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Adeno-Associated Virus–Mediated CTLA4Ig Gene Transfer Protects MHC-Mismatched Renal Allografts from Chronic Rejection

Ariela Benigni^*, Susanna Tomasoni^*, Laurence A. Turka, Lorena Longaretti^*, Lorena Zentilin, Marilena Mister^*,, Anna Pezzotta^*,, Nadia Azzollini^*,, Marina Noris^*,, Sara Conti^*, Mauro Abbate^*, Mauro Giacca and Giuseppe Remuzzi^*,||

^* Mario Negri Institute for Pharmacological Research; Transplant Research Center, "Chiara Cucchi de Alessandri e Gilberto Crespi,"; ^|| Azienda Ospedaliera, Ospedali Riuniti di Bergamo, Bergamo, Italy; Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy

Address correspondence to: Dr. Giuseppe Remuzzi, "Mario Negri" Institute for Pharmacological Research, Negri Bergamo Laboratories, Via Gavazzeni, 11-24125 Bergamo, Italy. Phone: +39-035-319888; Fax: +39-035-319331; gremuzzi{at}marionegri.it

Received for publication January 30, 2006. Accepted for publication March 14, 2006.

Short-term results of renal transplantation have improved considerably in the past 20 yr; however, similar improvements in long-term outcome have not been achieved. The primary cause of late graft loss is chronic rejection that might be treated by gene therapeutic approaches. Ideally, one would like to impair locally the contact between transplant antigen and the host immune system without compromising the generalized immune competence of the recipient. This can be achieved by local expression of the therapeutic protein in the site of interest using gene therapy. Here it is shown that chronic allograft rejection can be prevented effectively by local delivery of recombinant adeno-associated virus (AAV) vectors that encode the CTLA4Ig immunosuppressant protein to the donor kidney in a fully MHC-mismatched rat strain combination. AAV CTLA4Ig prevented progressive proteinuria and protected transplant kidneys from renal structural injury. A population of anergic T cells with regulatory activity, which eventually were responsible for the induction of tolerance, were found in recipient lymph nodes and in the graft as long as 120 d after transplantation. These data indicate that AAV-mediated CTLA4Ig gene transfer to donor graft represents a promising tool to prevent the onset of chronic rejection and circumvent the unwanted systemic adverse effects of the administration of immunomodulatory protein.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673