Constant subcutaneous infusion of rhIL-11 in mice: efficient delivery enhances biological activity.

Previous studies have shown that subcutaneous (SC) bolus administration of recombinant human interleukin-11 (rhIL-11) stimulates megakaryocytopoiesis 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 of the nature of the hematologic response. Female C57BL/6 mice were implanted subcutaneously with 7-day Alzet mini-osmotic pumps containing either rhIL-11 with 0.5% homologous mouse serum (delivery rate of 250 microg/kg/d) or vehicle alone. Mice were sacrificed on days 3, 7, 10, and 13 after pump implantation, and the hematopoietic response was compared to mice receiving an equivalent dose of rhIL-11 administered by SC injection (250 microg/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) returning 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 and 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 elevated on day 13 (84%), 6 days after rhIL-11 administration had stopped. Consistent with the platelet response, the modal ploidy of bone marrow megakaryocytes was shifted from 16N to 32N on days 3 and 7, with increases in 32N megakaryocytes still apparent on days 10 and 13. There was also a significant increase in reticulated platelets detected in the peripheral blood on days 3, 7, and 10 compared to mice administered rhIL-11 by SC injection, The changes in reticulated platelets and bone marrow megakaryocyte ploidy are consistent with the increased and prolonged platelet response following SC infusion of rhIL-11. In addition to the effects observed on peripheral platelet counts, constant SC infusion of rhIL-11 dramatically enhanced splenic hematopoietic activity, increasing spleen weight and cellularity as well as splenic megakaryocyte, erythroid, granulocyte, and macrophage progenitors compared to mice receiving rhIL-11 by SC injection.

Recombinant human interleukin-11 stimulates multilineage hematopoietic recovery in mice after a myelosuppressive regimen of sublethal irradiation and carboplatin.

Interleukin-11 (IL-11) is a novel multifunctional hematopoietic cytokine capable of stimulating cells of the myeloid, lymphoid, erythroid, and megakaryocytic lineages in vitro. We have tested the pleiotropic properties of this cytokine on the hematopoietic recovery of mice after a combined regimen of sublethal irradiation and carboplatin administration. This regimen results in severe myelosuppression, characterized by a prolonged period of thrombocytopenia and severe anemia. Administration of recombinant human IL-11 (rhIL-11; 250 micrograms/kg/d) had multilineage effects on bone marrow and spleen hematopoietic activity, increasing the number of megakaryocyte, erythroid, granulocyte, and macrophage progenitors compared with the vehicle-treated controls. This was reflected in the peripheral circulation by a reduction of both the platelet and hematocrit nadirs and a significantly reduced period of thrombocytopenia and anemia in the rhIL-11-treated mice. The results from this study support the broad spectrum of biologic activities that have been attributed to rhIL-11 in vitro and suggest that this cytokine may be an effective agent in the treatment of myelosuppression associated with cancer chemotherapy and bone marrow transplantation.