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Control of Humoral Response in Renal Transplantation by Belatacept Depends on a Direct Effect on B Cells and Impaired T Follicular Helper-B Cell Crosstalk.

Authors
  • Leibler, Claire1, 2, 3
  • Thiolat, Allan1, 2
  • Hénique, Carole1, 2
  • Samson, Chloé1, 2
  • Pilon, Caroline1, 2
  • Tamagne, Marie4
  • Pirenne, France4
  • Vingert, Benoit4
  • Cohen, José L1, 2, 3
  • Grimbert, Philippe5, 2, 3
  • 1 Université Paris-Est, Unité Mixte de Recherche 955, Université Paris-Est-Créteil, Creteil, France. , (France)
  • 2 U955, Team 21, Institut National de la Santé et de la Recherche Médicale, Creteil, France. , (France)
  • 3 Hopital Henri-Mondor-A. Chenevier, CIC-BT-504, Assistance Publique-Hôpitaux de Paris, Creteil, France; and. , (France)
  • 4 U955, Team 2, Institut National de la Santé et de la Recherche Médicale, Creteil, France. , (France)
  • 5 Université Paris-Est, Unité Mixte de Recherche 955, Université Paris-Est-Créteil, Creteil, France; [email protected] , (France)
Type
Published Article
Journal
Journal of the American Society of Nephrology
Publisher
American Society of Nephrology
Publication Date
Mar 01, 2018
Volume
29
Issue
3
Pages
1049–1062
Identifiers
DOI: 10.1681/ASN.2017060679
PMID: 29321143
Source
Medline
Keywords
License
Unknown

Abstract

Generation of de novo donor-specific antibodies (dnDSAs) after renal transplant is recognized as the leading cause of late transplant failure. Hence, the optimal immunosuppressive strategies to limit dnDSA development need to be defined. Recent clinical trials using the novel costimulatory blockade agent CTLA4-Ig (Belatacept) have shown that kidney transplant recipients (KTRs) treated with Belatacept have better graft survival and function and a lower proportion of dnDSAs than control-treated KTRs. Mechanisms involved in the control of humoral responses by Belatacept remain to be investigated. Here, we analyzed the effect of Belatacept on different steps of the B cell-mediated response in humans. In vitro, Belatacept reduced plasmablast differentiation, Ig production, and the expression of the major transcription factor involved in plasma cell function, Blimp-1, in a T cell-independent manner. Moreover, Belatacept induced activation of the STAT3 transcription factor in stimulated B cells and reduced the expression of CD86. Additionally, Belatacept blocked CD28-mediated activation of T follicular helper cells (Tfhs) in an autologous Tfh-memory B cells model. We then validated these observations in KTRs treated with Belatacept, who had a reduced proportion of blood effector B cells and activated Tfh (PD1+ICOS+) compared with control-treated KTRs. Our in vitro and in vivo results suggest that Belatacept modulates B cell function directly and at the level of B cell-Tfh interaction. These mechanisms likely account for the optimal control of humoral responses observed in KTRs treated with Belatacept.

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