Xenotransplantation of Galactosyl-Transferase Knockout, CD55, CD59, CD39, and Fucosyl-Transferase Transgenic Pig Kidneys Into Baboons S. Le Bas-Bernardet, X. Tillou, N. Poirier, N. Dilek, M. Chatelais, J. Devallière, B. Charreau, D. Minault, J. Hervouet, K. Renaudin, C. Crossan, L. Scobie, P.J. Cowan, A.J.F. d’Apice, C. Galli, E. Cozzi, J.P. Soulillou, B. Vanhove, and G. Blancho ABSTRACT Galactosyl-transferase knockout (GT-KO) pigs represent the latest major progress to reduce immune reactions in xenotransplantation. However, their organs are still subject to rapid humoral rejection involving complement activation requiring the ongoing develop- ment of further genetic modifications in the pig. In a pig-to-baboon renal transplantation setting, we have used donor pigs that are not only GT-KO, but also transgenic for human CD55 (hCD55), hCD59, hCD39, and fucosyl-transferase (hHT). We studied kidney xenograft survival, physiological and immunologic parameters, xenogeneic rejection characteristics, as well as viral transmission aspects among two groups of baboons: control animals (n = 2), versus those (n = 4) treated with a cocktail of cyclophosphamide, tacrolimus, mycophenolate mofetil, steroids, and a recombinant human C1 inhibitor. Whereas control animals showed clear acute humoral rejection at around day 4, the treated animals showed moderately improved graft survival with rejection at around 2 weeks posttransplantation. Biopsies showed signs of acute vascular rejection (interstitial hemorrhage, glomerular thrombi, and acute tubular necrosis) as well as immunoglobulin (Ig)M and complement deposition in the glomerular and peritubular capillaries. The low level of preformed non-Gal-1.3Gal IgM detected prior to transplantation increased at 6 days posttransplantation, whereas induced IgG appeared after day 6. No porcine endog- enous retrovirus (PERV) transmission was detected in any transplanted baboon. Thus, surprisingly, organs from the GT-KO, hCD55, hCD59, hCD39, and hHT transgenic donors did not appear to convey significant protection against baboon anti-pig antibodies and complement activation, which obviously continue to be significant factors under a suboptimal immunosuppression regimen. The association, timing, and doses of immunosuppressive drugs remain critical. They will have to be optimized to achieve longer graft survivals. A FTER INITIAL SPECTACULAR PROGRESS in the 1990s with the generation of pigs transgenic for com- plement regulatory proteins (CRP) leading to significant prevention of hyperacute rejection (HAR), xenotransplan- tation has seen another major progression with the gener- ation of pigs lacking expression of the major xenoantigen From the Institut de Transplantation–Urologie–Néphrologie, ITUN and INSERM UMR643 (S.L.B.-B., X.T., N.P., N.D., M.C., J.D., B.C., D.M., J.H., J.P.S., B.V., G.B.), Nantes, France; Pa- thology Laboratory (K.R.), CHU–Hôtel Dieu, Nantes, France; the Department of Biological and Biomedical Sciences, Glasgow Caledonian University (C.C., L.S.), Glasgow, UK; Immunology Research Centre, St Vicent’s Hospital (P.J.C., A.J.F.d’A.), Victo- ria, Australia; The Laboratorio di Tecnologie della Riproduzione, LTR, (C.G.), Cremona, Italy; and the Consorzio per la Ricerca sul Trapianto d’Organi, CORIT (E.C.), Padua, Italy. This work was supporting by the European Commission’s Sixth Framework Programme, under the priority thematic area Life Sciences, Genomics and Biotechnology for Health, contract No. LSHB-CT-2006-037377, XENOME. Address reprint requests to Pr Gilles Blancho, ITUN-INSERM UMR 643, CHU-Hôtel Dieu, 30 Boulevard Jean Monnet, 44093 Nantes Cedex 01, France. E-mail: gilles.blancho@chu-nantes.fr. S.L.B.-B., M.C., J.D., B.C., C.C., L.S., C.G., E.C., J.P.S., and G.B. are members of the European Consortium Xenome (No. LSHB-CT-2006-037377). 0041-1345/11/$–see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.transproceed.2011.09.024 360 Park Avenue South, New York, NY 10010-1710 3426 Transplantation Proceedings, 43, 3426 –3430 (2011)