BIOLOGIC EFFECTS OF RECOMBINANT HUMAN INTERLEUKIN-12 IN SQUIRREL-MONKEYS (SCIUREUS-SAIMIRI)

BACKGROUND: Interleukin-12 is a novel heterodimeric cytokine that stim ulates the proliferation of activated T and NK cells and induces lymph okine-activated killer cell activity in vitro. To investigate the biol ogical effects of recombinant human IL-12 (rHuIL-12) in vivo, two expl oratory studies were conducted in squirrel monkeys (Sciureus saimiri), which have been shown to be pharmacologically responsive to rHuIL-12 in vitro. EXPERIMENTAL DESIGN: In the first study, 18 monkeys (3/sex/g roup) were given daily subcutaneous injections of 0 (vehicle control), 10, or 50 mu g/kg/day rHuIL-12 for 14 days. In the second study, 18 m onkeys were given 0, 0.1, or 1 mu g/kg/day rHuIL-12 for 14 days. The a nimals were monitored for clinical signs, hematology and clinical chem istry changes, and sacrificed on day 15 to evaluate gross and histopat hologic changes. One monkey in the high dose group was sacrificed mori bund on day 14. RESULTS: Monkeys given rHuIL-12 had dose-related hemat ologic changes characterized by mild to moderate anemia and leukocytos is. Serum chemistry changes included hypoproteinemia, hypoalbuminemia, hypophosphatemia, and hypocalcemia. Gross pathologic findings include d generalized lymph node enlargement and splenomegaly with pulmonary e dema and peritoneal effusions in two high dose monkeys. Dose-related h istopathologic findings included thymic cortical atrophy, splenic lymp hoid hyperplasia with histiocytic hyperplasia and extramedullary hemat opoiesis of red pulp, Kupffer cell hypertrophy and hyperplasia, trilin eage bone marrow hyperplasia, and reactive hyperplasia of lymph nodes. Animals in the 10 and 50 mu g/kg/day dose groups developed high titer s of anti-rHuIL-12 antibodies by day 15. CONCLUSIONS: These studies in dicate that rHuIL-12 is bioactive over a wide dose range and induces p rominent hyperplasia of hematopoietic and lymphohistiocytic tissues in squirrel monkeys. Moreover, positive immunomodulatory activity (enhan ced lymphocyte lytic activity) was detected at a dose of rHuIL-12 that is 500-fold less than the dose causing severe toxicity.