, N-methyl-L-arginine; NO, nitric oxide; SCK.GM cells, SCK tumor cells engineered to secrete GM-CSF.
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