We have reported that immune (gamma) interferon (IFN-Gamma) appears to be the key T cell lymphokine required to induce the human monocyte-derived macrophage to display enhanced antimicrobial activity against a diverse group of intracellular pathogens including Toxoplasma gondii. We have also recently demonostrated that mononuclear cells from AIDS patients with opportunistic infections (01) (such as toxoplasmosis), patients whose 1 year mortality rate exceeds 95%, uniformly fail to generate IFN-Gamma in response to in vitro stimulation with previously-encountered, clinically relevant microbial antigens. Macrophages from these AIDS patients, however, are capable of responding normally with effective antimicrobial activity once appropriately stimulated with native or recombinant (r) human IFN-Gamma. Based on these results, we proposed to address two basic questions concerning the defect in the cell-mediated immune responses of AIDS patients: (1) Does impaired T cell secretion of IFN-Gamma patients at risk for this defect accurately predict the future development of 01? And (2) for AIDS patients who have survised a previous 01, can prophylactic immunotherapy with rIFN-Gamma prevent subsequent 01 and enhance survival? Our specific aims are to (1) examine the IFN-Gamma generating capacity of at-risk patients who have not yet acquired an 01, (2) determine in a prospective longitudinal study if impaired in vitro IFN-Gamma secretion by these patients is an accurate marker for the AIDS-related cellular immune defect which predisposes to 01, (3) determine the nature of the cellular or molecular mechanisms(s) responsible for deficient IFN-Gamma production in order to examine methods to reverse these mechanisms before 01 develop in at-risk patients, and test these hypotheses by (4) determining the efficacy of intermittent immunoprophylactic IFN-Gamma treatment in AIDS patients with a previous 01 -- a group of patients with a Greater than 95% mortality within 12 months from another 01. Thus, by utilizing clinical, basic laboratory, and therapeutic studies, this project will focus in detail on the role and effect of IFN-Gamma in the AIDS-related cellular immune defect.
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