Short-Term Cyclosporine Therapy and Cotransplantation of Donor Splenocytes: Effects on Graft Rejection and Survival Rates in Pigs Subjected to Renal Transplantation Marcello Maestri, M.D., Ph.D.,* , † ,1 Johannes Rademacher, M.D.,* Annalisa Gaspari, B.Sci., Ph.D.,* Luca M. Lenti, M.D.,* Stefania Crespi, M.D.,* Laura Cansolino, B.Sci., Ph.D.,* Giuseppe Novelli, M.D.,* Domenico Agoglitta, M.D.,* Federica Maffeis, M.D.,* Antonjacopo Ferrario di Tor Vajana, M.D.,* Graziano Oldani, M.D.,* and Paolo Dionigi, M.D.* , † *Laboratory of Experimental Surgery, Department of Surgical Sciences, University of Pavia, Pavia, Italy; and †Liver and Pancreas Surgical Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy Submitted for publication August 18, 2007 Background. Donor-specific allogeneic loading can prolong the survival of solid organ transplants by in- ducing a state known as acceptance. Several popula- tions of cells are known to be involved in this process, but their exact roles have yet to be defined. The aim of this study was to assess the effects of portal-vein trans- fusion of donor-specific splenocytes (DST) after short- term cyclosporine A (CyA) therapy in pigs subjected to renal transplantation. Methods. Four groups of unrelated swine underwent renal transplantation with removal of the native kid- neys. Antirejection protocols consisted in portal-vein DST (3  10 8 cells/kg) (Group 2, n  7); intravenous CyA (9 mg/kg/d) on postoperative days 1–12 (Group 3, n  14); and DST  CyA (as described above) (Group 4, n  13). Results (through postoperative day 90) were com- pared with those obtained in untreated control recip- ients (Group 1, n  7). Results. Compared with animals of Groups 1, 2, and 3, Group 4 recipients presented significantly longer survival (mean: 90 days, P < 0.01 in Kaplan-Meier anal- ysis) and better renal function (P < 0.05). Graft histol- ogy revealed preserved parenchyma. Conclusion. The role of spleen cells in the immune response has probably been underestimated. Co- transplantation of donor splenocytes seems to induce a certain degree of acceptance toward the renal al- lograft. The route of administration (portal-vein in- fusion in this study) may be crucial for developing favorable mechanisms of recognition. © 2008 Elsevier Inc. All rights reserved. Key Words: antigen-presenting cells; cyclosporine A; dendritic cells; donor-specific transfusion; kidney transplant. INTRODUCTION Over half a century has passed since the Medawar group demonstrated the immune basis of tissue graft rejection [1] and described the induction of allograft tolerance in mice [2]. Since then, donor-specific toler- ance induction has been viewed by many as the ideal solution to the problem of graft rejection after solid- organ transplantation. The precise definition of “trans- plant tolerance” is a matter of debate. Some authors envision it as long-term graft survival without any immunosuppressive drug therapy at all; others advo- cate an operational definition centered on the absence of signs of chronic rejection, with or without low-dose immunosuppression [3–5]. Research on transplant tolerance has been con- ducted largely in rodents [6–8] and a number of effec- tive tolerance-induction protocols have been developed in these models. Unfortunately, most of these have proved to be ineffective in large animals and humans [4, 9, 10]. The reasons for these discrepancies are still obscure. It has recently been suggested that the path- ways to tolerance/rejection in rodents are different from those in larger mammals. Adams et al. [11] and Sachs [12] have demonstrated the impact of the anti- gen exposure history on the outcome of protocols de- 1 To whom correspondence and reprint requests should be ad- dressed at Unità Operativa di Chirurgia Epatopancreatica, Univer- sity of Pavia and Fondazione IRCCS Policlinico San Matteo, P.le Golgi 19, 27100 Pavia PV, Italy. E-mail: mmaestri@smatteo.pv.it. Journal of Surgical Research 150, 100 –109 (2008) doi:10.1016/j.jss.2008.01.028 100 0022-4804/08 $34.00 © 2008 Elsevier Inc. All rights reserved.