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,
,
*
Biomedical Sciences Graduate Program and
Medical Scientist Training Program, and
Department of Medicine, University of California San Diego, and the
Research Service, Department of Veterans Affairs, San Diego Healthcare System, San Diego, CA 92161
Recent studies have suggested that IL-12 and IFN-
may impair the
ability of fed Ag to induce systemic tolerance. Because both of these
cytokines can function to directly or indirectly induce inducible NO
synthase (iNOS) expression, we have investigated whether the functional
expression of iNOS regulates oral tolerance. C57BL/6J wild-type or
C57BL/6J NOS2-/- mice were gavaged with a single dose of
20 mg of keyhole limpet hemocyanin (KLH), followed by s.c. immunization
with KLH/CFA. In the absence of feeding Ag, several parameters of the
immune response were more robust in C57BL/6J NOS2-/- mice
following KLH/CFA immunization, including the magnitude of the
delayed-type hypersensitivity response, the proliferative response, and
the production of IFN- and IL-2 by Ag-activated draining lymph node
cells. These heightened responses in the C57BL/6J NOS2-/-
mice are still effectively inhibited by feeding KLH. Feeding KLH to the
C57BL/6J NOS2-/- mice elicited heightened TGF-
1
production by Ag-activated lymphocytes, as well as augmented total IgG,
IgG1, and IgG2a responses to KLH/CFA compared with that seen in Ag-fed
wild-type mice. Feeding Ag to the NOS2-/- mice suppressed
proliferative responses and IFN- production, while increasing IL-4
production and the IgG1/IgG2a ratio even following a booster
immunization of KLH/CFA. Administrating
L-N6-(1-iminoethyl)-lysine · 2HCl
to wild-type mice during the period of Ag feeding reproduced the high
TGF-1 production seen in Ag-activated lymphocytes from Ag-fed
NOS2-/- mice. Feeding KLH is followed by transient
up-regulation of NOS2 mRNA expression in the Peyer’s patches of
wild-type mice. Selective inhibition of NOS2 may be a simple way to
augment tolerogenic mucosal immune responses.
This article has been cited by other articles:
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  R. Cunard, D. DiCampli, D. C. Archer, J. L. Stevenson, M. Ricote, C. K. Glass, and C. J. Kelly WY14,643, a PPAR{alpha} Ligand, Has Profound Effects on Immune Responses In Vivo J. Immunol., December 15, 2002; 169(12): 6806 - 6812. [Abstract] [Full Text] [PDF]
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 D. A. Kahn, D. C. Archer, D. P. Gold, and C. J. Kelly Adjuvant Immunotherapy Is Dependent on Inducible Nitric Oxide Synthase J. Exp. Med., June 4, 2001; 193(11): 1261 - 1268. [Abstract] [Full Text] [PDF]
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