The role of recombinant interleukin 11 in megakaryocytopoiesis.
Recombinant human interleukin 11 (rHuIL-11) is a multifunctional cytokine with activities on a broad range of hematopoietic cells including primitive stem cells and mature progenitor cells. Analysis of rHuIL-11 in vitro has revealed that its hematopoietic activities are predominantly a result of synergistic interactions with other early-acting factors such as IL-3 and Steel factor. Studies indicate that rHuIL-11 acts directly on purified stem and progenitor cell populations and can support the growth of colony forming units-megakaryocyte in these cultures. In normal animals, rHuIL-11 has a potent effect on cells of the megakaryocyte (MK) lineage. Administration of rHuIL-11 results in a two- to threefold increase in circulating platelets, stimulation of bone marrow (BM) and spleen progenitor numbers, and enhanced MK maturation as measured by a shift to higher ploidy values. rHuIL-11 administration in preclinical models of myelosuppression induced by chemotherapy and/or irradiation has shown a reproducible acceleration of platelet recovery and, in some models, enhanced neutrophil and red blood cell recovery. rHuIL-11 has been tested in a non-human primate myelosuppression model using carboplatin. Administration of rHuIL-11 following carboplatin treatment was found to eliminate the period of severe thrombocytopenia (<20,000 platelets/ml) and enhance the recovery of platelets to normal levels (>100,000/ml). Recently, human clinical trials conducted with rHuIL-11 in patients treated with chemotherapy have demonstrated its potent thrombopoietic activity, including improved platelet nadirs, enhanced platelet recovery and a significant decrease in the number of patients who require platelet transfusions. Combined with the preclinical results, these studies confirm that this cytokine will be an effective agent in the treatment of myelosuppression and thrombocytopenia associated with cancer chemotherapy and BM transplantation.
Turner
K J
KJ
Department of Immunology and Hematopoiesis, Genetics Institute, Inc., Cambridge, Massachusetts 02140, USA.
Neben
S
S
Weich
N
N
Schaub
R G
RG
Goldman
S J
SJ
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects; D016190:Carboplatin / Q000494:pharmacology; D002454:Cell Differentiation; D003115:Colony-Stimulating Factors / Q000187:drug effects; D006801:Humans; D017370:Interleukin-11 / Q000494:pharmacology / Q000502:physiology*; D008533:Megakaryocytes / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D008954:Models, Biological; D011003:Ploidies; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D013154:Spleen / Q000187:drug effects; D013234:Stem Cells / Q000187:drug effects; D013921:Thrombocytopenia / Q000188:drug therapy
D003115:Colony-Stimulating Factors; D017370:Interleukin-11; D011994:Recombinant Proteins; D016190:Carboplatin