UNIQUE ACTION OF AN IMMUNOSUPPRESSIVE AGENT, DEOXYSPERGUALIN, ON HEMATOPOIESIS IN MICE

Deoxyspergualin (DSG) is an immunosuppresive agent of proven effective ness in the prevention and treatment of transplant rejection; its most frequent side effect is reversible bone marrow suppression. To clarif y the mechanisms of bone marrow suppression induced by DSG, we monitor ed the numbers of peripheral blood and marrow stem cells in C3H/KeN mi ce receiving 14 days of DSG injections at a highly immunosuppressive d ose of 10 mg/kg/day. In the peripheral brood cells, DSG induced severe anemia and mild leukopenia because of a decrease in granulocyte count s, although these phenomena were reversible. During DSG administration , nucleated cell counts in the femur also markedly decreased, whereas the absolute numbers of various stem cells and progenitor cells, excep t for erythroid colony-forming units (CFU-E), remained normal or incre ased; CD34- or c-kit-positive and lineage-negative cell levels markedl y increased on the day DSG administration ceased. These findings indic ate that DSG-induced anemia and leukopenia are not initiated by a gene ralized killing of these stem cells, but rather by a transient suppres sion of their ability to mature. Significantly, the severe anemia indu ced by DSG resembles pure red cell aplasia in humans, because there we re marked decreases in peripheral reticulocytes, marrow CFU-E, and ery throblasts, with no decrease in renal erythropoietin mRNA expression. Furthermore, DSG-induced anemia was completely ameliorated by treatmen t with human recombinant erythropoietin.