Pathogenesis of toxicity with human-derived interleukin-2 in experimental animals

It should be pointed out that although repeated systemic administration of exogenous rIL-2 in nonphysiological doses to mice, rats, and monkeys produced various toxicity-related exaggerated pharmacodynamic effects in many experimental parameters, pathological findings were substantially similar among all species. Furthermore, because toxicities observed in our studies were identical to those reported in humans dosed with rIL-2, preclinical toxicity using animal models was fully predictive of the pathogenesis of rIL-2 in human. With continuous infusion, which maintained high blood concentrations of the product during the course of the study, rIL-2 constantly stimulated proliferation of lymphoblastoid cells in peripheral blood, subsequently causing vascular leakage, which consists of edema and extravasation of activated lymphoblastoid cells into perivascular areas. The migrating lymphoblastoid cells, identified as cytotoxic T lymphocytes and NK-LAK cells, caused perivascular and hepatocytic necrosis by means of enzymatic secretions from the cells in association with infiltration into parenchymal tissues. In addition to the stimulation of lymphoblastoid cells in peripheral blood, prolonged daily bolus administration of rIL-2 induced extravasation and infiltration of activated macrophages and B cells in tissues of all organs. Eosinophilia, fibrosis in the subcutis, or pseudolobular formations in the liver could be mediated by systemic release of many other cytokines from activated T cells, i.e., CTLs or LAK cells, B cells, and macrophages.