INTERACTIONS OF ERYTHROPOIETIN, GRANULOCYTE-COLONY-STIMULATING FACTOR, STEM-CELL FACTOR, AND INTERLEUKIN-11 ON MURINE HEMATOPOIESIS DURING SIMULTANEOUS ADMINISTRATION

We investigated how in vivo effects of single hematopoietic cytokines change if given in combination for a prolonged time. Mice were treated with every combination of recombinant human (rh) erythropoietin (EPO) , rh granulocyte colony-stimulating factor (G-CSF), recombinant rat (r r) stem cell factor (SCF), and rh interleukin (IL)-11 by continuous in fusion over 7 days (full factorial design with three dose levels for e ach cytokine). Burst-forming unit-erythroid (BFU-E), colony-forming un it-erythroid (CFU-E), and colony-forming unit-granulocyte-macrophage ( CFU-GM) were determined in bone marrow and spleen, reticulocytes, hema tocrit, granulocytes, and thrombocytes in the peripheral blood. An ana lysis of variance (ANOVA) and multiple comparison of means was used to evaluate the data. For several cell types, cytokine effects superimpo sed in an additive way if combined. However, in a large number of circ umstances, nonadditive pairwise interactions were found. They differed in type and magnitude involving high dose saturation, high dose antag onistic effects, and even effect reversals (qualitative interactions). Hence, in general, it was not possible to foresee the combination eff ects on the basis of existing knowledge of single effects. On the othe r hand, the cytokine network was robust and no system hazards were obs erved under multiple cytokine combinations. The results illustrate tha t the cytokine network has nonlinear dynamic properties in vivo with d ose-response characteristics of one cytokine being continuously modifi ed by other cytokines. (C) 1998 by The American Society of Hematology.