Induction of non-specific suppressor cells and myeloregulatory effects of an immunomodulatory azaspirane, SK&F 105685.
Administration of the immunosuppressive agent, SK&F 105685, has demonstrated immunosuppressive activity in several animal models of autoimmunity such as adjuvant arthritis and experimental autoimmune encephalomyelitis. The mechanism of action of SK&F 105685 in these autoimmune disease models appears to be the induction of non-specific suppressor cells (SC) detected in the spleen and bone marrow of treated animals. In this study we have examined the kinetics of SC appearance in the spleen and bone marrow following treatment with 30 mg/kg/day, p.o., for 1-6 days. SC activity was apparent following a single dose and increased with successive treatments. Treatment with SK&F 105685 also resulted in significantly enhanced myelopoiesis as measured by a 128% increase in the frequency of bone marrow myeloid progenitors (CFU-GM). Mechanistic studies indicated that in vitro treatment of bone marrow stromal cell cultures with SK&F 105685 upregulated the production of colony stimulating activity (CSA) detectable in a rat CFU-GM assay. Further, in vitro studies revealed that the SC in the bone marrow or spleens of SK&F 105685-treated rats admixed with normal marrow cells inhibited CFU-GM formation at a six-fold less cell concentration than cells obtained from control rats. These in vitro results suggest that the SK&F 105685-induced myelopoiesis is regulated by the subsequent generation of SC.
King
A G
AG
Smith Kline Beecham Pharmaceuticals, Department of Cell Sciences, King of Prussia, PA 19406.
Olivera
D
D
Talmadge
J E
JE
Badger
A M
AM
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects; D001854:Bone Marrow Cells; D003114:Colony-Forming Units Assay; D003115:Colony-Stimulating Factors / Q000096:biosynthesis; D006410:Hematopoiesis / Q000187:drug effects*; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D013141:Spiro Compounds / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects*
D000276:Adjuvants, Immunologic; D003115:Colony-Stimulating Factors; D013141:Spiro Compounds; C062162:SK&F 105685