       Document 0081
 DOCN  M9640081
 TI    Production of nitric oxide (NO) is not essential for protection against
       acute Toxoplasma gondii infection in IRF-1-/- mice.
 DT    9604
 AU    Khan IA; Matsuura T; Fonseka S; Kasper LH; Department of Medicine,
       Dartmouth Medical School, Hanover, NH; 03755, USA.
 SO    J Immunol. 1996 Jan 15;156(2):636-43. Unique Identifier : AIDSLINE
       MED/96132990
 AB    Production of nitric oxide (NO) by macrophages is important for the
       killing of intracellular pathogens. IFN-gamma and LPS stimulate NO
       production by transcriptional up-regulation of inducible nitric oxide
       synthetase (iNOS). In the present study we used mice with a targeted
       disruption of the IFN regulatory factor-1 gene (IRF-1-/-) to investigate
       the importance of NO in the host immune response against Toxoplasma
       gondii, a major cause of infection in newborns and those with AIDS.
       IRF-1-/- mice were more susceptible to acute Toxoplasma infection, and
       treatment with either exogenous IFN-gamma or in vivo neutralization of
       endogenous IFN-gamma had little effect on their susceptibility to
       infection. However, administration of exogenous IL-12 was able to
       prolong survival even when IFN-gamma was depleted. An in vivo depletion
       study suggested that the mechanism of this protective response is
       mediated in part by CD4+ T cells. The administration of IL-12 could not
       overcome the inhibition of lymphoproliferative response in T.
       gondii-infected mice and treatment with N-monomethyl-L-arginine
       (L-NMMA), a nitric oxide synthase (iNOS) antagonist in vitro was unable
       to reverse the immunosuppression. In response to Toxoplasma infection,
       splenocytes from IRF-1-/- mice exhibited increased production of IL-10
       as well as a 30-fold increase in its message expression. These studies
       indicate that NO may not be essential for host immunity to the parasite,
       and moreover that IL-12 appears to induce an IFN-gamma-independent
       mechanism of protection against this opportunistic pathogen.
 DE    Animal  Arginine/ANALOGS & DERIVATIVES/PHARMACOLOGY  Biological Response
       Modifiers/THERAPEUTIC USE  CD4-Positive T-Lymphocytes  Disease
       Susceptibility/GENETICS  DNA-Binding Proteins/GENETICS/*PHYSIOLOGY
       Female  Interferon Type II/PHARMACOLOGY  Interleukin-10/PHARMACOLOGY
       Interleukin-12/PHARMACOLOGY/*THERAPEUTIC USE  Lymphocyte Depletion
       Lymphocyte Transformation  Mice  Mice, Inbred C57BL  Mice, Knockout
       Nitric Oxide/*PHYSIOLOGY  Nitric-Oxide Synthase/ANTAGONISTS & INHIB
       Phosphoproteins/GENETICS/*PHYSIOLOGY  Support, U.S. Gov't, P.H.S.
       T-Lymphocyte Subsets/DRUG EFFECTS/*IMMUNOLOGY  Toxoplasma/*PHYSIOLOGY
       Toxoplasmosis, Animal/*PREVENTION & CONTROL/THERAPY  Transforming Growth
       Factor beta/PHARMACOLOGY  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

