EFFECTS OF RECOMBINANT HUMAN INTERLEUKIN-6 (RHIL-6) IN MARMOSETS (CALLITHRIX-JACCHUS) .1. GENERAL TOXICITY AND HEMATOLOGICAL-CHANGES

The physiological and toxicological properties of recombinant human in terleukin 6 (rhIL-6) were assessed in marmoset monkeys (Callithrix jac chus). Two experimental series were performed with daily subcutaneous administration: (a) 5 or 1000 mu g rhIL-6/kg per day for three weeks a nd (b) 25, 100 or 500 mu g rhIL-6/kg per day for 3 months. RhIL-6 was well tolerated and did not induce fever or any other non-specific sign s of toxicity. The main findings were: (1) A two- to threefold increas e in platelet counts at 2-4 weeks, which decreased following further c ontinuous rhIL-6 administration; (2) increase in total white blood cel ls between 1 and 4 weeks of administration, including an absolute incr ease in granulocytes (including band forms) and basophils. A change in the number of monocytes was not detected; (3) an increase in total re d blood cells, which peaked at 4 weeks, sustained elevation of red cel l distribution width and a slight decrease in hemoglobin between week 1 and 4, concurrent with a distinct decrease in mean corpuscular hemog lobin at 4 weeks. This effect persisted for 9 weeks in the 100 mu g/kg and 500 mu g/kg groups; (4) decrease in plasma AST activity and incre ase in plasma protein concentration after 2 weeks of treatment; (5) no clinical or biochemical signs of renal glomerular dysfunction; (6) Rh IL-6 after s.c. administration was detectable in the plasma, peak leve ls (mean values +/- SD) of 9.4 +/- 6.3 and 72.4 +/- 7.7 ng/ml were mea sured after a single dose of 100 or 1000 mu g/kg; (7) antibodies again st rhIL-6 developed within 2 weeks, increased during administration an d neutralized the biological effect of rhIL-6 progressively from 4 to 9 weeks. In conclusion, aside from a mild anemia, rhIL-6 was well tole rated in marmosets and had a profound and sustained effect on thrombop oiesis. Due to the formation of neutralizing antibodies, the chronic b iological effect of rhIL-6 is lost in marmosets and studies beyond 4 w eeks are rendered less meaningful. The analyses of antibody formation, induction of acute phase proteins, histological changes and alteratio ns on lymphocyte receptors will be reported in two following publicati ons.