Marianne Delville1,2,3, Baptiste Lamarthée4, Sylvain Pagie5,4, Sarah B See6, Marion Rabant3,7, Carole Burger3, Philippe Gatault8,9, Magali Giral10, Olivier Thaunat11,12,13, Nadia Arzouk14, Alexandre Hertig15,16, Marc Hazzan17,18,19, Marie Matignon20,21,22, Christophe Mariat23,24, Sophie Caillard25,26, Nassim Kamar27,28, Johnny Sayegh29,30, Pierre-François Westeel31, Cyril Garrouste32, Marc Ladrière33, Vincent Vuiblet34, Joseph Rivalan35, Pierre Merville36,37,38, Dominique Bertrand39, Alain Le Moine40,41, Jean-Paul Duong Van Huyen3,7, Anne Cesbron42, Nicolas Cagnard3,43, Olivier Alibeu3,44, Simon C Satchell45, Christophe Legendre3,46,47, Emmanuel Zorn6, Jean-Luc Taupin48,49,50, Béatrice Charreau5,4, Dany Anglicheau51,46,47. 1. French National Institute of Health and Medical Research (INSERM) Unit 1163 and. 2. Department of Biotherapy, Necker Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France. 3. Paris Descartes, Sorbonne Paris Cité University, Paris, France. 4. Nantes Universtity, Nantes, France. 5. Center for Research in Transplantation and Immunology, French National Institute of Health and Medical Research (INSERM) Unité Mixte de Recherche (UMR) 1064, Institut Hospitalo-Universitaire (IHU) Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (CESTI), Laboratoire d'excellence (LabEx) Immunotherapy Graft Oncology (IGO), LabEx Transplantex, Nantes, France. 6. Columbia Center for Translational Immunology, Columbia University Medical Center, New York, New York. 7. Department of Renal Pathology, Necker Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France. 8. Service de Néphrologie-Hypertension, Transplantation et Dialyses, University Hospital, Tours, France. 9. Equipe d'Accueil EA4245, Transplantation, Immunologie et Inflammation (T2I), University of Tours, Tours, France. 10. Nantes University Hospital, Institut de Transplantation-Urologie-Néphrologie (ITUN), Nantes, France. 11. Hospices Civils de Lyon, Edouard Herriot Hospital, Department of Transplantation, Nephrology and Clinical Immunology. 12. INSERM Unit 1111, Lyon, France. 13. Claude Berna Saint-Etienne University Hospital rd University (Lyon 1), Lyon, France. 14. Department of Urology, Nephrology and Kidney transplantation, Pitié Salpétrière Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France. 15. Sorbonne University, Paris, France. 16. Urgences Néphrologiques et Transplantation Rénale, Assistance Publique-Hôpitaux de Paris (AP-HP), Tenon Hospital, Paris, France. 17. Department of Nephrology, Lille University Hospital, Lille, France. 18. Lille University, Lille, France. 19. French National Institute of Health and Medical Research (INSERM) Unité Mixte de Recherche (UMR) 995, Lille, France. 20. Department of Nephrology and Renal Transplantation, Groupe Hospitalier Henri-Mondor/Albert-Chenevier, Assistance Publique-Hôpitaux de Paris (AP-HP), Créteil, France. 21. Paris-Est-Créteil University (UPEC), Créteil, France. 22. Institut Mondor de Recherche Biomédicale (IMRB), Equipe 21, French National Institute of Health and Medical Research (INSERM) Unit 955, Créteil, France. 23. Department of Nephrology, Dialysis and Renal Transplantation, Saint-Etienne University Hospital, Saint-Etienne, France. 24. Jean Monnet University, Saint-Etienne, France. 25. Department of Nephrology and Transplantation, Strasbourg, France. 26. French National Institute of Health and Medical Research (INSERM) Unité Mixte de Recherche (UMR) S1109, Fédération de Médecine Translationnelle de Strasbourg, Strasbourg, France. 27. Department of Nephrology and Organ Transplantation, Rangueil University Hospital, Toulouse, France. 28. French National Institute of Health and Medical Research (INSERM) Unit 1043, Institut Fédératif de Recherche Biomédicale de Toulouse (IFR-BMT), Paul Sabatier University, Toulouse, France. 29. Angers University, Angers, France. 30. Department of Nephrology, Dialysis and Kidney Transplantation, Angers University Hospital, Angers, France. 31. Department of Nephrology, Dialysis and Transplantation, University Hospital, Amiens, France. 32. Department of Nephrology, Clermont-Ferrand University Hospital, Clermont-Ferrand, France. 33. Department of Nephrology and Kidney Transplantation, Nancy University Hospital, Nancy, France. 34. Department of Nephrology and Renal Transplantation, Reims University Hospital, Reims, France. 35. Department of Nephrology, Pontchaillou University Hospital, Rennes, France. 36. Department of Nephrology, Transplantation, Dialysis and Apheresis, Pellegrin University Hospital, Bordeaux, France. 37. Centre National de la Recherche Scientifique-Unité Mixte de Recherche (CNRS-UMR) 5164 Immuno ConcEpT, , Bordeaux, France. 38. Bordeaux University, Bordeaux, France. 39. Nephrology, Dialysis and Kidney Transplantation, Rouen University Hospital, Rouen, France. 40. Erasme Hospital, Nephrology Dialysis and Transplantation Department, Bruxelles, Belgium. 41. Université Libre de Bruxelles, Brussels, Belgium. 42. HLA Laboratory, Etablissement Français du Sang (EFS) Centre Pays de la Loire, Nantes, France. 43. Bioinformatics, Structure Fédérative de Recherche Necker, French National Institute of Health and Medical Research (INSERM) US24/ Centre National de la Recherche Scientifique (CNRS) UMS3633, Paris, France. 44. Genomics Core Facility, Institut Imagine-Structure Fédérative de Recherche Necker, French National Institute of Health and Medical Research (INSERM) Unit 1163 and INSERM US24/ Centre National de la Recherche Scientifique (CNRS) UMS3633, Paris, France. 45. Bristol Renal, Bristol Heart Institute, Translational Health Sciences, Bristol Medical School, University of Bristol, Great Britain. 46. Necker-Enfants Malades Institute, French National Institute of Health and Medical Research (INSERM) Unit 1151, Paris, France. 47. Department of Nephrology and Kidney Transplantation, RTRS Centaure; LabEx Transplantex, Necker Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France. 48. Immunology and Histocompatibility Laboratory, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France. 49. French National Institute of Health and Medical Research (INSERM) Unit 1160, LabEx Transplantex, Paris France; and. 50. University Paris Diderot, Paris, France. 51. Paris Descartes, Sorbonne Paris Cité University, Paris, France; dany.anglicheau@aphp.fr.
Abstract
BACKGROUND: Although anti-HLA antibodies (Abs) cause most antibody-mediated rejections of renal allografts, non-anti-HLA Abs have also been postulated to contribute. A better understanding of such Abs in rejection is needed. METHODS: We conducted a nationwide study to identify kidney transplant recipients without anti-HLA donor-specific Abs who experienced acute graft dysfunction within 3 months after transplantation and showed evidence of microvascular injury, called acute microvascular rejection (AMVR). We developed a crossmatch assay to assess serum reactivity to human microvascular endothelial cells, and used a combination of transcriptomic and proteomic approaches to identify non-HLA Abs. RESULTS: We identified a highly selected cohort of 38 patients with early acute AMVR. Biopsy specimens revealed intense microvascular inflammation and the presence of vasculitis (in 60.5%), interstitial hemorrhages (31.6%), or thrombotic microangiopathy (15.8%). Serum samples collected at the time of transplant showed that previously proposed anti-endothelial cell Abs-angiotensin type 1 receptor (AT1R), endothelin-1 type A and natural polyreactive Abs-did not increase significantly among patients with AMVR compared with a control group of stable kidney transplant recipients. However, 26% of the tested AMVR samples were positive for AT1R Abs when a threshold of 10 IU/ml was used. The crossmatch assay identified a common IgG response that was specifically directed against constitutively expressed antigens of microvascular glomerular cells in patients with AMVR. Transcriptomic and proteomic analyses identified new targets of non-HLA Abs, with little redundancy among individuals. CONCLUSIONS: Our findings indicate that preformed IgG Abs targeting non-HLA antigens expressed on glomerular endothelial cells are associated with early AMVR, and that in vitro cell-based assays are needed to improve risk assessments before transplant.
BACKGROUND: Although anti-HLA antibodies (Abs) cause most antibody-mediated rejections of renal allografts, non-anti-HLA Abs have also been postulated to contribute. A better understanding of such Abs in rejection is needed. METHODS: We conducted a nationwide study to identify kidney transplant recipients without anti-HLA donor-specific Abs who experienced acute graft dysfunction within 3 months after transplantation and showed evidence of microvascular injury, called acute microvascular rejection (AMVR). We developed a crossmatch assay to assess serum reactivity to human microvascular endothelial cells, and used a combination of transcriptomic and proteomic approaches to identify non-HLA Abs. RESULTS: We identified a highly selected cohort of 38 patients with early acute AMVR. Biopsy specimens revealed intense microvascular inflammation and the presence of vasculitis (in 60.5%), interstitial hemorrhages (31.6%), or thrombotic microangiopathy (15.8%). Serum samples collected at the time of transplant showed that previously proposed anti-endothelial cell Abs-angiotensin type 1 receptor (AT1R), endothelin-1 type A and natural polyreactive Abs-did not increase significantly among patients with AMVR compared with a control group of stable kidney transplant recipients. However, 26% of the tested AMVR samples were positive for AT1R Abs when a threshold of 10 IU/ml was used. The crossmatch assay identified a common IgG response that was specifically directed against constitutively expressed antigens of microvascular glomerular cells in patients with AMVR. Transcriptomic and proteomic analyses identified new targets of non-HLA Abs, with little redundancy among individuals. CONCLUSIONS: Our findings indicate that preformed IgG Abs targeting non-HLA antigens expressed on glomerular endothelial cells are associated with early AMVR, and that in vitro cell-based assays are needed to improve risk assessments before transplant.
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