Comparative effects of rapamycin, FK 506 and cyclosporine on antibody production, lymphocyte populations and immunoglobulin isotype switching in the rat.
The immunosuppressive activity and comparative efficacy of rapamycin (RAPA), FK 506 and cyclosporine A (CsA) were investigated in rats following immunization with either xenogeneic sheep red blood cells (SRBC) or allogeneic blood transfusion. RAPA formulated in a polyethylene glycol vehicle, and at a dose of 1.5 mg.kg-1 i.p., was relatively ineffective when compared with FK 506 (1 mg.kg-1) or CsA (15 mg.kg-1) in suppressing antibody production to SRBC. Like FK 506 and CsA however, RAPA proved highly effective in suppressing both the B lymphocytosis and the increase in circulating major histocompatibility complex class II+ cells observed following immunization. All three immunosuppressants caused thymic medullary atrophy, with evidence of epithelial cell damage and increased macrophage phagocytic activity. Administered i.m. (3 mg.kg-1 in olive oil), RAPA was also highly effective in suppressing 1 degree alloantibody responses to MHC class I antigens following blood transfusion. Unlike FK 506 and CsA however, a short (14-day) course of RAPA following 1 degree immunization (transfusion) did no suppress 2 degree alloantibody responses elicited 6 weeks later. Moreover, RAPA did not prevent immunoglobulin isotype switching as observed with FK 506 and CsA. This may reflect the distinct mechanisms of action of RAPA and the latter two agents on T-cell activation/proliferation. Further comparative and combination studies of RAPA with in particular, CsA, are required to further explore to potential of RAPA as an immunotherapeutic agent.
Thomson
A W
AW
Department of Pathology, University of Aberdeen, UK.
Propper
D J
DJ
Woo
J
J
Whiting
P H
PH
Milton
J I
JI
Macleod
A M
AM
D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D004912:Erythrocytes / Q000276:immunology; D007107:Immune System / Q000187:drug effects*; D007132:Immunoglobulin Isotypes / Q000187:drug effects / Q000235:genetics; D007134:Immunoglobulin Switch Region / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016131:Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology; D008297:Male; D011090:Polyenes / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012756:Sheep; D020123:Sirolimus; D016559:Tacrolimus / Q000494:pharmacology*; D013950:Thymus Gland / Q000187:drug effects / Q000473:pathology
D007132:Immunoglobulin Isotypes; D007166:Immunosuppressive Agents; D011090:Polyenes; D016572:Cyclosporine; D020123:Sirolimus; D016559:Tacrolimus