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 have demonstrated that Tcl CD8+ T-cells, as defined by strong endogenous interferon-gamma (IFN) production, are associated with eradication of PC in the absence of CD4+ T-cells. Preliminary studies in our lab using a novel in vitro PC killing assay demonstrate that Tcl CD8+ T-cells have preferential PC killing activity and also augment macrophage-mediated killing. Based on these studies we hypothesize that specific subsets of CD8+ T-cells are effector cells against PC. We will test this hypothesis with the following Specific Aims.
Specific Aim 1. Our hypothesis predicts that overexpression of IFN-g, using adenoviral-mediated gene transfer (ADIFN) will enhance recruitment of CXCR3+, CD8 + T-cells with a Tcl phenotype.
Specific Aim 2. Our hypothesis predicts that these CXCR3+ cells are required for CD8+ T-cell mediated clearance of PC in the AdlFN model.
Specific Aim 3. Our hypothesis predicts that CXCR3+/Tcl+/CD8+ T-cells have preferential killing of PC in vitro and effect clearance of P. carinii in the reconstituted scid mouse model, compared to other CD8+ T-cell populations. 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 understanding lung host defenses, but also may lead to novel methods of therapy for opportunistic infections.
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