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and Type 1 and 2 TNF Receptor Genes1
,§
*
Department of Pathology, Genentech, Inc., South San Francisco, CA 94066, and Department of Veterinary Pathobiology, Purdue University, West Lafayette, IN 47907;
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109;
Deltagen, San Francisco, CA 94131; and
§
Pulmonary Section, Department of Veterans Affairs Medical Center, Ann Arbor, MI 48105
Pneumocystis carinii pneumonia is an important cause of
morbidity and mortality in immunosuppressed patients, particularly
HIV-infected individuals. An improved understanding of pulmonary host
response, including the cytokines required for defense, could suggest
novel immunotherapeutic approaches to this infection. The cytokines
IFN-
and TNF have contributory roles in host defense against
P. carinii, but their combined and interactive importance
is unclear. To test the roles of these cytokines in defense against
P. carinii directly, organisms were inoculated
intratracheally into wild-type mice and into three groups of
gene-deleted mice: those lacking genes for IFN-
(IFN--/-), for TNF receptors 1 and 2
(TNFR-/-), and for both IFN- and TNFR
(TNFR-IFN--/-). Four weeks after P.
carinii inoculation, lungs of the wild-type,
IFN--/-, and TNFR-/- mice demonstrated
clearance of P. carinii and only mild inflammation.
However, TNFR-IFN--/- mice demonstrated severe
P. carinii infection and lung inflammation. Our findings
demonstrate conclusively that deletion of either IFN- or TNF
activity alone does not block clearance of P. carinii.
However, simultaneous deletion of IFN- and TNF receptor genes
results in susceptibility to P. carinii. Rather than
focusing exclusively on individual cytokines, our data suggest that
immunotherapy targeted at maximizing both the IFN- and TNF responses
to P. carinii may be required to augment host defense
against this important opportunistic pathogen.
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