ALPHA BETA-T CELL RECEPTOR-DIRECTED THERAPY IN RAT ALLOGRAFT RECIPIENTS - LONG-TERM SURVIVAL OF CARDIAC ALLOGRAFTS AFTER PRETREATMENT WITH R73 MAB IS ASSOCIATED WITH UP-REGULATION OF TH2-TYPE CYTOKINES/

Rejection of vascularized allografts still poses the major problem in organ transplantation. Therefore, transplant rejection of cardiac allo grafts was investigated in a rat model (BN-to-LEW) under alpha/beta-TC R (R73) mAb-targeted therapy, Two protocols were studied: posttranspla nt (''immunosuppressive'') and pretransplant conditioning therapy, In posttransplant therapy over a wide dose range, R73 mAb only marginally improved cardiac allograft survival (7.8+/-0.8 days vs. 12.5+/-0.8 da ys at 0.1 mg/kg for 7 days), In contrast, conditioning treatment with low-dose (0,1 mg/kg) anti-alpha/beta-TCR mAb given 3 to 7 days prior t o organ transplantation was highly effective and resulted in 50% perma nent acceptance of cardiac allografts. R73 mAb-treated rats were monit ored with respect to peripheral lymphocyte populations and intragraft cytokine levels, A temporary, incomplete reduction (CD5+ cells) and pa rtial modulation (alpha/beta-TCR/CD5 double+ cells) in the peripheral blood was observed, In contrast to untreated controls, intragraft prod uction of IL-2 and IFN-gamma at the mRNA and protein level was abolish ed in both post- and pretreated recipients, Interestingly, pretranspla nt mAb application was associated with augmented in situ elaboration o f the Th2-type cytokines, IL-4 and IL-10, together with upregulated TG F-beta and PGE. Increased expression of IL-4 and IL-10 continued to be observed in long-term surviving allografts, In conclusion, the mechan ism of conditioning therapy with alpha/beta-TCR mAb prior to alloantig en exposure appears to be a switch from Th1 to Th2 response allowing l ong-term acceptance of allogeneic grafts.