Sarmiento U M, Riley J H, Knaack P A, Lipman J M, Becker J M, Gately M K, Chizzonite R, Anderson T D
Department of Toxicology, Hoffmann-La Roche Inc., Nutley, New Jersey.
Lab Invest. 1994 Dec;71(6):862-73.
Interleukin-12 is a novel heterodimeric cytokine that stimulates the proliferation of activated T and NK cells and induces lymphokine-activated killer cell activity in vitro. To investigate the biological effects of recombinant human IL-12 (rHuIL-12) in vivo, two exploratory studies were conducted in squirrel monkeys (Sciureus saimiri), which have been shown to be pharmacologically responsive to rHuIL-12 in vitro.
In the first study, 18 monkeys (3/sex/group) were given daily subcutaneous injections of 0 (vehicle control), 10, or 50 micrograms/kg/day rHuIL-12 for 14 days. In the second study, 18 monkeys were given 0, 0.1, or 1 micrograms/kg/day rHuIL-12 for 14 days The animals were monitored for clinical signs, hematology and clinical chemistry changes, and sacrificed on day 15 to evaluate gross and histopathologic changes. One monkey in the high dose group was sacrificed moribund on day 14.
Monkeys given rHuIL-12 had dose-related hematologic changes characterized by mild to moderate anemia and leukocytosis. Serum chemistry changes included hypoproteinemia, hypoalbuminemia, hypophosphatemia, and hypocalcemia. Gross pathologic findings included generalized lymph node enlargement and splenomegaly with pulmonary edema and peritoneal effusions in two high dose monkeys. Dose-related histopathologic findings included thymic cortical atrophy, splenic lymphoid hyperplasia with histiocytic hyperplasia and extramedullary hematopoiesis of red pulp, Kupffer cell hypertrophy and hyperplasia, trilineage bone marrow hyperplasia, and reactive hyperplasia of lymph nodes. Animals in the 10 and 50 micrograms/kg/day dose groups developed high titers of anti-rHuIL-12 antibodies by day 15.
These studies indicate that rHuIL-12 is bioactive over a wide dose range and induces prominent hyperplasia of hematopoietic and lymphohistiocytic tissues in squirrel monkeys. Moreover, positive immunomodulatory activity (enhanced lymphocyte lytic activity) was detected at a dose of rHuIL-12 that is 500-fold less than the dose causing severe toxicity.
