Cargando…

Chronic CD40L blockade is required for long-term cardiac allograft survival with a clinically relevant CTLA4-Ig dosing regimen

INTRODUCTION: In de-novo kidney transplantation, the CTLA4-Ig fusion protein belatacept is associated with improved graft function but also an increased risk of acute rejection compared to calcineurin inhibitor therapy. The combination with a second costimulation blocker could potentially improve ou...

Descripción completa

Detalles Bibliográficos
Autores principales: Unger, Lukas W., Muckenhuber, Moritz, Mahr, Benedikt, Schwarz, Christoph, Pilat, Nina, Granofszky, Nicolas, Regele, Heinz, Wekerle, Thomas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9773869/
https://www.ncbi.nlm.nih.gov/pubmed/36569922
http://dx.doi.org/10.3389/fimmu.2022.1060576
_version_ 1784855281664000000
author Unger, Lukas W.
Muckenhuber, Moritz
Mahr, Benedikt
Schwarz, Christoph
Pilat, Nina
Granofszky, Nicolas
Regele, Heinz
Wekerle, Thomas
author_facet Unger, Lukas W.
Muckenhuber, Moritz
Mahr, Benedikt
Schwarz, Christoph
Pilat, Nina
Granofszky, Nicolas
Regele, Heinz
Wekerle, Thomas
author_sort Unger, Lukas W.
collection PubMed
description INTRODUCTION: In de-novo kidney transplantation, the CTLA4-Ig fusion protein belatacept is associated with improved graft function but also an increased risk of acute rejection compared to calcineurin inhibitor therapy. The combination with a second costimulation blocker could potentially improve outcome while avoiding calcineurin inhibitor toxicity. The aim of this study was to define the conditions under which the combination of CTLA4-Ig and CD40L blockade leads to rejection-free permanent graft survival in a stringent murine heart transplantation model. METHODS: Naïve wild-type or CD40L (CD154) knock-out mice received a fully mismatched BALB/c cardiac allograft. Selected induction and maintenance protocols for CTLA4-Ig and blocking αCD40L monoclonal antibodies (mAB) were investigated. Graft survival, rejection severity and donor-specific antibody (DSA) formation were assessed during a 100-day follow-up period. RESULTS AND DISCUSSION: Administering αCD40L mAb as monotherapy at the time of transplantation significantly prolonged heart allograft survival but did not further improve the outcome when given in addition to chronic CTLA4-Ig therapy (which prolongs graft survival to a median of 22 days). Likewise, chronic αCD40L mAb therapy (0.5mg) combined with perioperative CTLA4-Ig led to rejection in a proportion of mice and extensive histological damage, despite abrogating DSA formation. Only the permanent interruption of CD40-CD40L signaling by using CD40L(-/-) recipient mice or by chronic αCD40L administration synergized with chronic CTLA4-Ig to achieve long-term allograft survival with preserved histological graft integrity in all recipients without DSA formation. The combination of α-CD40L and CTLA4-Ig works most effectively when both therapeutics are administered chronically.
format Online
Article
Text
id pubmed-9773869
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-97738692022-12-23 Chronic CD40L blockade is required for long-term cardiac allograft survival with a clinically relevant CTLA4-Ig dosing regimen Unger, Lukas W. Muckenhuber, Moritz Mahr, Benedikt Schwarz, Christoph Pilat, Nina Granofszky, Nicolas Regele, Heinz Wekerle, Thomas Front Immunol Immunology INTRODUCTION: In de-novo kidney transplantation, the CTLA4-Ig fusion protein belatacept is associated with improved graft function but also an increased risk of acute rejection compared to calcineurin inhibitor therapy. The combination with a second costimulation blocker could potentially improve outcome while avoiding calcineurin inhibitor toxicity. The aim of this study was to define the conditions under which the combination of CTLA4-Ig and CD40L blockade leads to rejection-free permanent graft survival in a stringent murine heart transplantation model. METHODS: Naïve wild-type or CD40L (CD154) knock-out mice received a fully mismatched BALB/c cardiac allograft. Selected induction and maintenance protocols for CTLA4-Ig and blocking αCD40L monoclonal antibodies (mAB) were investigated. Graft survival, rejection severity and donor-specific antibody (DSA) formation were assessed during a 100-day follow-up period. RESULTS AND DISCUSSION: Administering αCD40L mAb as monotherapy at the time of transplantation significantly prolonged heart allograft survival but did not further improve the outcome when given in addition to chronic CTLA4-Ig therapy (which prolongs graft survival to a median of 22 days). Likewise, chronic αCD40L mAb therapy (0.5mg) combined with perioperative CTLA4-Ig led to rejection in a proportion of mice and extensive histological damage, despite abrogating DSA formation. Only the permanent interruption of CD40-CD40L signaling by using CD40L(-/-) recipient mice or by chronic αCD40L administration synergized with chronic CTLA4-Ig to achieve long-term allograft survival with preserved histological graft integrity in all recipients without DSA formation. The combination of α-CD40L and CTLA4-Ig works most effectively when both therapeutics are administered chronically. Frontiers Media S.A. 2022-12-08 /pmc/articles/PMC9773869/ /pubmed/36569922 http://dx.doi.org/10.3389/fimmu.2022.1060576 Text en Copyright © 2022 Unger, Muckenhuber, Mahr, Schwarz, Pilat, Granofszky, Regele and Wekerle https://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
Unger, Lukas W.
Muckenhuber, Moritz
Mahr, Benedikt
Schwarz, Christoph
Pilat, Nina
Granofszky, Nicolas
Regele, Heinz
Wekerle, Thomas
Chronic CD40L blockade is required for long-term cardiac allograft survival with a clinically relevant CTLA4-Ig dosing regimen
title Chronic CD40L blockade is required for long-term cardiac allograft survival with a clinically relevant CTLA4-Ig dosing regimen
title_full Chronic CD40L blockade is required for long-term cardiac allograft survival with a clinically relevant CTLA4-Ig dosing regimen
title_fullStr Chronic CD40L blockade is required for long-term cardiac allograft survival with a clinically relevant CTLA4-Ig dosing regimen
title_full_unstemmed Chronic CD40L blockade is required for long-term cardiac allograft survival with a clinically relevant CTLA4-Ig dosing regimen
title_short Chronic CD40L blockade is required for long-term cardiac allograft survival with a clinically relevant CTLA4-Ig dosing regimen
title_sort chronic cd40l blockade is required for long-term cardiac allograft survival with a clinically relevant ctla4-ig dosing regimen
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9773869/
https://www.ncbi.nlm.nih.gov/pubmed/36569922
http://dx.doi.org/10.3389/fimmu.2022.1060576
work_keys_str_mv AT ungerlukasw chroniccd40lblockadeisrequiredforlongtermcardiacallograftsurvivalwithaclinicallyrelevantctla4igdosingregimen
AT muckenhubermoritz chroniccd40lblockadeisrequiredforlongtermcardiacallograftsurvivalwithaclinicallyrelevantctla4igdosingregimen
AT mahrbenedikt chroniccd40lblockadeisrequiredforlongtermcardiacallograftsurvivalwithaclinicallyrelevantctla4igdosingregimen
AT schwarzchristoph chroniccd40lblockadeisrequiredforlongtermcardiacallograftsurvivalwithaclinicallyrelevantctla4igdosingregimen
AT pilatnina chroniccd40lblockadeisrequiredforlongtermcardiacallograftsurvivalwithaclinicallyrelevantctla4igdosingregimen
AT granofszkynicolas chroniccd40lblockadeisrequiredforlongtermcardiacallograftsurvivalwithaclinicallyrelevantctla4igdosingregimen
AT regeleheinz chroniccd40lblockadeisrequiredforlongtermcardiacallograftsurvivalwithaclinicallyrelevantctla4igdosingregimen
AT wekerlethomas chroniccd40lblockadeisrequiredforlongtermcardiacallograftsurvivalwithaclinicallyrelevantctla4igdosingregimen