Studies on the mechanism of the increased dose-response of erythropoietin after stimulation with erythropoietin.

By JAN FOGH A NUMBER OF AUTHORS’-4 have observed that the response to erythropoietin ( ESF ) in the erythremic mouse assay is substantially enhanced when the ESF dose is administered in fractions. Fogh5 demonstrated that the response to 1.0 IRP units of ESF, determined by #{176}9Fe incorporation into RBC or by the number of reticulocytes in the blood, is increased one to four days after a previous ESF stimulation. It was suggested that this increase in dose response is the explanation for the increased effect of the fractionation, and that the increased dose response is caused by an increase in number of ESFresponding cells provoked by the previous ESF injection. The nature of the cell that responds to ESF has not been elucidated. It has been definitely proven that at least one ESF-responding cell must be a primitive cell preceding the earliest recognizable cell in the red cell series. Some authors6’7 suggest that in addition to the primitive progenitor, nucleated red cells within the erythron are responsive to ESF. If ESF exerts a stimulatory effect on erythroblasts, and such an effect leads to an increase in the net production of red cells, the explanation of the increased dose response after ESF stimulation would be rather trivial. The spleen and bone marrow of erythremic mice, which have not previously been stimulated with ESF, contain no nucleated red cells. Consequently the response to the first injection of ESF is mainly the result of interaction of ESF with primitive ESF-responding cells. ( This must especially be the case if the ESF dose is small and administered i.v. or i.p., so that the hormone, which has a T% in the blood of a few hours,8 #{176} is eliminated before any nucleated red cells have been developed. ) From one to four or five days after the first injection of ESF, however, nucleated red cells will be available, and an additional effect on these cells of a second ESF injection could be the cause of the increased dose response of ESF after ESF stimulation. An alternative explanation could be that the increased dose response is caused by an increase in number of primitive ESF-responding cells per se. The term “primitive ESF-responding cells (P-ERC)” will be used with reference to the primitive cells which, when exposed to ESF, respond instantaneously and contribute to an increase in red cell production. The purpose of the present work was to determine the significance of nucleated red cells for the increased dose response to ESF after previous ESF stimulation.