Thrombopoietic activity of recombinant human interleukin 11 (rHuIL-11) in normal and myelosuppressed nonhuman primates.

We have extensively characterized the hematological response of normal and myelosuppressed nonhuman primates to treatment with recombinant human interleukin 11 (rHuIL-11) in vivo. In normal cynomolgus monkeys, rHuIL-11 significantly increased peripheral platelet counts when administered at doses of 10 micrograms/kg/day to 100 micrograms/kg/day either by constant i.v. infusion or s.c. injection. As few as four days of rHuIL-11 treatment were sufficient to increase peripheral platelet counts significantly. In addition, extending the treatment period enhanced both the magnitude and the duration of the response. Bone marrow megakaryocytes from animals treated with 100 micrograms/kg/day of rHuIL-11 were increased in size compared to controls and were ultrastructurally normal. A nonhuman primate myelosuppression model using carboplatin, which causes severe thrombocytopenia with platelet counts of < or = 20 x 10(3) platelets/microliters, was developed. This novel model was used to evaluate the effectiveness of rHuIL-11 in platelet restoration. rHuIL-11, administered s.c. at a dose of 125 micrograms/kg/day either concurrently or following chemotherapy, prevented severe thrombocytopenia in addition to accelerating platelet recovery compared to control animals receiving no rHuIL-11. These data demonstrate that rHuIL-11 has potent in vivo thrombopoietic effects when administered to normal and myelosuppressed nonhuman primates, and that rHuIL-11 can be an important therapy to reduce the severity and duration of thrombocytopenia following chemotherapy.

Recombinant human macrophage colony-stimulating factor in nonhuman primates: selective expansion of a CD16+ monocyte subset with phenotypic similarity to primate natural killer cells.

The CD16 receptor (Fc gamma R-III) is found on many tissue macrophages (M phi s), but its expression on circulating monocytes is restricted to a small, phenotypically distinct subset. The number of these CD16+ monocytes may be markedly increased in response to sepsis, human immunodeficiency virus infection, or metastatic malignancy. We have recently shown that the CD16+ monocyte population is selectively expanded by administration of recombinant human macrophage colony-stimulating factor (rhM-CSF). In the current study, we used the highly rhM-CSF-responsive cynomolgus primate model to further characterize this novel monocyte population. Animals treated with rhM-CSF underwent a progressive and essentially complete conversion to the CD16+ monocyte phenotype, with up to a 50-fold increase in the number of CD16+ cells. This increase was paralleled by the emergence of a population of circulating cells that morphologically resembled large granular lymphocytes (LGLs). However, quantitatively, this population corresponded closely to the number of CD16+ monocytes, and fluorescence-activated cell sorting (FACS) confirmed that they were the same. In addition to their LGL-like morphology, many rhM-CSF-induced CD16+ monocytes showed a pattern of size, granularity, and quantitative cell surface marker expression that closely resembled the pretreatment LGL/natural killer (NK) cell population but that did not resemble the pretreatment monocyte population. However, rhM-CSF-induced CD16+ monocytes could be distinguished from LGL/ NK cells by fact that they all expressed cell surface receptors for rhM-CSF, and many of them showed reduced but detectable phagocytic and respiratory burst activity. Studies of human subjects treated with rhM-CSF also showed an analogous population of "LGL-appearing" CD16+ mononuclear cells. Thus, our studies reveal a previously unsuspected ability of cells in the monocyte lineage to adopt a phenotype similar to that of LGL/NK cells. The extent of this phenotypic convergence suggests that the two lineages retain access to elements of a similar developmental pathway.

Multiple effects on peripheral hematology following administration of recombinant human interleukin 12 to nonhuman primates.

Interleukin 12 has demonstrated a wide spectrum of bioactivity on T and NK cells both in vitro and in vivo. Therapeutic potential of these activities has been suggested by studies in murine tumor, viral and microbial models of disease. We have investigated the in vivo effect of rhlL-12 in cynomolgus monkeys treated with 1 micrograms/kg/day by bolus i.v. or s.c. injection for 5 days. Treated group transient decreases in total WBC counts as compared to controls, with reversable decreases seen mainly in the lymphocyte and monocyte subsets. Phenotypic analysis showed a decrease in the number of CD4+ and CD8+ cells/microL on Days 2 and 4. Reversible thrombocytopenia and anemia were noted in both treated groups as compared to controls. Plasma neopterin concentrations were increased in both treated groups as compared to controls. These data show that rhlL-12 has multiple effects on peripheral hematology and suggests that this model may be useful to investigate in vivo bioactivity of rhlL-12.