Despite current strategies to treat HIV infection and its complications, Pneumocystis carinii pneumonia (PCP) remains a common clinical problem. Although there is a well-known relationship between CD4+ lymphocyte count and the risk of PC infection, the role of mononuclear phagocytes, CD8+ cells, gamma/delta T cells, and their secreted cytokines in host defense against this infection are far less clear. As it is unknown at the present time, whether highly active antiretroviral therapy will result in long term immune reconstitution in patients with AIDS, understanding non-CD4+ T cell dependent host defense mechanisms operative in opportunistic infections may be critical. Among CD4+ T cell derived cytokines, interferon-gamma (IFN-g) is likely to play a key role in host defense against PC infection. Lymphocytes exposed to PC organisms or the major surface glycoprotein of PC in vitro elaborate IFN and lymphocytes recovered from HIV-infected individuals are deficient in IFN-g production. Preliminary studies from our laboratory demonstrate that overexpression of IFN-g in the lung, using adenoviral- mediated lung delivery of the murine IFN cDNA, (AdIFN) enhances clearance of PC in normal mice, and eradication of infection in mice depleted of CD4 lymphocytes, with a monoclonal antibody. Moreover, this augmented host response is associated with a significant increase in lung CD8+and gamma/delta T-cells. Furthermore, AdIFN fails to eradicate PC infection in scid mice which lack both T and B cells, suggesting that overexpression of IFN is not solely through macrophage activation and/or NK cells. We hypothesize that IFN is critical to host defense against PC and that overexpression of IFN in the lungs of mice depleted of CD4+ T cells will substitute for CD4+ T-lymphocytes, and mediate clearance of PC pneumonia through a Non-CD4 T-cell-dependent mechanism. We will test this hypothesis with the following Specific Aims.
Specific Aim 1. Our hypothesis predicts that overexpression of IFN-g will enhance recruitment of inflammatory cells and permit clearance of P. carinii in CD4-depleted mice.
Specific Aim 2. Our hypothesis predicts that AdIFN induces the recruitment of CD8+ T cells, specifically of the Tc1-like phenotype, in CD4-depleted mice challenged with P. carinii.
Specific Aim 3. Our hypothesis predicts that gamma delta T cells are critical to IFN-g mediated clearance of P. carinii in CD4-depleted mice. These studies will investigate non-CD4 dependent host defenses utilizing a novel form of immunotherapy against an important opportunistic pathogen. The results of these studies will not only aid us in further under- standing lung host defenses, but also may lead to novel methods of therapy for opportunistic infections.
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