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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.02071

CXCR5+PD1+ICOS+ circulating T follicular helpers are associated with de novo donor-specific antibodies after renal transplantation

 Richard Danger1, 2*,  Melanie Chesneau1, 3, Florent Delbos4, Sabine Lebot3, 5, Clarisse Kerleau2, 5,  Alexis Chenouard3, 5,  Simon VILLE3, 5,  Nicolas Degauque3, 5,  Sophie Conchon3, 5,  Anne CESBRON4, Magali Giral3, 5 and  Sophie Brouard3, 5*
  • 1Université de Nantes, INSERM U1064 Centre de Recherche en Transplantation et Immunologie, France
  • 2Institut de Transplantation Urologie en Nephrologie (INSERM), France
  • 3Institut de transplantation urologie-néphrologie (ITUN), France
  • 4Etablissement Français du sang, Pays de la Loire, France
  • 5INSERM U1064 Centre de Recherche en Transplantation et Immunologie, France

Donor-specific anti-HLA antibodies (DSAs) are a major risk factor associated with renal allograft outcomes. As a trigger of B cell antibody production, T follicular helper cells (Tfhs) promote DSA appearance. Herein, we evaluated whether circulating Tfhs (cTfhs) are associated with the genesis of antibody-mediated rejection. We measured cTfh levels on the day of transplantation and one year after transplantation in blood from a prospective cohort of 237 renal transplantation patients without DSA during the first year post-transplantation. Total cTfhs were characterized as CD4+CD45RA-CXCR5+, and the three following subsets of activated cTfh were analyzed: CXCR5+PD1+, CXCR5+PD1+ICOS+ and CXCR5+PD1+CXCR3-. Immunizing events (previous blood transfusion and/or pregnancy) and the presence of class II anti-HLA antibodies were associated with increased frequencies of activated CXCR5+PD1+, CXCR5+PD1+ICOS+ and CXCR5+PD1+CXCR3- cTfh subsets. In addition, ATG-depleting induction and calcineurin inhibitor treatments were associated with a relative increase of activated cTfh subsets frequencies at one year post-transplantation. In multivariate survival analysis, we reported that a decrease in activated CXCR5+PD1+ICOS+ at one year after transplantation in the blood of DSA-free patients was significantly associated with the risk of developing de novo DSA after the first year (p=0.018, HR =0.39), independently of HLA mismatches (p=0.003, HR =3.79). These results highlight the importance of monitoring activated Tfhs in patients early after transplantation and show that current treatments cannot provide early, efficient prevention of Tfh activation and migration. These findings indicate the need to develop innovative treatments to specifically target Tfhs to prevent DSA appearance in renal transplantation.

Keywords: Donor-specific antibodies (DSA), circulating T follicular helper lymphocytes, TFH, Renal Transplantation (RTx), Follicular T helper cells

Received: 09 Apr 2019; Accepted: 16 Aug 2019.

Copyright: © 2019 Danger, Chesneau, Delbos, Lebot, Kerleau, Chenouard, VILLE, Degauque, Conchon, CESBRON, Giral and Brouard. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Dr. Richard Danger, INSERM U1064 Centre de Recherche en Transplantation et Immunologie, Université de Nantes, Nantes, 44093, Pays de la Loire, France, richard.danger@univ-nantes.fr
Dr. Sophie Brouard, INSERM U1064 Centre de Recherche en Transplantation et Immunologie, Nantes, 44093, Pays de la Loire, France, sophie.brouard@univ-nantes.fr