THE TOLERABILITY AND PHARMACOLOGY OF INTERLEUKIN-6 ADMINISTERED IN COMBINATION WITH GM-CSF OR G-CSF IN THE RHESUS-MONKEY

The tolerability and potential target organ toxicity of rhIL-6 adminis tered subcutaneously (s.c.) with rhGM-CSF or rhG-CSF were investigated in healthy nonhuman primates. Fifteen Rhesus monkeys were randomized to receive one of the following five regimens: rhIL-6, rhGM-CSF, rhG-C SF, rhIL-6 and rhGM-CSF, or rhIL-6 and rhG-CSF. Each cytokine was admi nistered s.c. once dairy at 20 mu g/kg/day for 30-31 days. Marked incr eases in blood leukocyte counts (predominantly neutrophils) were obser ved in the rhGM-CSF and rhG-CSF treatment groups, but only a mild tren d toward increased WBCs was observed with rhIL-6 alone. Platelet count s increased 1.7- to 2.2-fold in the rhIL-6 and rhGM-CSF groups. All re gimens were well tolerated. RhIL-6, alone or in combination with eithe r CSF, had no significant toxic effects at the dosages tested. Minimal to moderate bone marrow hyperplasia was observed in all except rhIL-6 -treated animals, which correlated well with peripheral blood increase s in WBCs. RhIL-6-treated animals demonstrated increased fibrinogen co ncentrations and erythrocyte sedimentation rates, decreased serum albu min/globulin ratios, and increased serum alpha-2-macroglobulin concent rations. Increased synthesis of acute-phase proteins was not observed in the other groups. Combining rhIL-6 with rhGM-CSF or rhG-CSF may red uce the rhIL-6-mediated acute-phase response while maintaining the des irable hematopoietic effects of the stimulating factors.