The Immunotoxicology Group has initiated 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 alpha-interferon on pulmonary macrophages. The endpoints for these studies being cytokine production, antigen presentation, phagocytosis, and reactive oxygen intermediate production, and NK cell mediated tumor killing; b) Mechanistic studies on the cellular and subcellular targets of these drugs; and c) Immunopharmacologic examinations of pentamidine and alpha-interferon in disease models. The results of these studies demonstrated an inhibition of cytokine production by pentamidine, most notably interleukin 1. This inhibition was shown to be mediated via a post-translational protein modification event. Consistent with this, pentamidine protected mice from endotoxin shock and inhibited the hypersensitivity response to the sensitizer, oxazalone. With respect to alpha-interferon, pulmonary macrophages were specifically stimulated functionally by the drug. This correlated with increased resistance to pulmonary melanoma metastasis and marginally with pulmonary influenza.
