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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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2019
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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 |
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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 |
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