Administration of an immunomodulatory azaspirane, SK&F 105685, or human recombinant interleukin 1 stimulates myelopoiesis and enhances survival from lethal irradiation in C57Bl/6 mice.
The immunomodulatory azaspirane SK&F 105685 has immunosuppressive activity in animal models of autoimmune disease such as adjuvant-induced arthritis and experimental autoimmune encephalomyelitis. The mechanism of SK&F 105685 appears to be the induction of nonspecific suppressor cell (SC) activity. SC appear to be "null cells," that is, cells that lack specific cell surface markers of mature B cells, T cells, natural killer (NK) cells, or macrophages. Because we hypothesized that the induction of SC was associated with enhanced hematopoiesis, we sought to determine the hematopoietic potential of SK&F 105685. Recombinant interleukin 1 alpha (rIL-1) was included as a positive control for hematopoietic stimulation in our studies. We demonstrate here that administration of SK&F 105685 increases the number of granulocyte-macrophage colony-forming units (CFU-GM) within the bone marrow 24 h after injection in a dose-dependent manner. In addition, the percentage of CFU-GM in S-phase of the cell cycle was significantly increased, as was colony-stimulating activity (CSA) present in the serum of treated animals. In our experiments IL-1 did not increase marrow CFU-GM; however, splenic CFU-GM, the proportion of CFU-GM in S-phase of the cell cycle, and serum CSA were all increased 24 h after a single treatment. Administration of SK&F 105685 24 h prior to lethal irradiation resulted in a dose-related increase in the number of surviving mice. These results demonstrate that SK&F 105685 and rIL-1 stimulate myelopoiesis in vivo and suggest a mechanism by which prophylactic treatment with these agents protects mice from otherwise lethal irradiation.
King
A G
AG
Department of Anti-Infectives, Smith Kline Beecham Pharmaceuticals, King of Prussia, PA 19406.
Badger
A M
AM
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D001853:Bone Marrow / Q000528:radiation effects; D001854:Bone Marrow Cells; D003115:Colony-Stimulating Factors / Q000097:blood; D005260:Female; D005720:Gamma Rays; D006098:Granulocytes / Q000166:cytology*; D006410:Hematopoiesis / Q000187:drug effects / Q000528:radiation effects*; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D007375:Interleukin-1 / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000494:pharmacology; D016196:S Phase / Q000187:drug effects; D013141:Spiro Compounds / Q000494:pharmacology*; D013154:Spleen / Q000166:cytology
D000276:Adjuvants, Immunologic; D003115:Colony-Stimulating Factors; D007375:Interleukin-1; D011994:Recombinant Proteins; D013141:Spiro Compounds; C062162:SK&F 105685