THE ROLE OF GRANULOCYTE-COLONY-STIMULATING FACTOR IN MOBILIZATION ANDTRANSPLANTATION OF PERIPHERAL-BLOOD PROGENITOR AND STEM-CELLS

The article provides a review of the role of granulocyte colony-stimul ating factor (G-CSF) for mobilization and transplantation of periphera l blood progenitor and stem cells. Recombinant gene technology has per mitted the production of highly purified material for therapeutic use in humans. Progenitor cells can be assessed using semisolid and liquid culture assays or direct immunofluorescence analysis of cells express ing CD34. This antigen is found on lineage-determined hematopoietic pr ogenitor cells as well as on more primitive stem cells with extensive self-renewal capacity. Administration of G-CSF during steady-state hem atopoiesis or following cytotoxic chemotherapy leads to an increase of hematopoietic progenitor cells in the peripheral blood. The level of circulating CD34(+) cells post-chemotherapy Is greater compared with G -CSF administration during steady state. On the other hand, CD34(+) ce lls harvested post-chemotherapy contain a smaller proportion of more p rimitive progenitor cells (CD34(+)/HLA-DR(-) or CD34(+)/CD38(-)) compa red with G-CSF treatment alone. Independent of the mobilization modali ty, the amount of previous cytotoxic chemo- and radiotherapy adversely affects the yield of hematopoietic progenitor cells. While continuous subcutaneous administration of G-CSF between 5 and 16 mu g/kg bodywei ght is preferred, additional dose-finding studies may be helpful to op timize current dose schedules. Adhesion molecules like L-selectin, VLA (very late antigen)-4 and LFA (leukocyte function antigen)-1 are like ly to play a role in mobilization, since these antigens are expressed on CD34(+) cells from bone marrow in different densities compared with blood-derived CD34(+) cells collected following G-CSF-supported cytot oxic chemotherapy. It is also relevant for transplantation that during G-CSF-enhanced recovery post-chemotherapy, peripheral blood is enrich ed with a greater proportion of CD34(+) cells expressing Thy-1 in comp arison with CD34(+) cells from bone marrow samples obtained on the sam e day or before the mobilization therapy was started. The early nature of the CD34(+)/Thy-1(+) cells is very likely since this phenotype has been found on stem cells from human fetal liver and bone marrow and o n cord blood cells. As a result, G-CSF-mobilized blood stem cells prov ide rapid and sustained engraftment following high-dose therapy, inclu ding myeloablative regimens. Positive selection of CD34(+) cells as we ll as ex vivo expansion using different cytokines are currently being investigated for purging and improvement of short-term recovery post-t ransplantation. Future developments include the use of blood-derived h ematopoietic stem cells for somatic gene therapy. The availability of growth factors has been an important prerequisite for the development of these new avenues for cell therapy.