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. During the prior funding period we demonstrated that overexpression of the interferon-gamma (IFN) gene in the lung in CD4-deficient mice results in eradication of PC. Clearance of PC is mediated by augmented lung recruitment of CD8+ T cells, which have a Tc1-like phenotype (as defined by strong endogenous IFN production). We demonstrated that CD8+ T-cell effectors expressed CXCR3 and were recruited to the lung via IP-10. These cells mediate clearance of PC by secreting GM-CSF which augments macrophage clearance of the organism. In the absence of IFN overexpression GMCSF+ CD8+ T-cells require CD4+ T-cell help however the Th subset requirement is not defined. We hypothesize that clinical PCP is due to loss of Th1, Th2, and Th17 immunity and that vaccine induced CD4+ T-cells belonging to any of these CD4+ T-cell subsets will be sufficient to induce clearance of PC infection in the lung.
The aims are 1. Determine the role of IFNAR, IL- 23, and IL-12, in regulating Th1 immunity to PC. 2. To generate mice deficient in Th1, Th2, and Th17 immunity to determine contributions of these CD4+ T-cell subsets in the clearance of PCP. 3. Our hypothesis predicts that vaccination of mice sufficient for Th1, Th2, or Th17 immunity will be sufficient to protect against PCP. These studies will confirm the role of Th subsets in PCP and optimize vaccination strategies for this important opportunistic infection.
This project defines the types of T-cells required for prevention of Pneumocystis pneumonia a major complication of AIDS and organ transplantation. This research will improve the potential development of a vaccine for this infection.
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