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Clinical Research
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Coordinated Circulating T Follicular Helper and Activated B Cell Responses Underlie the Onset of Antibody-Mediated Rejection in Kidney Transplantation

Kevin Louis, Camila Macedo, Elodie Bailly, Louis Lau, Bala Ramaswami, Marilyn Marrari, Douglas Landsittel, Alexander Chang, Uma Chandran, Paul Fadakar, Masaki Yamada, Geetha Chalasani, Parmjeet Randhawa, Adriana Zeevi, Harinder Singh, Carmen Lefaucheur and Diana Metes
JASN October 2020, 31 (10) 2457-2474; DOI: https://doi.org/10.1681/ASN.2020030320
Kevin Louis
1Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
2Human Immunology and Immunopathology, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 976, Université de Paris, Paris, France
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Camila Macedo
1Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
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Elodie Bailly
1Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
2Human Immunology and Immunopathology, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 976, Université de Paris, Paris, France
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Louis Lau
3Center for Systems Immunology, Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania
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Bala Ramaswami
1Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
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Marilyn Marrari
1Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
4Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
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Douglas Landsittel
5Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania
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Alexander Chang
5Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania
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Uma Chandran
5Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania
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Paul Fadakar
1Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
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Masaki Yamada
1Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
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Geetha Chalasani
1Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
6Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
7Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania
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Parmjeet Randhawa
1Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
4Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
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Adriana Zeevi
1Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
4Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
7Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania
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Harinder Singh
3Center for Systems Immunology, Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania
7Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania
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Carmen Lefaucheur
8Paris Translational Research Center for Organ Transplantation, Inserm UMR S970, Université de Paris, Paris, France
Roles: Please change the affiliation of this author. Remove affiliation 2 and 3, and replace by the following affiliation (that will have to be added): Paris Translational Research Center for Organ Transplantation, Inserm UMR S970, Université de Paris, Paris, France
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Diana Metes
1Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
7Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania
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Significance Statement

Most studies investigating the mechanisms of antibody-mediated rejection, a major cause of kidney allograft failure, have focused on characterizing the role of donor-specific antibodies (DSAs), whereas the alloreactive cellular component has been less studied. On the basis of a multidimensional and concomitant profiling of circulating T follicular helper (TFH) cells and B cells, the authors identified highly coordinated responses of circulating TFH cells and activated B cells at phenotypic, functional, and transcriptional levels in patients with antibody-mediated rejection. The levels of circulating TFH cell and B cell activation were predictive of DSA pathogenicity, histologic severity, and allograft loss. This study provides novel mechanistic insights into the cellular and molecular processes underlying antibody-mediated rejection and a rationale for monitoring and therapeutic targeting of circulating TFH cell–B cell interaction during antibody-mediated rejection.

Abstract

Background Although antibody-mediated rejection (ABMR) has been long recognized as a leading cause of allograft failure after kidney transplantation, the cellular and molecular processes underlying the induction of deleterious donor-specific antibody (DSA) responses remain poorly understood.

Methods Using high-dimensional flow cytometry, in vitro assays, and RNA sequencing, we concomitantly investigated the role of T follicular helper (TFH) cells and B cells during ABMR in 105 kidney transplant recipients.

Results There were 54 patients without DSAs; of those with DSAs, ABMR emerged in 20 patients, but not in 31 patients. We identified proliferating populations of circulating TFH cells and activated B cells emerging in blood of patients undergoing ABMR. Although these circulating TFH cells comprised heterogeneous phenotypes, they were dominated by activated (ICOS+PD-1+) and early memory precursor (CCR7+CD127+) subsets, and were enriched for the transcription factors IRF4 and c-Maf. These circulating TFH cells produced large amounts of IL-21 upon stimulation with donor antigen and induced B cells to differentiate into antibody-secreting cells that produced DSAs. Combined analysis of the matched circulating TFH cell and activated B cell RNA-sequencing profiles identified highly coordinated transcriptional programs in circulating TFH cells and B cells among patients with ABMR, which markedly differed from those of patients who did not develop DSAs or ABMR. The timing of expansion of the distinctive circulating TFH cells and activated B cells paralleled emergence of DSAs in blood, and their magnitude was predictive of IgG3 DSA generation, more severe allograft injury, and higher rate of allograft loss.

Conclusions Patients undergoing ABMR may benefit from monitoring and therapeutic targeting of TFH cell–B cell interactions.

  • acute allograft rejection
  • lymphocytes
  • immunology
  • kidney transplantation
  • transcriptional profiling
  • transplant outcomes
  • Copyright © 2020 by the American Society of Nephrology
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Journal of the American Society of Nephrology: 31 (10)
Journal of the American Society of Nephrology
Vol. 31, Issue 10
October 2020
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Coordinated Circulating T Follicular Helper and Activated B Cell Responses Underlie the Onset of Antibody-Mediated Rejection in Kidney Transplantation
Kevin Louis, Camila Macedo, Elodie Bailly, Louis Lau, Bala Ramaswami, Marilyn Marrari, Douglas Landsittel, Alexander Chang, Uma Chandran, Paul Fadakar, Masaki Yamada, Geetha Chalasani, Parmjeet Randhawa, Adriana Zeevi, Harinder Singh, Carmen Lefaucheur, Diana Metes
JASN Oct 2020, 31 (10) 2457-2474; DOI: 10.1681/ASN.2020030320

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Coordinated Circulating T Follicular Helper and Activated B Cell Responses Underlie the Onset of Antibody-Mediated Rejection in Kidney Transplantation
Kevin Louis, Camila Macedo, Elodie Bailly, Louis Lau, Bala Ramaswami, Marilyn Marrari, Douglas Landsittel, Alexander Chang, Uma Chandran, Paul Fadakar, Masaki Yamada, Geetha Chalasani, Parmjeet Randhawa, Adriana Zeevi, Harinder Singh, Carmen Lefaucheur, Diana Metes
JASN Oct 2020, 31 (10) 2457-2474; DOI: 10.1681/ASN.2020030320
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Keywords

  • acute allograft rejection
  • lymphocytes
  • immunology
  • kidney transplantation
  • transcriptional profiling
  • transplant outcomes

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