Induction of suppressor cell activity in vivo and suppression of lymphoproliferative responses in vitro by SK&F 105.685 in the dog.
SK&F 105.685 (N,N-dimethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2-propanamine+ ++ dihydrochloride) is a novel azaspirane with beneficial activity in rat models of adjuvant-induced arthritis and experimental autoimmune encephalomyelitis as well as in the murine lupus model. The mechanism of action in these models appears to be the induction of non-specific suppressor cell activity which is measured by the ability of cells from treated animals to partially inhibit the proliferative response of lymphocytes from control animals to concanavalin A (ConA) in a co-culture assay. In this study we have shown that oral administration of 0.1-3 mg/kg/day of SK&F 105.685 to purebred beagle dogs induced suppressor cell activity in the spleen and bone marrow but not in the peripheral blood. In vitro, SK&F 105.685 partially suppressed the proliferative response of dog splenocytes to the mitogens phytohemagglutinin (PHA), ConA and, to a lesser extent, pokeweed mitogen (PWM). Peripheral blood lymphocytes (PBLs) differed from spleen cells in their susceptibility to suppression by SK&F 105.685. While the PWM and ConA responses of PBLs and spleen cells showed similar levels of inhibition, the PHA response of PBLs, in marked contrast to spleen cells, was resistant to suppression by the compound. Our results show that the immunoregulatory effects of SK&F 105,685 are not limited to rodents and that suppressor cell activity in dogs is induced quickly and by relatively low doses of the compound.
Thiem
P A
PA
Department of Experimental Pathology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939.
Kaplan
J M
JM
Bugelski
P J
PJ
Ruggieri
E V
EV
Badger
A M
AM
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000276:immunology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D066298:In Vitro Techniques; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D013141:Spiro Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D013154:Spleen / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology
D000276:Adjuvants, Immunologic; D013141:Spiro Compounds; C062162:SK&F 105685