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 follo wing immunization with either xenogeneic sheep red blood cells (SRBC) or allogeneic blood transfusion. RAPA formulated in a polyethylene gly col vehicle, and at a dose of 1. 5 mg. kg-1 i.p. , was relatively inef fective when compared with FK 506 (1 mg.kg-1) or CsA (15 mg.kg-1) in s uppressing antibody production to SRBC. Like FK 506 and CsA however, R APA proved highly effective in suppressing both the B lymphocytosis an d the increase in circulating major histocompatibility complex class I I+ cells observed following immunization. All three immunosuppressants caused thymic medullary atrophy, with evidence of epithelial cell dam age and increased macrophage phagocytic activity. Administered i.m. (3 mg.kg-1 in olive oil), RAPA was also highly effective in suppressing 1-degrees alloantibody responses to MHC class I antigens following blo od transfusion. Unlike FK 506 and CsA however, a short (14-day) course of RAPA following 1-degrees immunization (transfusion) did no suppres s 2-degrees alloantibody responses elicited 6 weeks later. Moreover, R APA 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. Fur ther comparative and combination studies of RAPA with in particular, C sA, are required to further explore to potential of RAPA as an immunot herapeutic agent,