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1. Mode of Delivery and Cell Tropism Versus Immunotoxicity of Recombinant AAV in Nonhuman Primate

Author

Toromanoff, A., Adjali, O., Moreau, A., Thibaut Larcher, Hill, M., Guigand, L., Chenuaud, P., Deschamps, Jy, Gauthier, O., Blancho, G., Vanhove, B., Rolling, F., Cherel, Y., Moullier, P., Anegon, I., Le Guiner, C., Faculté de Médecine, Université Francois Rabelais [Tours], Centre hospitalier universitaire de Nantes (CHU Nantes), UMR649, Institut National de la Santé et de la Recherche Médicale (INSERM), Développement et Pathologie du Tissu Musculaire (DPTM), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Nantes, Université de Nantes (UN), UMR643, and Ecole Nationale Vétérinaire de Nantes

Subjects
GENETICS, MEDICINE, EXPERIMENTAL, [SDV]Life Sciences [q-bio], APPLIED MICROBIOLOGY, RESEARCH, BIOTECHNOLOGY, HEREDITY
Abstract

s 8th Annual Meeting French Society of Cell and Gene Therapy, 21–23 June 2009, Faculté de Médecine de la Pitié-Salpêtrière Paris, France SFTCG 2009 Invited Presentations

8. Xenotransplantation of Galactosyl-Transferase Knockout, CD55, CD59, CD39, and Fucosyl-Transferase Transgenic Pig Kidneys Into Baboons

Author

Mathias Chatelais, Nahzli Dilek, Jeremy Hervouet, Emanuele Cozzi, Linda Scobie, Bernard Vanhove, J. P. Soulillou, Gilles Blancho, David Minault, Claire Crossan, Cesare Galli, Béatrice Charreau, Julie Devalliere, Peter J. Cowan, Nicolas Poirier, Karine Renaudin, Xavier Tillou, Anthony J F D'Apice, S. Le Bas-Bernardet, Le Bas-Bernardet S, Tillou X, Poirier N, Dilek N, Chatelais M, Devallière J, Charreau B, Minault D, Hervouet J, Renaudin K, Crossan C, Scobie L, Cowan PJ, d'Apice AJ, Galli C, Cozzi E, Soulillou JP, Vanhove B, and Blancho G

Subjects
Graft Rejection, Time Factors, Swine, Xenotransplantation, medicine.medical_treatment, Transplantation, Heterologous, CD59 Antigens, Biology, Animals, Genetically Modified, KIDNEY, Antigens, CD, biology.animal, medicine, Animals, Humans, XENOTRANSPLANTATION, Acute tubular necrosis, Kidney transplantation, PIG, Transplantation, Kidney, CD55 Antigens, Apyrase, Endogenous Retroviruses, Graft Survival, Immunosuppression, Fucosyltransferases, medicine.disease, Kidney Transplantation, Tacrolimus, medicine.anatomical_structure, Immunoglobulin G, Immunology, Surgery, Immunosuppressive Agents, Papio, Baboon
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 development 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-α1.3Gal IgM detected prior to transplantation increased at 6 days posttransplantation, whereas induced IgG appeared after day 6. No porcine endogenous 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.

Published
2011
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9. Bortezomib, C1-inhibitor and plasma exchange do not prolong the survival of multi-transgenic GalT-KO pig kidney xenografts in baboons

Author

Andrea Perota, Simon C. Robson, David H. Sachs, Cesare Galli, Gilles Blancho, Mark B. Nottle, Emanuele Cozzi, Paolo Simioni, Béatrice Charreau, S. Le Bas-Bernardet, N. Klar, Giovanna Lazzari, Nahzli Dilek, Anthony J. F. D'apice, Evelyn J Salvaris, Irina Lagutina, Nicolas Poirier, Kazuhiko Yamada, Jeremy Hervouet, J. P. Soulillou, Julien Branchereau, Linda Scobie, Claire Crossan, Xavier Tillou, Karine Renaudin, Michael E. Breimer, Bernard Vanhove, M. Châtelais, Y Takeuchi, Peter J. Cowan, M. Diswall, Roberto Duchi, David Minault, Mohamed R. Daha, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Transplant Immunology Unit [Padua, Italy], Padua General Hospital [Padua, Italy], Consorzio per la Ricerca sul Trapianto d'Organ = Consortium for Research in Organ Transplantation (CORIT), Effimune SAS [Nantes], Département de Pathologie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Biological & Biomedical Sciences [Glasgow, UK], Glasgow Caledonian University (GCU), University College of London [London] (UCL), Department of Surgery [Gothenburg, Sweden] (Institute of Clinical Sciences), Sahlgrenska Academy at University of Gothenburg [Göteborg], Department of Nephrology [Leiden, The Netherlands], Leiden University Medical Center (LUMC), Department of Cardiologic, Thoracic and Vascular Sciences [Padua, Italy], Università degli Studi di Padova = University of Padua (Unipd), Department of Medicine [Boston, MA, USA], Beth Israel Deaconess Medical Center [Boston] (BIDMC), Harvard Medical School [Boston] (HMS)-Harvard Medical School [Boston] (HMS), School of Paediatrics and Reproductive Health [Adelaide, Australia], University of Adelaide-Robinson Research Institute, University of Adelaide, Immunology Research Centre [Melbourne, VIC, Australia], St Vincent's Hospital Melbourne [Australia], Transplantation Biology Research Center [Boston, MA, USA], Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Avantea [Cremona, Italy], Department of Veterinary Medical Science [Ozzano Emilia, Italy], University of Bologna/Università di Bologna, This work was supported by the European Commission’s Sixth Framework Programme, under the priority thematic area Life Sciences, Genomics and Biotechnology for Health, contract N°. LSHB-CT- 2006- 037377, XENOME and by NIH Grant #5P01AI45897., Le Bihan, Sylvie, Consortium for Research in Organ Transplantation [Padua, Italy] (CORIT), University of Padua [Italy], University of Bologna, Le Bas-Bernardet, S., Tillou, X., Branchereau, J., Dilek, N., Poirier, N., Chatelais, M., Charreau, B., Minault, D., Hervouet, J., Renaudin, K., Crossan, C., Scobie, L., Takeuchi, Y., Diswall, M., Breimer, M.E., Klar, N., Daha, M.R., Simioni, P., Robson, S.C., Nottle, M.B., Salvaris, E.J., Cowan, P.J., D'Apice, A.J.F., Sachs, D.H., Yamada, K., Lagutina, I., Duchi, R., Perota, A., Lazzari, G., Galli, C., Cozzi, E., Soulillou, J.-P., Vanhove, B., and Blancho, G.

Subjects
basic (laboratory) research/science, translational research/science, medicine.medical_treatment, Sus scrofa, Cytomegalovirus, kidney transplantation/nephrology, immunosuppression/immune modulation, 030230 surgery, Pharmacology, Kidney, Virus Replication, xenoantibody, Animals, Genetically Modified, Bortezomib, Gene Knockout Techniques, 0302 clinical medicine, Models, xenotransplantation, Innate, Immunology and Allergy, genetics, Pharmacology (medical), 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, Plasma Exchange, Medicine (all), Graft Survival, Immunosuppression, Galactosyltransferases, Boronic Acids, Papio anubis, 3. Good health, Pyrazines, Models, Animal, Heterografts, Complement C1 Inhibitor Protein, Immunosuppressive Agents, medicine.drug, plasmapheresis/plasma exchange, Xenotransplantation, Genetically Modified, Animal models: nonhuman primate, immunosuppressive regimens, Animals, Autoimmune Diseases, Immunity, Innate, Kidney Transplantation, Transplantation, Article, 03 medical and health sciences, Classical complement pathway, biology.animal, medicine, 030304 developmental biology, business.industry, Animal, Immunity, Complement system, immunosuppressive regimen, Immunology, Alternative complement pathway, genetic, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Baboon
Abstract

Galactosyl-transferase KO (GalT-KO) pigs represent a potential solution to xenograft rejection, particularly in the context of additional genetic modifications. We have performed life supporting kidney xenotransplantation into baboons utilizing GalT-KO pigs transgenic for human CD55/CD59/CD39/HT. Baboons received tacrolimus, mycophenolate mofetil, corticosteroids and recombinant human C1 inhibitor combined with cyclophosphamide or bortezomib with or without 2-3 plasma exchanges. One baboon received a control GalT-KO xenograft with the latter immunosuppression. All immunosuppressed baboons rejected the xenografts between days 9 and 15 with signs of acute humoral rejection, in contrast to untreated controls (n = 2) that lost their grafts on days 3 and 4. Immunofluorescence analyses showed deposition of IgM, C3, C5b-9 in rejected grafts, without C4d staining, indicating classical complement pathway blockade but alternate pathway activation. Moreover, rejected organs exhibited predominantly monocyte/macrophage infiltration with minimal lymphocyte representation. None of the recipients showed any signs of porcine endogenous retrovirus transmission but some showed evidence of porcine cytomegalovirus (PCMV) replication within the xenografts. Our work indicates that the addition of bortezomib and plasma exchange to the immunosuppressive regimen did not significantly prolong the survival of multi-transgenic GalT-KO renal xenografts. Non-Gal antibodies, the alternative complement pathway, innate mechanisms with monocyte activation and PCMV replication may have contributed to rejection.

Published
2015
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10. hCTLA4-Ig transgene expression in keratocytes modulates rejection of corneal xenografts in a pig to non-human primate anterior lamellar keratoplasty model

Author

Jean-Marie Bach, Jean-Paul Soulillou, Flora Coulon, Gilles Blancho, David Minault, Stéphanie Le Bas-Bernardet, Eric Venturi, Pascal Mermillod, Peter J. Cowan, Roberto Duchi, Cesare Galli, Mark B. Nottle, Yan Cherel, Philippe Brachet, Simon C. Robson, Jeremy Hervouet, Yvette Ducournau, Anne Moreau, Veronique Daguin, Irina Lagutina, David Riochet, Bernard Vanhove, Annaïck Pallier, Bertrand Vabres, Sophie Brouard, Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut de Transplantation Urologie Néphrologie, Université de Nantes (UN), Développement et Pathologie du Tissu Musculaire (DPTM), Ecole Nationale Vétérinaire de Nantes-Institut National de la Recherche Agronomique (INRA), Department of Medicine, Transplant Center, Harvard Medical School [Boston] (HMS), Department of Obstetrics and Gynecology, University of Adelaide, Immunology Research Center, St Vincent's Hospital, Department of Medicine, University of Melbourne-Royal Melbourne Hospital, UE 1297 Unité Expérimentale de Physiologie Animale de l'Orfrasière, Institut National de la Recherche Agronomique (INRA)-Physiologie Animale et Systèmes d'Elevage (PHASE), Institut National de la Recherche Agronomique (INRA)-Unité Expérimentale de Physiologie Animale de l'Orfrasière (UE PAO), Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Centre National de la Recherche Scientifique (CNRS)-Université de Tours-Institut Français du Cheval et de l'Equitation [Saumur]-Institut National de la Recherche Agronomique (INRA), Unité Mixte de Recherche en Santé Végétale (INRA/ENITA) (UMR SAVE), Institut National de la Recherche Agronomique (INRA)-École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut des Sciences de la Vigne et du Vin (ISVV), Laboratorio di Tecnologie della Riproduzione, Dipartimento di Scienze Mediche Veterinarie, Alma Mater Studiorum University of Bologna (UNIBO), Immuno-Endocrinologie Cellulaire et Moléculaire (IECM), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN)-Ecole Nationale Vétérinaire de Nantes, Pays de la Loire Regional Council, European Commission LSHB-CT-2006-037377, French government ANR-10-IBHU-005, Nantes Metropole, Pays de la Loire Region, Vabres B, Le Bas-Bernardet S, Riochet D, Chérel Y, Minault D, Hervouet J, Ducournau Y, Moreau A, Daguin V, Coulon F, Pallier A, Brouard S, Robson SC, Nottle MB, Cowan PJ, Venturi E, Mermillod P, Brachet P, Galli C, Lagutina I, Duchi R, Bach JM, Blancho G, Soulillou JP, Vanhove B, Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Unité Expérimentale de Physiologie Animale de l‘Orfrasiére (UE PAO), Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche en Santé Végétale (INRA/ENITA) (UMRSV), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Nantes, and Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS)

Subjects
Graft Rejection, Male, [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], Immunoconjugates, Transgene, Xenotransplantation, medicine.medical_treatment, CD3, Sus scrofa, Transplantation, Heterologous, Immunology, Heterologous, Corneal Keratocytes, Abatacept, Animals, Genetically Modified, Corneal Transplantation, Andrology, Stroma, medicine, Animals, Transgenes, Corneal transplantation, hctla4-ig, corneal blindness, alpha1, Transplantation, biology, pig to non-human primate model, Graft Survival, Immunosuppression, transgenic pig line, 3. Good health, Macaca fascicularis, corneal blindne, Models, Animal, biology.protein, corneal xenograft, lamellar keratoplasty, 3-galactosyl transferase knockout, Biomarkers
Abstract

Background Human corneal allografting is an established procedure to cure corneal blindness. However, a shortage of human donor corneas as well as compounding economic, cultural, and organizational reasons in many countries limit its widespread use. Artificial corneas as well as porcine corneal xenografts have been considered as possible alternatives. To date, all preclinical studies using de-cellularized pig corneas have shown encouraging graft survival results; however, relatively few studies have been conducted in pig to non-human primate (NHP) models, and particularly using genetically engineered donors. Methods In this study, we assessed the potential benefit of using either hCTLA4-Ig transgenic or α1,3-Galactosyl Transferase (GT) Knock-Out (KO) plus transgenic hCD39/hCD55/hCD59/fucosyl-transferase pig lines in an anterior lamellar keratoplasty pig to NHP model. Results Corneas from transgenic animals expressing hCTLA4-Ig under the transcriptional control of a neuron-specific enolase promoter showed transgene expression in corneal keratocytes of the stroma and expression was maintained after transplantation. Although a first acute rejection episode occurred in all animals during the second week post-keratoplasty, the median final rejection time was 70 days in the hCTLA4-Ig group vs. 21 days in the wild-type (WT) control group. In contrast, no benefit for corneal xenograft survival from the GTKO/transgenic pig line was found. At rejection, cell infiltration in hCTLA4Ig transgenic grafts was mainly composed of macrophages with fewer CD3+ CD4+ and CD79+ cells than in other types of grafts. Anti-donor xenoantibodies increased dramatically between days 9 and 14 post-surgery in all animals. Conclusions Local expression of the hCTLA4-Ig transgene dampens rejection of xenogeneic corneal grafts in this pig-to-NHP lamellar keratoplasty model. The hCTLA4-Ig transgene seems to target T-cell responses without impacting humoral responses, the control of which would presumably require additional peripheral immunosuppression.

Published
2014
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