CONSTANT SUBCUTANEOUS INFUSION OF RHIL-11 IN MICE - EFFICIENT DELIVERY ENHANCES BIOLOGICAL-ACTIVITY

Previous studies have shown that subcutaneous (SC) bolus administratio n of recombinant human interleukin-11 (rhIL-11) stimulates megakaryocy topoiesis and increases peripheral platelet counts in naive mice. This study was designed to determine whether administration of rhIL-11 by constant SC infusion altered either the magnitude or the nature of the hematologic response. Female C57BL/6 mice were implanted subcutaneous ly with 7-day Alzet mini-osmotic pumps containing either rhIL-11 with 0.5% homologous mouse serum (delivery rate of 250 mu g/kg/d) or vehicl e alone. Mice were sacrificed on days 3, 7, 10, and 13 after pump impl antation, and the hematopoietic response was compared to mice receivin g an equivalent dose of rhIL-11 administered by SC injection (250 mu g /kg/d, 7 days) or vehicle controls. Subcutaneous injection of rhIL-11 resulted in a significant increase in peripheral platelet counts with a maximum platelet increase of 44% over controls observed on day 7 of the study. Platelet counts subsequently declined (24% by day 10) retur ning to control values by day 13. The increase in peripheral platelet counts was accompanied by an increase in reticulated platelets on day 7 and a shift to higher ploidy bone marrow megakaryocytes on days 3 an d 7. Compared to SC injection, both the magnitude and duration of the platelet increase were significantly enhanced following continuous SC infusion of rhIL-11. Maximum platelet counts were detected on day 10 ( 115% above vehicle controls), and platelets remained significantly ele vated on day 13 (84%), 6 days after rhIL-11 administration had stopped . Consistent with the platelet response, the modal ploidy of bone marr ow megakaryocytes was shifted from 16N to 32N on days 3 and 7, with in creases in 32N megakaryocytes still apparent on days 10 and 13. There was also a significant increase in reticulated platelets detected in t he peripheral blood on days 3, 7, and 10 compared to mice administered rhIL-11 by SC injection. The changes in reticulated platelets and bon e marrow megakaryocyte ploidy are consistent with the increased and pr olonged platelet response following SC infusion of rhIL-11. In additio n to the effects observed on peripheral platelet counts, constant SC i nfusion of rhIL-11 dramatically enhanced splenic hematopoietic activit y, increasing spleen weight and cellularity as well as splenic megakar yocyte, erythroid, granulocyte, and macrophage progenitors compared to mice receiving rhIL-11 by SC injection.