Early Acute Microvascular Kidney Transplant Rejection in the Absence of Anti-HLA Antibodies Is Associated with Preformed IgG Antibodies against Diverse Glomerular Endothelial Cell Antigens.
Marianne Delville
(1)
,
Baptiste Lamarthee
(2)
,
Sylvain Pagie
(3)
,
Sarah B See
,
Marion Rabant
(4)
,
Carole Burger
(5)
,
Philippe Gatault
(6)
,
Magali Giral
(7)
,
Olivier Thaunat
(8)
,
Nadia Arzouk
(9)
,
Alexandre Hertig
(10)
,
Marc Hazzan
(11)
,
Marie Matignon
(12)
,
Christophe Mariat
(13)
,
Sophie Caillard
(14)
,
Nassim Kamar
(15)
,
Johnny Sayegh
(16)
,
Pierre-Francois Westeel
(17)
,
Cyril Garrouste
(18)
,
Marc Ladriere
(19)
,
Vincent Vuiblet
(20)
,
Joseph Rivalan
(21)
,
Pierre Merville
(22)
,
Dominique Bertrand
(23)
,
Alain Le Moine
(24)
,
Jean Paul Duong van Huyen
(5)
,
Anne Cesbron
(25)
,
Nicolas Cagnard
(26)
,
Olivier Alibeu
(26)
,
Simon C. Satchell
(27)
,
Christophe M. Legendre
(28)
,
Emmanuel Zorn
,
Jean-Luc Taupin
(29)
,
Béatrice Charreau
(30)
,
Dany Anglicheau
(28)
1
Imagine - U1163 -
Imagine - Institut des maladies génétiques (IHU)
2 INEM - UM 111 (UMR 8253 / U1151) - Institut Necker Enfants-Malades
3 U1064 Inserm - CRTI - Centre de Recherche en Transplantation et Immunologie
4 UPCité - Université Paris Cité
5 UPD5 - Université Paris Descartes - Paris 5
6 UT - Université de Tours
7 ITERT - Institut de Transplantation et de Recherche en Transplantation [CHU Nantes]
8 UCBL - Université Claude Bernard Lyon 1
9 CHU Pitié-Salpêtrière [AP-HP]
10 SU - Sorbonne Université
11 LIRIC - Lille Inflammation Research International Center - U 995
12 UPEC UP12 - Université Paris-Est Créteil Val-de-Marne - Paris 12
13 UJM - Université Jean Monnet - Saint-Étienne
14 CHU Strasbourg - Centre Hospitalier Universitaire [Strasbourg]
15 UT3 - Université Toulouse III - Paul Sabatier
16 UA - Université d'Angers
17 CHU Amiens-Picardie
18 CHU Clermont-Ferrand
19 Service de Cardiologie et Transplantation [CHRU Nancy]
20 CHU Reims - Hôpital universitaire Robert Debré [Reims]
21 Service de néphrologie [Rennes]
22 UB - Université de Bordeaux
23 CHU Rouen
24 ULB - Université libre de Bruxelles
25 Etablissement Français du Sang [Nantes]
26 UAR 3633 / US24 - Structure Fédérative de Recherche Necker
27 University of Bristol [Bristol]
28 Hôpital Necker - Enfants Malades [AP-HP]
29 UPD7 - Université Paris Diderot - Paris 7
30 UN - Université de Nantes
2 INEM - UM 111 (UMR 8253 / U1151) - Institut Necker Enfants-Malades
3 U1064 Inserm - CRTI - Centre de Recherche en Transplantation et Immunologie
4 UPCité - Université Paris Cité
5 UPD5 - Université Paris Descartes - Paris 5
6 UT - Université de Tours
7 ITERT - Institut de Transplantation et de Recherche en Transplantation [CHU Nantes]
8 UCBL - Université Claude Bernard Lyon 1
9 CHU Pitié-Salpêtrière [AP-HP]
10 SU - Sorbonne Université
11 LIRIC - Lille Inflammation Research International Center - U 995
12 UPEC UP12 - Université Paris-Est Créteil Val-de-Marne - Paris 12
13 UJM - Université Jean Monnet - Saint-Étienne
14 CHU Strasbourg - Centre Hospitalier Universitaire [Strasbourg]
15 UT3 - Université Toulouse III - Paul Sabatier
16 UA - Université d'Angers
17 CHU Amiens-Picardie
18 CHU Clermont-Ferrand
19 Service de Cardiologie et Transplantation [CHRU Nancy]
20 CHU Reims - Hôpital universitaire Robert Debré [Reims]
21 Service de néphrologie [Rennes]
22 UB - Université de Bordeaux
23 CHU Rouen
24 ULB - Université libre de Bruxelles
25 Etablissement Français du Sang [Nantes]
26 UAR 3633 / US24 - Structure Fédérative de Recherche Necker
27 University of Bristol [Bristol]
28 Hôpital Necker - Enfants Malades [AP-HP]
29 UPD7 - Université Paris Diderot - Paris 7
30 UN - Université de Nantes
Sarah B See
- Fonction : Auteur
Olivier Thaunat
- Fonction : Auteur
- PersonId : 768194
- ORCID : 0000-0002-3648-8963
- IdRef : 074257544
Emmanuel Zorn
- Fonction : Auteur
Résumé
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 cell-based assays are needed to improve risk assessments before transplant.