Unique action of an immunosuppressive agent, deoxyspergualin, on hematopoiesis in mice.
Deoxyspergualin (DSG) is an immunosuppresive agent of proven effectiveness in the prevention and treatment of transplant rejection; its most frequent side effect is reversible bone marrow suppression. To clarify the mechanisms of bone marrow suppression induced by DSG, we monitored the numbers of peripheral blood and marrow stem cells in C3H/HeN mice receiving 14 days of DSG injections at a highly immunosuppressive dose of 10 mg/kg/day. In the peripheral blood cells, DSG induced severe anemia and mild leukopenia because of a decrease in granulocyte counts, 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, except for erythroid colony-forming units (CFU-E), remained normal or increased; CD34- or c-kit-positive and lineage-negative cell levels markedly increased on the day DSG administration ceased. These findings indicate that DSG-induced anemia and leukopenia are not initiated by a generalized killing of these stem cells, but rather by a transient suppression of their ability to mature. Significantly, the severe anemia induced by DSG resembles pure red cell aplasia in humans, because there were marked decreases in peripheral reticulocytes, marrow CFU-E, and erythroblasts, with no decrease in renal erythropoietin mRNA expression. Furthermore, DSG-induced anemia was completely ameliorated by treatment with human recombinant erythropoietin.
Nemoto
K
K
Department of Therapeutic Drugs, Nippon Kayaku Co., Ltd., Tokyo.
Ogino
M
M
Ohinata
A
A
Hirashima
K
K
D000818:Animals; D001772:Blood Cell Count / Q000187:drug effects; D001854:Bone Marrow Cells / Q000166:cytology; D016026:Bone Marrow Transplantation / Q000473:pathology; D002452:Cell Count / Q000187:drug effects; D004359:Drug Therapy, Combination; D004921:Erythropoietin / Q000096:biosynthesis / Q000627:therapeutic use; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control; D006146:Guanidines / Q000494:pharmacology*; D006410:Hematopoiesis / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000166:cytology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007668:Kidney / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D011994:Recombinant Proteins / Q000627:therapeutic use; D013154:Spleen / Q000166:cytology; D013997:Time Factors
D006146:Guanidines; D007166:Immunosuppressive Agents; D011994:Recombinant Proteins; D004921:Erythropoietin; C037258:gusperimus