Long-term allograft acceptance induced by single dose anti-leukocyte common antigen (RT7) antibody in the rat

Background In clinical organ transplantation monoclonal antibodies (mAb) to different surface molecules of immunocompetent cells become integral parts of the immunosuppressive therapy. In this study, a mAb against the rat leu kocyte common antigen CD45 (RT7) was tested for its immunosuppressive poten cy after a sing;le perioperative injection. Methods. Binding and depleting properties of the anti-RT7 mAb were investig ated by flow cytometry. In the fully major histocompatibility complex-dispa rate heart and skin transplantation models (LEW [RT1(1)] --> LEW.1W [RT1(u) ]), a single dose of anti-RT7 mAb (10 mg/kg) was administered intravenously (day -1), To characterize the long-term acceptance of heart allografts sec ond set skin transplantation (day 100), mixed lymphocyte reaction studies ( day 100) and reverse transcriptase-polymerase chain reaction analysis for i ntragraft cytokine expression (day 200) were performed. Results, The anti-RT7 mAb bound to nearly all hematopoietic lineage cells, but particularly T and NK cells, and profoundly depleted these cells in cir culation and lymphoid tissues. Anti-RT7 mAb-treated rats showed long-term a cceptance of heart allografts (>200 days; n=12), whereas untreated recipien ts rejected allografts by day 8 (n=6), In contrast to hearts, primary skin allograft survival was only moderately prolonged. Animals with stable heart allograft acceptance showed normal in vitro lymphocyte proliferation respo nses to donor and third party antigen. These recipients also acutely reject ed second set donor-strain skin grafts without inducing rejection of persis ting heart allografts, Reverse transcriptase-polymerase chain reaction anal ysis of intragraft cytokines showed up-regulation of Fas-ligand and IL-4 mR NA in long-surviving heart allografts. Conclusions. The findings demonstrate that a single injection of an anti-RT 7 mAb in the rat can induce stable long-term acceptance of heart allografts by transient but profound T-cell depletion. Local immunoregulatory mechani sms seem to play a role for maintenance of long term graft acceptance.