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 - Université Paris-Est-Créteil-Val-de-Marne Access content directly
Journal Articles Journal of the American Society of Nephrology Year : 2018

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

Claire Leibler
  • Function : Author
Allan Thiolat
  • Function : Author
Chloé Samson
  • Function : Author
Caroline Pilon
  • Function : Author
Marie Tamagne
  • Function : Author
France Pirenne
  • Function : Author
Benoit Vingert
  • Function : Author
José Cohen
  • Function : Author
Philippe Grimbert
  • Function : Author

Abstract

Generation of de novo donor-specific antibodies ( dn DSAs) after renal transplant is recognized as the leading cause of late transplant failure. Hence, the optimal immunosuppressive strategies to limit dn DSA 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 dn DSAs 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.

Dates and versions

hal-04395253 , version 1 (15-01-2024)

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Claire Leibler, Allan Thiolat, Carole Hénique, Chloé Samson, Caroline Pilon, et al.. 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. Journal of the American Society of Nephrology, 2018, 29 (3), pp.1049-1062. ⟨10.1681/ASN.2017060679⟩. ⟨hal-04395253⟩

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