Haemopoietic growth factor interactions: in vitro and in vivo preclinical evaluation

Proliferation and differentiation within the haemopoietic system is closely regulated by a family of haemopoietic growth factors. To date, nine interleukins (IL), three colony stimulating factors (CSF) and erythropoietin (Epo) have been implicated in control of haemopoiesis and lymphopoiesis. These cytokines form a family of glycoproteins with pleiotropic effects at different levels. Certain factors (IL-1, IL-6, IL-3) are active at the level of the pluripotential stem cell, whereas others (eg macrophage-CSF, granulocyte-CSF, Epo) facilitate differentiation of lineage restricted cell populations. The cytokines are inducible products of a variety of cell types of which T lymphocytes, macrophages, endothelial cells and fibroblasts are of particular importance. High affinity receptors for all of these factors have been identified, characterized and, in a number of cases, the genes for the receptors have been cloned. Regulation of haemopoiesis involves (a) transcriptional and translational control of cytokine gene expression; (b) post-translational modification of cytokines; (3) receptor downregulation, upregulation, and trans-down modulation; and (d) redistribution of stem cells and progenitor cells to different microenvironments. In vivo administration of these factors in normal animals and in situations of myelosuppression following chemotherapy or irradiation has revealed their efficacy in stimulating various pathways of haemopoiesis. An understanding of the mechanism of action of these factors is providing a rationale for future clinical applications in appropriate combinations.