Pneumocystis carinii pneumonia (PCP) is a major cause of morbidity and mortality in persons with AIDS. The onset of PCP in AIDS patients is associated with low numbers of circulating CD4+ T cells. However, causal evidence that CD4+ T cell deficiency is responsible for susceptibility to PCP has not been published. Moreover, if CD4+ T cells are indeed responsible for resistance to PCP, it needs to be determined whether they function by mediating humoral or cellular anti-PC immunity. One reason for the paucity of knowledge about the immunopathogenesis of PCP is the lack of information concerning mechanisms of resistance to PCP in experimental animals. The purpose of the proposed studies is to determine the mechanism of resistance to PCP in immunocompetent mice. To this end, the studies will utilize mice which are homozygous for the recessive mutation """"""""severe combined immunodeficiency"""""""" scid (SCID) and which are deficient in both T- and B-lymphocyte numbers and functions. These mice are susceptible to PCP, whereas normal mice are highly resistant. All mice from the SCID colony bred at this Institute have large numbers of PC in their lungs by 8 weeks of age. Preliminary results from this laboratory show that the transfer of spleen cells from syngeneic and immunocompetent donors to SCID mice causes the SCID recipients to clear PC from their lungs, and that this clearance is dependent on the presence of CD4+ cells, but not CD8+. Moreover, it was found that treatment of conventional B6D2Fl mice with anti-CD4 mAb depleted the recipients of CD4+ cells and caused them to develop PCP. Proposed experiments will determine whether CD4+ cells are necessary for anti-PC antibody production, cell-mediated immunity, or both. Cells necessary for antibody-mediated or cell-mediated immune responses will be enriched and transferred to SCID recipients, in order to identify the cells necessary for resolution of PCP. In a second approach, mAbs to specific immune components will be infused into reconstituted SCID mice, or into conven- tional mice, in order to deplete cells considered essential for anti-PCP resistance. If depletion of one or more types of cells causes development of PCP in recipients, it would indicate that these cells plays a role in resistance to PCP. Once these cellular components of resistance are identified, the mechanisms by which they express resistance to PCP will be investigated. It is suggested that results of the proposed experiments will provide an understanding of the basis of susceptibility of the immunocompetent host to PCP.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Special Emphasis Panel (ARR (V1))
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Trudeau Institute, Inc.
Saranac Lake
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