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 locus 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 an Inhibition of cytokines which require post-translational processing, including interleukin 6. interleukin 1 and tumor necrosis factor. Mechanistic studies with pentamidine analogs demonstrate that portion of the molecule necessary for this effect lies in the di-amidine portion of the compound and does not appear to be related to carbon chain length between the aromatic ring structures. With respect to immunopharmacologic action, consistent with inhibition of cytokine release, the administration of pentamidine reverses the pathophysiologic effects of endotoxemia, including increased survival and lessened hypothermia.
