The experiments described in his proposal provide a framework from which rational decisions can be made for the selection of promising new therapeutic strategies for cryptococcal disease in AIDS patients. We intend first, to determine how anti-cryptococcal agents affect host-cell interactions in vitro, and second, to design and test, in the murine model, strategies based on the knowledge gained from our in vitro studies. The agents used will be derived from the individual investigators of this Program Project. The agents will be tested alone and in combination with each other, in combination with conventional agents currently available such as amphotericin B, fluconazole, 5- fluorocytosine, and itraconazole, and in combination with the biological response modifiers such as Interleukin 2 (IL)-2, IL-1, interferon gamma (IFN-gamma), tumor necrosis factor (TNF) and the colony stimulating factors (CSF), granulocyte-CSF, granulocyte-macrophage-CSF, and monocyte- CSF. Our reason for using the biological response modifiers is based on the hypothesis that optimal therapy for cryptococcal infection will entail both the use of agents directed at directly killing or inhibiting the organism and on improvement of host defense mechanisms. To determine the effect of these agents and combinations, we will study, in vitro, the adherence of Cryptococcus to neutrophils, monocytes, macrophages, natural killer (NK) cells, and human vascular endothelial cells. Because crytococcal infection is a hematogenous infection in organs other than the lung, we will determine how anti-cryptococcal agents affect adherence of Cryptococcus to the endothelium and we will determine their effect on damage of the endothelial cells caused by Cryptococcus. Also, we will examine the effect of therapeutic strategies on cryptococcal opsonization and phagocytosis by neutrophils, monocytes, and macrophages, and on the killing or inhibition of growth of Cryptococcus. After we have identified anti-cryptococcal agents that have desirable effects in vitro we will test their therapeutic efficacy in the murine model of disseminated cryptococcosis. With this structured approach we will have to opportunity to identify promising new anti-cryptococcal agents and new strategies for their use in combination with biological response modifiers to improve the currently highly unsatisfactory therapy of this increasingly important disease in AIDS patients.
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