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Presenter: Marta, Vadori, Padova, Italy
Authors: Marta Vadori1, Moh Daha2, Ngaisah Klar2, Federica Besenzon1, Nicola Baldan3, Laura Cavicchioli4, Giulia Maria De Benedictis5, Massimo Boldrin1, Valentina Innocente1, Fabio Fante1, Fiorella Calabrese6, Gilles Blancho7, Pierre Giannello8, Cesare Galli9, Mark B. Nottle10, Peter Cowan11, Anthony J.F. D'Apice11, Emanuele Cozzi1,12
Study of complement activation in a life supporting pig to primate xenotransplantation model using GAL KO pigs
Marta Vadori1, Moh Daha2, Ngaisah Klar2, Federica Besenzon1, Nicola Baldan3, Laura Cavicchioli4, Giulia Maria De Benedictis5, Massimo Boldrin1, Valentina Innocente1, Fabio Fante1, Fiorella Calabrese6, Gilles Blancho7, Pierre Giannello8, Cesare Galli9, Mark B. Nottle10, Peter Cowan11, Anthony J.F. D’Apice11, Emanuele Cozzi1,12
1Immunology Laboratory, CORIT (Consortium for Research on Organ Transplantation), Padua, Italy; 2Department of Nephrology, Leiden University Medical Center, Leiden, Netherlands; 3Department of Surgical and Gastrointestinal Sciences, Clinica Chirurgica I, University of Padua, Padua, Italy; 4Department of Public Health, Comparative Pathology and Veterinary Hygiene, University of Padua, Padua, Italy; 5Clinical Veterinary Medicine, University of Padua, Padua, Italy; 6Department of Pathological Anatomy, University of Padua, Padua, Italy; 7INSERM U643, CHU Hotel Dieu, Nantes, France; 8Institut de recherche expérimentale et clinique, University of Louvain, Bruxelles, Belgium; 9Centro riproduzione animale, Avantea, Cremona, Italy; 10Discipline of Obstetrics and Gynaecology, University of Adelaide, Adelaide, Australia; 11Immunology Research Centre, St Vincent’s Hospital, Melbourne, Victoria, Australia; 12Direzione Sanitaria, Padua General Hospital, Padua, Italy
Background: Generation of α1,3-galactosyltransferase gene-knockout (GTKO) pigs that are also transgenic for human complement regulatory proteins (hCRP) may improve xenograft survival in the pig-to-primate model. In this study, complement activation was evaluated in primate recipients of a GTKO pig kidney expressing hCRP in a life supporting model. The impact of two different induction treatments on humoral responses and classical and alternative complement cascade was also evaluated.
Methods: Ten bilaterally nephrectomized cynomolgus monkeys received a kidney from GTKO pigs transgenic for human CD39, CD55, CD59 and fucosyltransferase (FT). Animals in group 1 (n=6) received cyclophosphamide, cyclosporin A, mycophenolate sodium and steroids. Animals in Group 2 (n=4) received Rituximab instead of cyclophosphamide. IgM and IgG anti- donor porcine aortic endothelial cells (PAEC) were measured by flow cytometry pre- and post-transplantation. Classical and alternative complement pathway and properdin, C1q, C3, C4, complement fragments were also measured.
Results: Median survival was 16 and 12 days in Group 1 and 2, respectively. Except for two animals, all primates were euthanized in the presence of kidney failure. In Group 1, anti-PAEC IgM and IgG increased in the first week and persisted throughout the post operative period. In Group 2, a limited amount of elicited anti pig antibodies was observed. A progressive activation of the classical and alternative pathway complement cascades was detected in both groups, with consumption of C1q, C4 and C3. In Group 2, a delay in classical pathway activation was observed. Additionally we detected a decrease in circulating properdin in agreement with alternative pathway involvement.
Conclusion: In our model, rituximab therapy is useful in controlling anti-donor antibody production and delay the activation of the complement pathways. These studies implicate that a combination of inhibitory antibodies together with downmodulation of complement activation may be useful to control the rejection of xenotransplants using GTKO pig organs.
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