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 upregulation of Th2-type cytokines.

ABSTRACT

Rejection of vascularized allografts still poses the major problem in organ transplantation. Therefore, transplant rejection of cardiac allografts was investigated in a rat model (BN-to-LEW) under alpha/beta-TCR (R73) mAb-targeted therapy. Two protocols were studied posttransplant ("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 days 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 to organ transplantation was highly effective and resulted in 50% permanent acceptance of cardiac allografts. R73 mAb-treated rats were monitored with respect to peripheral lymphocyte populations and intragraft cytokine levels. A temporary, incomplete reduction (CD5+ cells) and partial modulation (alpha/beta-TCR/CD5 double+ cells) in the peripheral blood was observed. In contrast to untreated controls, intragraft production of IL-2 and IFN-gamma at the mRNA and protein level was abolished in both post- and pretreated recipients. Interestingly, pretransplant mAb application was associated with augmented in situ elaboration of the Th2-type cytokines, IL-4 and IL-10, together with up-regulated TGF-beta and PGE. Increased expression of IL-4 and IL-10 continued to be observed in long-term surviving allografts. In conclusion, the mechanism of conditioning therapy with alpha/beta-TCR mAb prior to alloantigen exposure appears to be a switch from Th1 to Th2 response allowing long-term acceptance of allogeneic grafts.