http://repub.eur.nl/res/aut/7262/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/17604/ 1998-11-20T00:00:00Z Peripheral blood cells are in majority short lived and exert a whole spectnull of actions, ranging from the transport of oxygen and carbon dioxide to the production of highly specific immunoglobulins targeted at antigens. The system is velY adaptive and substantially increased numbers of cells can be produced after, for example, major losses of blood, or in response to infections. Peripheral blood cells originate from a small population of bone marrow progenitor cells, together approximately 1.5 % of all bone marrow cells, which are morphologically nearly identical and share the expression of the CD34 antigen. (I) These cells all derive from an even smaller population of hemopoielic stem cells, which have the potential to self renew and are muliipotent. (2) Most of the slem cells in Ihe bone matTow do not actively participate in blood cell formation but remain in a quiescent state. The process from the hemopoielic stem cell to mature peripheral blood cells and several specific tissue cells, termed hematopoiesis, takes approximately 20 to 30 cell divisions, through which cells become increasingly 1110re specialized. TIlis whole process is tightly controlled by hormone like proteins, the hemopoietic growth factors or cytokines, in combination with envirOllllental influences conducted by stromal cclls and direct cell-cell contact. (2,3) Many cytokines have become known in the last 20 years, and new cytokines and cytokine receptors are still being identified. Immature cells in the bone marrow ,u-e positive for the CD34 antigen. http://repub.eur.nl/res/pub/8938/ 1998-01-01T00:00:00Z Radiation-induced pancytopenia proved to be a suitable model system in mice and rhesus monkeys for studying thrombopoietin (TPO) target cell range and efficacy. TPO was highly effective in rhesus monkeys exposed to the mid-lethal dose of 5 Gy (300 kV x-rays) TBI, a model in which it alleviated thrombocytopenia, promoted red cell reconstitution, accelerated reconstitution of immature CD34+ bone marrow cells, and potentiated the response to growth factors such as GM-CSF and G-CSF. In contrast to the results in the 5 Gy TBI model, TPO was ineffective following transplantation of limited numbers of autologous bone marrow or highly purified stem cells in monkeys conditioned with 8 Gy TBI. In the 5 Gy model, a single dose of TPO augmented by GM-CSF 24 h after TBI was effective in preventing thrombocytopenia. The strong erythropoietic stimulation may result in iron depletion, and TPO treatment should be accompanied by monitoring of iron status. This preclinical evaluation thus identified TPO as a potential major therapeutic agent for counteracting radiation-induced pancytopenia and demonstrated pronounced stimulatory effects on the reconstitution of immature CD34+ hemopoietic cells with multilineage potential. The latter observation explains the potentiation of the hematopoietic responses to G-CSF and GM-CSF when administered concomitantly. It also predicts the effective use of TPO to accelerate reconstitution of immature hematopoietic cells as well as possible synergistic effects in vivo with various other growth factors acting on immature stem cells and their direct lineage-committed progeny. The finding that a single dose of TPO might be sufficient for a clinically significant response emphasizes its potency and is of practical relevance. The heterogeneity of the TPO response encountered in the various models used for evaluation points to multiple mechanisms operating on the TPO response and heterogeneity of its target cells. Mechanistic mouse studies made apparent that the response of multilineage cells shortly after TBI to a single administration of TPO is quantitatively more important for optimal efficacy than the lineage-restricted response obtained at later intervals after TBI and emphasized the importance of a relatively high dose of TPO to overcome initial c-mpl-mediated clearance. Further elucidation of mechanisms determining efficacy might very well result in a further improvement, e.g., following transplantation of limited numbers of stem cells. Adverse effects of TPO administration to myelosuppressed or stem cell transplanted experimental animals were not observed.