Non-CD4 Host defense against P. carinii Pneumonia

Children'S Hosp Pittsburgh/Upmc Hlth Sys, Pittsburgh PA

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Abstract

DESCRIPTION (provided by applicant): Pneumocystis carinii (PC) pneumonia remains a serious complication of HIV infection and other immunocompromised states. We have been seeking to better understand how CD4+ T cell independent (CD4IND) host defense mechanisms might defend against PC. During the prior funding period we demonstrated that overexpression of the interferon-gamma (IFN) gene in the lung can result in eradication of PC via a CD41ND mechanism, mediated by augmented lung recruitment of CD8+ T cells, which have a Tc1-like phenotype. During the next grant period we will focus our efforts on CD41ND vaccine responses against PC. CD4O Ligand (CD4OL) is a expressed on activated CD4+ T cells and is critical for host defense against PC. Our preliminary data show that bone-marrow derived dendritic cells (DCs), can be genetically engineered to express CD4OL (using an E1-deleted adenovirus, AdCD4OL), pulsed with PC antigen, and when injected into mice, produce protective anti-PC IgG that is independent of CD4+ T cells. Adoptive transfer of this immune serum or CD4-depleted splenocytes from vaccinated mice confer protection to CD4-depleted mice, suggesting that B cells are critical for protection against PC after DC vaccination. Furthermore the DC-based vaccine approach, unlike an adjuvant approach, resulted in a restricted repertoire of anti-PC IgG. These results lead us to hypothesize that bone-marrow derived DCs, activated by CD4O signaling, and pulsed with PC antigen, can result in effective vaccination and protection against PC in the absence of CD4+ T-cells. Moreover we hypothesize that this CD4IND protection is mediated by activation of B-cells in vivo and selective induction of high titer IgG against specific PC antigens. We will test this hypothesis with the following Specific Aims: Specific Aim 1. If our hypotheses are correct then AdCD4OL-modified DCs, pulsed with PC antigen, should increase the production of protective anti-PC IgG in CD4-deficient mice. Specific Aim 2. Our hypothesis also predicts that this strategy should result in durable vaccine responses and protection against PC in both CD4+ T-cell deficient mice and CD4OL knockout mice. Specific Aim 3. Test the hypothesis that immune responses against specific PC antigens are required for protection against PC in CD4-deficient mice. Specific Aim 4. Test in a Rhesus AIDS model, SIV, whether AdCD4OL modified DCs pulsed with PC can result in anti-PC IgG in serum and bronchoalveolar lavage fluid (BALF). The completion of these studies should significantly advance our knowledge regarding Non-CD4 host defenses against PCP and assist in the development of CD4IND vaccines for opportunistic infections.