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J. Exp. Med.,
Volume 188, Number 9, November 2, 1998 1603-1610
Induction of Nitric Oxide
Synthase 2 (iNOS) Activity: Inhibitors of NO Generation
Reveal the Extent of rIL-12 Vaccine Adjuvant Effect
By




From the * Cell and Molecular Biology Graduate Group and the 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-
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
(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.
;
nitric oxide;
nitric oxide
synthase 2
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