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Clinical Research
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CRISPR/Cas9-Engineered HLA-Deleted Glomerular Endothelial Cells as a Tool to Predict Pathogenic Non-HLA Antibodies in Kidney Transplant Recipients

Baptiste Lamarthée, Carole Burger, Charlotte Leclaire, Emilie Lebraud, Aniela Zablocki, Lise Morin, Xavier Lebreton, Béatrice Charreau, Renaud Snanoudj, Soëli Charbonnier, Tifanie Blein, Mélanie Hardy, Julien Zuber, Simon Satchell, Morgan Gallazzini, Fabiola Terzi, Christophe Legendre, Jean Luc Taupin, Marion Rabant, Claire Tinel and Dany Anglicheau
JASN December 2021, 32 (12) 3231-3251; DOI: https://doi.org/10.1681/ASN.2021050689
Baptiste Lamarthée
1Necker-Enfants Malades Institute, Institut National de la Santé et de la Recherche Médicale (INSERM) U1151, University of Paris, Paris, France
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Carole Burger
1Necker-Enfants Malades Institute, Institut National de la Santé et de la Recherche Médicale (INSERM) U1151, University of Paris, Paris, France
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Charlotte Leclaire
1Necker-Enfants Malades Institute, Institut National de la Santé et de la Recherche Médicale (INSERM) U1151, University of Paris, Paris, France
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Emilie Lebraud
1Necker-Enfants Malades Institute, Institut National de la Santé et de la Recherche Médicale (INSERM) U1151, University of Paris, Paris, France
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Aniela Zablocki
1Necker-Enfants Malades Institute, Institut National de la Santé et de la Recherche Médicale (INSERM) U1151, University of Paris, Paris, France
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Lise Morin
1Necker-Enfants Malades Institute, Institut National de la Santé et de la Recherche Médicale (INSERM) U1151, University of Paris, Paris, France
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Xavier Lebreton
2Department of Nephrology and Kidney Transplantation, Necker Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
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Béatrice Charreau
3Center for Research in Transplantation and Immunology, INSERM UMR1064, IHU CESTI, LabEx IGO and LabEx Transplantex, Nantes University, Nantes, France
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Renaud Snanoudj
4Immunology and Histocompatibility Laboratory, Saint-Louis Hospital, AP-HP, LabEx Transplantex, INSERM U1160, University Paris Diderot, Paris, France
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Soëli Charbonnier
5Laboratory of Human Lymphohematopoiesis, Imagine Institute, INSERM U1163, University of Paris, Paris, France
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Tifanie Blein
5Laboratory of Human Lymphohematopoiesis, Imagine Institute, INSERM U1163, University of Paris, Paris, France
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Mélanie Hardy
6Immunology and Histocompatibility Laboratory, Saint-Louis Hospital, AP-HP, INSERM U976, IRSL, University of Paris, Paris, France
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Julien Zuber
2Department of Nephrology and Kidney Transplantation, Necker Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
5Laboratory of Human Lymphohematopoiesis, Imagine Institute, INSERM U1163, University of Paris, Paris, France
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Simon Satchell
7Bristol Renal, Bristol Heart Institute, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
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Morgan Gallazzini
1Necker-Enfants Malades Institute, Institut National de la Santé et de la Recherche Médicale (INSERM) U1151, University of Paris, Paris, France
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Fabiola Terzi
1Necker-Enfants Malades Institute, Institut National de la Santé et de la Recherche Médicale (INSERM) U1151, University of Paris, Paris, France
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Christophe Legendre
2Department of Nephrology and Kidney Transplantation, Necker Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
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Jean Luc Taupin
6Immunology and Histocompatibility Laboratory, Saint-Louis Hospital, AP-HP, INSERM U976, IRSL, University of Paris, Paris, France
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Marion Rabant
1Necker-Enfants Malades Institute, Institut National de la Santé et de la Recherche Médicale (INSERM) U1151, University of Paris, Paris, France
8Department of Pathology, Necker Hospital, AP-HP, Paris, France
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Claire Tinel
1Necker-Enfants Malades Institute, Institut National de la Santé et de la Recherche Médicale (INSERM) U1151, University of Paris, Paris, France
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Dany Anglicheau
1Necker-Enfants Malades Institute, Institut National de la Santé et de la Recherche Médicale (INSERM) U1151, University of Paris, Paris, France
2Department of Nephrology and Kidney Transplantation, Necker Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
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Significance Statement

Evidence for the deleterious role of non-HLA antibodies after kidney transplantation is growing. Still, given the high heterogeneity and the number of potential targets, a candidate-based strategy to detect these antibodies can be misleading. We introduce a cell-based assay using human glomerular endothelial cells deleted for all HLA antigens as targets and recapitulate a large array of potential non-HLA antibodies in a single test. This approach confirms that the global burden of non-HLA antibodies targeting the endothelium is associated with microvascular inflammation and worse graft outcome, independent of HLA donor-specific antibodies. Our results demonstrate the clinical utility of the test for improving the pretransplant evaluation of immunologic risk and for designing mechanism-driven therapeutic approaches targeting non-HLA antibodies.

Abstract

Background After kidney transplantation, donor-specific antibodies against human leukocyte antigen donor-specific antibodies (HLA-DSAs) drive antibody-mediated rejection (ABMR) and are associated with poor transplant outcomes. However, ABMR histology (ABMRh) is increasingly reported in kidney transplant recipients (KTRs) without HLA-DSAs, highlighting the emerging role of non-HLA antibodies (Abs).

Methods W e designed a non-HLA Ab detection immunoassay (NHADIA) using HLA class I and II–deficient glomerular endothelial cells (CiGEnCΔHLA) that had been previously generated through CRISPR/Cas9-induced B2M and CIITA gene disruption. Flow cytometry assessed the reactivity to non-HLA antigens of pretransplantation serum samples from 389 consecutive KTRs. The intensity of the signal observed with the NHADIA was associated with post-transplant graft histology assessed in 951 adequate biopsy specimens.

Results W e sequentially applied CRISPR/Cas9 to delete the B2M and CIITA genes to obtain a CiGEnCΔHLA clone. CiGEnCΔHLA cells remained indistinguishable from the parental cell line, CiGEnC, in terms of morphology and phenotype. Previous transplantation was the main determinant of the pretransplantation NHADIA result (P<0.001). Stratification of 3-month allograft biopsy specimens (n=298) according to pretransplantation NHADIA tertiles demonstrated that higher levels of non-HLA Abs positively correlated with increased glomerulitis (P=0.002), microvascular inflammation (P=0.003), and ABMRh (P=0.03). A pretransplantation NHADIA threshold of 1.87 strongly discriminated the KTRs with the highest risk of ABMRh (P=0.005, log-rank test). A multivariate Cox model confirmed that NHADIA status and HLA-DSAs were independent, yet synergistic, predictors of ABMRh.

Conclusion The NHADIA identifies non-HLA Abs and strongly predicts graft endothelial injury independent of HLA-DSAs.

  • antibody-mediated rejection
  • non-HLA antibodies
  • kidney rejection
  • endothelial inflammation
  • kidney transplantation
  • endothelial cells
  • CRISPR-Cas systems
  • antibodies
  • Copyright © 2021 by the American Society of Nephrology
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Journal of the American Society of Nephrology: 32 (12)
Journal of the American Society of Nephrology
Vol. 32, Issue 12
December 2021
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CRISPR/Cas9-Engineered HLA-Deleted Glomerular Endothelial Cells as a Tool to Predict Pathogenic Non-HLA Antibodies in Kidney Transplant Recipients
Baptiste Lamarthée, Carole Burger, Charlotte Leclaire, Emilie Lebraud, Aniela Zablocki, Lise Morin, Xavier Lebreton, Béatrice Charreau, Renaud Snanoudj, Soëli Charbonnier, Tifanie Blein, Mélanie Hardy, Julien Zuber, Simon Satchell, Morgan Gallazzini, Fabiola Terzi, Christophe Legendre, Jean Luc Taupin, Marion Rabant, Claire Tinel, Dany Anglicheau
JASN Dec 2021, 32 (12) 3231-3251; DOI: 10.1681/ASN.2021050689

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CRISPR/Cas9-Engineered HLA-Deleted Glomerular Endothelial Cells as a Tool to Predict Pathogenic Non-HLA Antibodies in Kidney Transplant Recipients
Baptiste Lamarthée, Carole Burger, Charlotte Leclaire, Emilie Lebraud, Aniela Zablocki, Lise Morin, Xavier Lebreton, Béatrice Charreau, Renaud Snanoudj, Soëli Charbonnier, Tifanie Blein, Mélanie Hardy, Julien Zuber, Simon Satchell, Morgan Gallazzini, Fabiola Terzi, Christophe Legendre, Jean Luc Taupin, Marion Rabant, Claire Tinel, Dany Anglicheau
JASN Dec 2021, 32 (12) 3231-3251; DOI: 10.1681/ASN.2021050689
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Keywords

  • antibody-mediated rejection
  • non-HLA antibodies
  • kidney rejection
  • endothelial inflammation
  • kidney transplantation
  • endothelial cells
  • CRISPR-Cas systems
  • antibodies

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