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dc.contributor.authorUehara, Mayuko
dc.contributor.authorSolhjou, Zhabiz
dc.contributor.authorBanouni, Naima
dc.contributor.authorKasinath, Vivek
dc.contributor.authorXiaqun, Ye
dc.contributor.authorDai, Li
dc.contributor.authorYilmam, Osman
dc.contributor.authorYilmaz, Mine
dc.contributor.authorIchimura, Takaharu
dc.contributor.authorFiorina, Paolo
dc.contributor.authorMartins, Paulo N.A.
dc.contributor.authorOhori, Shunsuke
dc.contributor.authorGuleria, Indira
dc.contributor.authorMaarouf, Omar H.
dc.contributor.authorTullius, Stefan G.
dc.contributor.authorMcGrath, Martina M.
dc.contributor.authorAbdi, Reza
dc.date2022-08-11T08:09:49.000
dc.date.accessioned2022-08-23T16:44:56Z
dc.date.available2022-08-23T16:44:56Z
dc.date.issued2018-02-06
dc.date.submitted2018-05-17
dc.identifier.citation<p>Sci Rep. 2018 Feb 6;8(1):2461. doi: 10.1038/s41598-018-20858-4. <a href="https://doi.org/10.1038/s41598-018-20858-4">Link to article on publisher's site</a></p>
dc.identifier.issn2045-2322 (Linking)
dc.identifier.doi10.1038/s41598-018-20858-4
dc.identifier.pmid29410442
dc.identifier.urihttp://hdl.handle.net/20.500.14038/40596
dc.description.abstractIschemia 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(+) IFNgamma(+) infiltrate. This process is dependent on the presence of alloreactive CD4(+) T cells, where depletion prevented infiltration of ischemic grafts by CD8(+) IFNgamma(+) T cells. IL-6 is a known driver of ischemia-induced rejection. Herein, depletion of donor antigen-presenting cells reduced ischemia-induced CD8(+) IFNgamma(+) 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.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=29410442&dopt=Abstract">Link to Article in PubMed</a></p>
dc.rights© The Author(s) 2018. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectImmunology
dc.subjectTransplant immunology
dc.subjectImmunity
dc.subjectOther Immunology and Infectious Disease
dc.subjectPathological Conditions, Signs and Symptoms
dc.subjectSurgery
dc.subjectSurgical Procedures, Operative
dc.titleIschemia augments alloimmune injury through IL-6-driven CD4(+) alloreactivity
dc.typeArticle
dc.source.journaltitleScientific reports
dc.source.volume8
dc.source.issue1
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=4411&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/3400
dc.identifier.contextkey12142888
refterms.dateFOA2022-08-23T16:44:56Z
html.description.abstract<p>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(+) IFNgamma(+) infiltrate. This process is dependent on the presence of alloreactive CD4(+) T cells, where depletion prevented infiltration of ischemic grafts by CD8(+) IFNgamma(+) T cells. IL-6 is a known driver of ischemia-induced rejection. Herein, depletion of donor antigen-presenting cells reduced ischemia-induced CD8(+) IFNgamma(+) 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.</p>
dc.identifier.submissionpathoapubs/3400
dc.contributor.departmentDepartment of Surgery
dc.source.pages2461


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© The Author(s) 2018. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Except where otherwise noted, this item's license is described as © The Author(s) 2018. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.