Ischemia augments alloimmune injury through IL-6-driven CD4+ alloreactivity

Abstract Ischemia reperfusion injuries (IRI) are unavoidable in solid organ transplantation. IRI augments alloimmunity but the mechanisms involved are poorly understood. Herein, we examined the effect of IRI on antigen specific alloimmunity. We demonstrate that ischemia promotes alloimmune activatio...

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Autores principales:	Mayuko Uehara, Zhabiz Solhjou, Naima Banouni, Vivek Kasinath, Ye Xiaqun, Li Dai, Osman Yilmam, Mine Yilmaz, Takaharu Ichimura, Paolo Fiorina, Paulo N. Martins, Shunsuke Ohori, Indira Guleria, Omar H. Maarouf, Stefan G. Tullius, Martina M. McGrath, Reza Abdi
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9fc14267ab754224a3f118398408edc2
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spelling	oai:doaj.org-article:9fc14267ab754224a3f118398408edc22021-12-02T15:08:17ZIschemia augments alloimmune injury through IL-6-driven CD4+ alloreactivity10.1038/s41598-018-20858-42045-2322https://doaj.org/article/9fc14267ab754224a3f118398408edc22018-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-20858-4https://doaj.org/toc/2045-2322Abstract Ischemia reperfusion injuries (IRI) are unavoidable in solid organ transplantation. IRI augments alloimmunity but the mechanisms involved are poorly understood. Herein, we examined the effect of IRI on antigen specific alloimmunity. We demonstrate that ischemia promotes alloimmune activation, leading to more severe histological features of rejection, and increased CD4+ and CD8+ T cell graft infiltration, with a predominantly CD8+ IFNγ+ infiltrate. This process is dependent on the presence of alloreactive CD4+ T cells, where depletion prevented infiltration of ischemic grafts by CD8+ IFNγ+ T cells. IL-6 is a known driver of ischemia-induced rejection. Herein, depletion of donor antigen-presenting cells reduced ischemia-induced CD8+ IFNγ+ allograft infiltration, and improved allograft outcomes. Following prolonged ischemia, accelerated rejection was observed despite treatment with CTLA4Ig, indicating that T cell costimulatory blockade failed to overcome the immune activating effect of IRI. However, despite severe ischemic injury, treatment with anti-IL-6 and CTLA4Ig blocked IRI-induced alloimmune injury and markedly improved allograft survival. We describe a novel pathway where IRI activates innate immunity, leading to upregulation of antigen specific alloimmunity, resulting in chronic allograft injury. Based on these findings, we describe a clinically relevant treatment strategy to overcome the deleterious effect of IRI, and provide superior long-term allograft outcomes.Mayuko UeharaZhabiz SolhjouNaima BanouniVivek KasinathYe XiaqunLi DaiOsman YilmamMine YilmazTakaharu IchimuraPaolo FiorinaPaulo N. MartinsShunsuke OhoriIndira GuleriaOmar H. MaaroufStefan G. TulliusMartina M. McGrathReza AbdiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-14 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mayuko Uehara Zhabiz Solhjou Naima Banouni Vivek Kasinath Ye Xiaqun Li Dai Osman Yilmam Mine Yilmaz Takaharu Ichimura Paolo Fiorina Paulo N. Martins Shunsuke Ohori Indira Guleria Omar H. Maarouf Stefan G. Tullius Martina M. McGrath Reza Abdi Ischemia augments alloimmune injury through IL-6-driven CD4+ alloreactivity
description	Abstract Ischemia reperfusion injuries (IRI) are unavoidable in solid organ transplantation. IRI augments alloimmunity but the mechanisms involved are poorly understood. Herein, we examined the effect of IRI on antigen specific alloimmunity. We demonstrate that ischemia promotes alloimmune activation, leading to more severe histological features of rejection, and increased CD4+ and CD8+ T cell graft infiltration, with a predominantly CD8+ IFNγ+ infiltrate. This process is dependent on the presence of alloreactive CD4+ T cells, where depletion prevented infiltration of ischemic grafts by CD8+ IFNγ+ T cells. IL-6 is a known driver of ischemia-induced rejection. Herein, depletion of donor antigen-presenting cells reduced ischemia-induced CD8+ IFNγ+ allograft infiltration, and improved allograft outcomes. Following prolonged ischemia, accelerated rejection was observed despite treatment with CTLA4Ig, indicating that T cell costimulatory blockade failed to overcome the immune activating effect of IRI. However, despite severe ischemic injury, treatment with anti-IL-6 and CTLA4Ig blocked IRI-induced alloimmune injury and markedly improved allograft survival. We describe a novel pathway where IRI activates innate immunity, leading to upregulation of antigen specific alloimmunity, resulting in chronic allograft injury. Based on these findings, we describe a clinically relevant treatment strategy to overcome the deleterious effect of IRI, and provide superior long-term allograft outcomes.
format	article
author	Mayuko Uehara Zhabiz Solhjou Naima Banouni Vivek Kasinath Ye Xiaqun Li Dai Osman Yilmam Mine Yilmaz Takaharu Ichimura Paolo Fiorina Paulo N. Martins Shunsuke Ohori Indira Guleria Omar H. Maarouf Stefan G. Tullius Martina M. McGrath Reza Abdi
author_facet	Mayuko Uehara Zhabiz Solhjou Naima Banouni Vivek Kasinath Ye Xiaqun Li Dai Osman Yilmam Mine Yilmaz Takaharu Ichimura Paolo Fiorina Paulo N. Martins Shunsuke Ohori Indira Guleria Omar H. Maarouf Stefan G. Tullius Martina M. McGrath Reza Abdi
author_sort	Mayuko Uehara
title	Ischemia augments alloimmune injury through IL-6-driven CD4+ alloreactivity
title_short	Ischemia augments alloimmune injury through IL-6-driven CD4+ alloreactivity
title_full	Ischemia augments alloimmune injury through IL-6-driven CD4+ alloreactivity
title_fullStr	Ischemia augments alloimmune injury through IL-6-driven CD4+ alloreactivity
title_full_unstemmed	Ischemia augments alloimmune injury through IL-6-driven CD4+ alloreactivity
title_sort	ischemia augments alloimmune injury through il-6-driven cd4+ alloreactivity
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/9fc14267ab754224a3f118398408edc2
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Ischemia augments alloimmune injury through IL-6-driven CD4+ alloreactivity

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