The Immunotoxicology Group is continuing the assessment of immunotoxicity of AIDS therapeutics. The ongoing objectives include: (1) to evaluate the potential adverse effects of promising AIDS therapeutics on systemic as well as local systems; (2) if possible, to examine potential mechanisms of toxicity (or therapeutic action, if unknown); (3) to relate these observed changes in immune function to clinicians and regulatory agencies so that improved treatment and monitoring may be facilitated. Studies were performed in the following areas: a) descriptive immunotoxicity studies on pentamidine isethionate and related analogs on lung macrophages. The endpoints for these studies focus on cytokine production; b) mechanistic studies on the cellular and subcellular targets of these drugs; and c) immunopharmacologic examinations of pentamidine and in disease models. The results of these studies demonstrated that following endotoxin administration, pentamidine has a protective and anti-inflammatory role both systemically and in the lung and suggests that inhibition of inflammatory cytokines such as TNF and IL-6 may be one mechanism operable in the therapeutic activity of the drug against P. carinii pneumonia.
