Cargando…

CXCR5(+)PD1(+)ICOS(+) Circulating T Follicular Helpers Are Associated With de novo Donor-Specific Antibodies After Renal Transplantation

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 an...

Descripción completa

Detalles Bibliográficos
Autores principales: Danger, Richard, Chesneau, Mélanie, Delbos, Florent, Le Bot, Sabine, Kerleau, Clarisse, Chenouard, Alexis, Ville, Simon, Degauque, Nicolas, Conchon, Sophie, Cesbron, Anne, Giral, Magali, Brouard, Sophie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746839/
https://www.ncbi.nlm.nih.gov/pubmed/31552030
http://dx.doi.org/10.3389/fimmu.2019.02071
_version_ 1783451764418150400
author Danger, Richard
Chesneau, Mélanie
Delbos, Florent
Le Bot, Sabine
Kerleau, Clarisse
Chenouard, Alexis
Ville, Simon
Degauque, Nicolas
Conchon, Sophie
Cesbron, Anne
Giral, Magali
Brouard, Sophie
author_facet Danger, Richard
Chesneau, Mélanie
Delbos, Florent
Le Bot, Sabine
Kerleau, Clarisse
Chenouard, Alexis
Ville, Simon
Degauque, Nicolas
Conchon, Sophie
Cesbron, Anne
Giral, Magali
Brouard, Sophie
author_sort Danger, Richard
collection PubMed
description 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 1 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(+), an 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 1 year post-transplantation. In multivariate survival analysis, we reported that a decrease in activated CXCR5(+)PD1(+)ICOS(+) at 1 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.
format Online
Article
Text
id pubmed-6746839
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-67468392019-09-24 CXCR5(+)PD1(+)ICOS(+) Circulating T Follicular Helpers Are Associated With de novo Donor-Specific Antibodies After Renal Transplantation Danger, Richard Chesneau, Mélanie Delbos, Florent Le Bot, Sabine Kerleau, Clarisse Chenouard, Alexis Ville, Simon Degauque, Nicolas Conchon, Sophie Cesbron, Anne Giral, Magali Brouard, Sophie Front Immunol Immunology 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 1 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(+), an 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 1 year post-transplantation. In multivariate survival analysis, we reported that a decrease in activated CXCR5(+)PD1(+)ICOS(+) at 1 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. Frontiers Media S.A. 2019-09-10 /pmc/articles/PMC6746839/ /pubmed/31552030 http://dx.doi.org/10.3389/fimmu.2019.02071 Text en Copyright © 2019 Danger, Chesneau, Delbos, Le Bot, Kerleau, Chenouard, Ville, Degauque, Conchon, Cesbron, Giral and Brouard. http://creativecommons.org/licenses/by/4.0/ 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.
spellingShingle Immunology
Danger, Richard
Chesneau, Mélanie
Delbos, Florent
Le Bot, Sabine
Kerleau, Clarisse
Chenouard, Alexis
Ville, Simon
Degauque, Nicolas
Conchon, Sophie
Cesbron, Anne
Giral, Magali
Brouard, Sophie
CXCR5(+)PD1(+)ICOS(+) Circulating T Follicular Helpers Are Associated With de novo Donor-Specific Antibodies After Renal Transplantation
title CXCR5(+)PD1(+)ICOS(+) Circulating T Follicular Helpers Are Associated With de novo Donor-Specific Antibodies After Renal Transplantation
title_full CXCR5(+)PD1(+)ICOS(+) Circulating T Follicular Helpers Are Associated With de novo Donor-Specific Antibodies After Renal Transplantation
title_fullStr CXCR5(+)PD1(+)ICOS(+) Circulating T Follicular Helpers Are Associated With de novo Donor-Specific Antibodies After Renal Transplantation
title_full_unstemmed CXCR5(+)PD1(+)ICOS(+) Circulating T Follicular Helpers Are Associated With de novo Donor-Specific Antibodies After Renal Transplantation
title_short CXCR5(+)PD1(+)ICOS(+) Circulating T Follicular Helpers Are Associated With de novo Donor-Specific Antibodies After Renal Transplantation
title_sort cxcr5(+)pd1(+)icos(+) circulating t follicular helpers are associated with de novo donor-specific antibodies after renal transplantation
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746839/
https://www.ncbi.nlm.nih.gov/pubmed/31552030
http://dx.doi.org/10.3389/fimmu.2019.02071
work_keys_str_mv AT dangerrichard cxcr5pd1icoscirculatingtfollicularhelpersareassociatedwithdenovodonorspecificantibodiesafterrenaltransplantation
AT chesneaumelanie cxcr5pd1icoscirculatingtfollicularhelpersareassociatedwithdenovodonorspecificantibodiesafterrenaltransplantation
AT delbosflorent cxcr5pd1icoscirculatingtfollicularhelpersareassociatedwithdenovodonorspecificantibodiesafterrenaltransplantation
AT lebotsabine cxcr5pd1icoscirculatingtfollicularhelpersareassociatedwithdenovodonorspecificantibodiesafterrenaltransplantation
AT kerleauclarisse cxcr5pd1icoscirculatingtfollicularhelpersareassociatedwithdenovodonorspecificantibodiesafterrenaltransplantation
AT chenouardalexis cxcr5pd1icoscirculatingtfollicularhelpersareassociatedwithdenovodonorspecificantibodiesafterrenaltransplantation
AT villesimon cxcr5pd1icoscirculatingtfollicularhelpersareassociatedwithdenovodonorspecificantibodiesafterrenaltransplantation
AT degauquenicolas cxcr5pd1icoscirculatingtfollicularhelpersareassociatedwithdenovodonorspecificantibodiesafterrenaltransplantation
AT conchonsophie cxcr5pd1icoscirculatingtfollicularhelpersareassociatedwithdenovodonorspecificantibodiesafterrenaltransplantation
AT cesbronanne cxcr5pd1icoscirculatingtfollicularhelpersareassociatedwithdenovodonorspecificantibodiesafterrenaltransplantation
AT giralmagali cxcr5pd1icoscirculatingtfollicularhelpersareassociatedwithdenovodonorspecificantibodiesafterrenaltransplantation
AT brouardsophie cxcr5pd1icoscirculatingtfollicularhelpersareassociatedwithdenovodonorspecificantibodiesafterrenaltransplantation