ROLE OF GAMMA-INTERFERON IN THE HOST IMMUNE AND INFLAMMATORY RESPONSES TO PNEUMOCYSTIS-CARINII INFECTION

The role of gamma interferon (IFN-gamma) in host defense to Pneumocyst is carinii was investigated by use of three different murine models of infection. C57BL/6 scid/scid (severe combined immunodeficient [SCID]) mice were given intratracheal inoculations of P. carinii and reconsti tuted with splenocytes from either mice with disrupted IFN-gamma genes (IFN-gamma(-/-) mice) or homozygous wild-type (IFN-gamma(+/+)) mice. Unreconstituted SCID mice had log(10) 7.08 +/- 0.13 P. carinii nuclei in their lungs at day 22 postinfection, whereas SCID mice reconstitute d,vith splenocytes from either wild-type or IFN-gamma(-/-) mice had cl eared the infection, However, there was a prolonged and exacerbated in flammatory response in the lungs of SCID mice reconstituted with IFN-g amma(-/-) splenocytes which was characterized by interstitial pneumoni a, eosinophilia, and multinucleated giant cell formation, Similar resu lts were found in C.B17 SCID mice reconstituted with CD4(+) cells from P. carinii-immunized donors treated with neutralizing anti-IFN-gamma monoclonal antibody (MAb). These mice resolved their P. carinii infect ions; however, they also exhibited exacerbated lung pathology compared with mice treated with a control MAb. Finally, IFN-gamma(-/-) mice ch allenged intratracheally with P. carinii resolved their infection with in 56 days as did IFN-gamma(+/-) mice. Furthermore, depletion of T cel ls in vivo with a MAb resulted in IFN-gamma(-/-) mice becoming suscept ible to P. carinii infection. Together, these data indicate that IFN-g amma is not required for resolution of P. carinii infection; however, in the absence of IFN-gamma, there is a prolonged and exacerbated P. c arinii-driven interstitial pneumonia characterized by eosinophilia and formation of multinucleated giant cells.