Treatment of AIDS-related opportunistic pneumonias is limited by (1) drug toxicity (2) inadequate drug levels at tissue sites of infection, and (3) an inadequate pulmonary immune response. We have studied lung specific targeting via both aerosolization and the drug carrier system liposomes. We have demonstrated selective enhancement of the pulmonary immune response in rats, lung- specific antimicrobial therapy in rodent models of PCP and CMV pneumonia, and that aerosolized pentamidine appears to be effective, largely non-toxic therapy in a recent trial in AIDS-PCP patients. We propose to further enhance the pulmonary immune response by optimizing lung specific delivery of the cytokines interferon- gamma and tumor necrosis factor. Lung immunomodulation will be assessed by alveolar macrophage(AM) activation measured by IL-1 release, Ia expression, and tumor lysis. We will try to maximize 1) the level and duration of cytokine activity in the lung, 2) optimize the level of AM activation produced, and 3) minimize or avoid cytokine-induced lung and systemic toxicity. Using a rat PCP model, we will determine whether targeted cytokine delivery can prophylax or treat PCP in rats. We will also assess if a range of anti-PCP agents delivered as aerosols demonstrate significant anti-PCP activity and lung selectivity, and whether these agents, or targeted cytokines can produce additive or synergistic activity with either coaerosolized pentamidine, or with concurrent iv administration of pentamidine. We will also examine the anti-CMV pneumonia activity of lung- targeted cytokine therapy, both alone and in combination with aerosolized DHPG in a mouse model of CMV infection. We have perviously shown that aerosolized DHPG is an effective, lung specific anti-CMV pneumonia therapy in infected mice. We will also evaluate the anti-CMV activity of a CMV specific monoclonal antibody administered either as soluble antibody alone or attached to the surface of DHPG loaded-liposomes. These studies should improve methods to selectivity enhance the pulmonary immune response, better define the role of macrophage activation in controlling opportunistic pneumonias, and examine new approaches to targeted therapy of both PCP and CMV pneumonia in relevant animal models of infaction. These studies may lead directly to improved prophylaxis and therapy of PCP and CMV pneumonia in AIDS patients.
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