Enhancement of hematopoietic reconstitution with recombinant cytokines: effect of rhIL-6 in combination with rhGM-CSF and rhIL-3 on unmodified or T cell-depleted bone marrow.
We have investigated the response of unmanipulated and lymphocyte-depleted BM cells (BMC), pretreated with monoclonal rat antihuman lymphocyte (CD52) antibody (Campath-1G) used for prevention of GvHD, to incubation with rhIL-6 alone or in combination with rhGM-CSF, rhIL-3, or both. We investigated optimal conditions needed for incubation of human BMC under conditions that can be upscaled for clinical application prior to autologous (auto-BMT) and allogeneic blood or BM transplantation (allo-BMT). When used as a single agent, rhIL-6 showed no or a minimal effect in enhancing in vitro CFU-GM colony formation of human BMC. A potent additive effect was obtained when rhIL-6 was added to rhGM-CSF, rhIL-3, or a combination of both. Binding of the mAb Campath-1G, which is used for in vivo and in vitro depletion of immunocompetent lymphocytes to BMC, did not reduce the enhancing effect of a combination of rhGM-CSF and rhIL-3 on CFU-GM in the presence or absence of rhIL-6. Our present and previously published observations suggest that enhancement of hematopoiesis by rhIL-6 and other hematopoietic growth factors is T cell independent. Based on the present observations, pilot clinical studies to determine the potential benefit of in vitro activation of BMC prior to BMT with various cytokine combinations, including rhIL-6, seems justified. Our goal is to enhance hematopoietic reconstitution in vivo, focusing on possible enhancement of platelet reconstitution in vivo toward safer auto-BMT and more effective allo-BMT with better engraftment of T cell-depleted allografts while avoiding GvHD.
Department of Bone Marrow Transplantation & Cancer Immunobiology Research Laboratory, Hadassah University Hospital, Jerusalem, Israel.
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Mumcuoglu
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Slavin
D000074323:Alemtuzumab; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007377:Interleukin-3 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D008212:Lymphocyte Depletion; D011994:Recombinant Proteins / Q000494:pharmacology; D013234:Stem Cells / Q000187:drug effects
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D016207:Cytokines; D007166:Immunosuppressive Agents; D007377:Interleukin-3; D015850:Interleukin-6; D011994:Recombinant Proteins; D000074323:Alemtuzumab; D016178:Granulocyte-Macrophage Colony-Stimulating Factor