Objective. Hemopoiesis is regulated by cytokines with positive or negative effects on proliferation of lineage-committed or multipotent hemopoietic stem cells. We have investigated the roles of interleukin-6 and other gp130-dependent ligands on the proliferation of macrophage-Lineage hemopoietic progenitor cells.Methods. The responses of human and murine hemopoietic cells to combinations of cytokines involving interleukin-6 or related factors were assessed in short-term culture by clonogenic assay.Results. Interleukin-6, leukemia inhibitory factor, and ciliary neurotrophic factor inhibited formation of colonies stimulated by macrophage colony-stimulating factor, These effects were dose dependent and selective for macrophage-lineage precursors. Progenitors from murine peripheral blood were inhibited by 37-93% in cultures containing interleukin-6 (11 experiments; median, 68%). Macrophage progenitors from murine bone marrow were also inhibited by interleukin-6 but were less sensitive (seven experiments; median, 48%). In cultures costimulated with leukemia inhibitory factor, peripheral blood and bone marrow progenitors were inhibited by 82% and 58%, respectively, Ciliary neurotrophic factor inhibited macrophage colonies by 66%. Multilineage bone marrow colony formation was not affected. In cultures of human bone marrow cells stimulated with macrophage colony stimulating factor and stem cell factor, interleukin-6 inhibited colony formation by 51-74%. Bone marrow colonies stimulated by granulocyte-macrophage colony stimulating factor were not inhibited by costimulation with interleukin-6.Conclusions. These results suggest a novel mechanism for the negative regulation of macrophage-lineage hemopoietic cells, They also demonstrate new properties of interleukin-6 and certain other gp 130-dependent ligands, (C) 2000 International Society for Experimental Hematology. Published by Elsevier Science Inc.

The in vivo growth of 8 human primary acute lymphoblastic (ALL) and 17 primary acute myeloblastic (AML) cell populations was investigated in severe combined immunodeficient (SCID) mice. Bone marrow (BM) or peripheral blood (PB) samples, either fresh or cryopreserved, were implanted i.v. into irradiated SCID mice. The cells from 5/8 patients with ALL resulted in engraftment with systemic proliferation and dissemination leading to morbidity and mortality of the animals within 12-18 weeks from implantation. In contrast, none of the 17 AML samples resulted in sustained engraftment. Four of the 5 engrafted ALL populations have been successfully passaged into fresh recipients and phenotypic and karyotypic characteristics remain unaltered. The data presented indicate that the SCID mouse may be a useful model for studying the pathogenesis of ALL and may also enable the development and investigation of new therapies for this disease.

Seven populations of human leukaemic cells were implanted i.v. into sublethally irradiated severe combined immunodeficient (scid) mice. Growth of leukaemia was monitored by labelling murine peripheral blood (PB) cells with an anti-HLA monoclonal antibody and flow cytometric analysis. Two of the populations transplanted were fresh acute lymphoblastic leukaemia (ALL) bone marrow (BM) cells which both caused sustained proliferative growth in scid mice. Human cells accounted for up to a mean of 87% of the total nucleated cells (TNC) in the PB of these mice between weeks 12-15. One of these populations was passaged into fresh mice and frank leukaemia was again established. Three populations of cryopreserved acute myeloblastic leukaemia (AML) cells (2 obtained from PB and 1 from BM) and one population of cryopreserved biphenotypic acute leukaemia BM cells, only grew to a maximum of 4% within the 15 week period of the experiment. A cell population from an AML cell line (HL60), however, did engraft and proliferate resulting in a rapid deterioration of these mice between weeks 3-6 when the proportion of human cells accounted for 9% of the TNC in the PB.