American Journal of Transplantation最新文献_第10页

A two-threshold algorithm using donor-derived cell-free DNA fraction and quantity to detect acute rejection after heart transplantation 利用供体无细胞DNA分数和数量检测心脏移植后急性排斥反应的双阈值算法。

IF 8.2 2区医学

American Journal of Transplantation Pub Date : 2025-09-01 DOI: 10.1016/j.ajt.2025.04.021

Paul J. Kim , Michael Olympios , Konstantinos Sideris , Eleni Tseliou , Taylor Y. Tran , Spencer Carter , Alison Brann , Navchetan Kaur , Sandra A. Carey , Sangeeta Bhorade , Yen-An Chen , David Barnes , Ebad Ahmed , Jing Xie , Adam Prewett , Matthew Rabinowitz , Bernhard G. Zimmermann , Michelle S. Bloom , Zachary Demko , Eric Adler , Josef Stehlik

{"title":"A two-threshold algorithm using donor-derived cell-free DNA fraction and quantity to detect acute rejection after heart transplantation","authors":"Paul J. Kim , Michael Olympios , Konstantinos Sideris , Eleni Tseliou , Taylor Y. Tran , Spencer Carter , Alison Brann , Navchetan Kaur , Sandra A. Carey , Sangeeta Bhorade , Yen-An Chen , David Barnes , Ebad Ahmed , Jing Xie , Adam Prewett , Matthew Rabinowitz , Bernhard G. Zimmermann , Michelle S. Bloom , Zachary Demko , Eric Adler , Josef Stehlik","doi":"10.1016/j.ajt.2025.04.021","DOIUrl":"10.1016/j.ajt.2025.04.021","url":null,"abstract":"<div><div>Donor-derived cell-free DNA (dd-cfDNA) is a promising biomarker of acute rejection (AR) after heart transplantation (HTx). dd-cfDNA, measured as a fraction of total cfDNA, can be affected by changes in total cfDNA whereas dd-cfDNA quantity can mitigate this impact. This study investigated the performance of a 2-threshold algorithm (2TA) that combines dd-cfDNA fraction (dd-cfDNA%) and donor-quantity score (DQS). A total of 808 plasma samples were prospectively collected for dd-cfDNA testing from 187 adult HTx patients with contemporaneous endomyocardial biopsies. cfDNA was analyzed by a single nucleotide polymorphism-based next-generation sequencing workflow; dd-cfDNA% and DQS were measured using the sequencing reads and single nucleotide polymorphism genotypes. Both dd-cfDNA% and DQS were significantly higher in AR than in non-AR samples (<em>P</em> < 10<sup>−14</sup>). Considering samples exceeding either dd-cfDNA% = 0.26% or DQS = 18 copies/mL as positive, the 2TA demonstrated 86.5% sensitivity and 83.6% specificity for AR detection and an area under the curve of 0.881. Compared to dd-cfdNA% alone, performance improved with a mean net reclassification index of 16.4% (standard deviation: 4.0%; <em>P</em> = .015) and a 37.3% reduction in the number of the false positive cases compared to the previously established cutoff of 0.15%. Combining dd-cfDNA fraction and quantity estimate in a 2TA may improve AR detection accuracy in HTx recipients compared with dd-cfDNA% alone.</div></div>","PeriodicalId":123,"journal":{"name":"American Journal of Transplantation","volume":"25 9","pages":"Pages 1895-1905"},"PeriodicalIF":8.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143921085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Post-transplantat recurrence of lipoprotein glomerulopathy: report of 4 cases and literature review 脂蛋白肾小球病移植后复发4例报告并文献复习。

IF 8.2 2区医学

American Journal of Transplantation Pub Date : 2025-09-01 DOI: 10.1016/j.ajt.2025.04.018

Precil Diego Miranda de Menezes Neves , Juliana Mansur , Miguel Moyses-Neto , Roberta Weisheimer Rohde , Carlos Eduardo Poli-de-Figueiredo , Stanley Almeida Araújo , David Campos Wanderley , Henrique Machado Sousa Proença , Karla Lais Pêgas , Andréia Watanabe , Elieser Hitoshi Watanabe , Hélio Tedesco-Silva , Gianna Mastroianni Kirsztajn , Clotilde Druck Garcia , Gyl Eanes de Barros Silva , Osvaldo Merege Vieira-Neto , Márcio Dantas , Sergio Ricardo Antônio , Gilson Masahiro Murata , Irene Lourdes Noronha , Luiz Fernando Onuchic

{"title":"Post-transplantat recurrence of lipoprotein glomerulopathy: report of 4 cases and literature review","authors":"Precil Diego Miranda de Menezes Neves , Juliana Mansur , Miguel Moyses-Neto , Roberta Weisheimer Rohde , Carlos Eduardo Poli-de-Figueiredo , Stanley Almeida Araújo , David Campos Wanderley , Henrique Machado Sousa Proença , Karla Lais Pêgas , Andréia Watanabe , Elieser Hitoshi Watanabe , Hélio Tedesco-Silva , Gianna Mastroianni Kirsztajn , Clotilde Druck Garcia , Gyl Eanes de Barros Silva , Osvaldo Merege Vieira-Neto , Márcio Dantas , Sergio Ricardo Antônio , Gilson Masahiro Murata , Irene Lourdes Noronha , Luiz Fernando Onuchic","doi":"10.1016/j.ajt.2025.04.018","DOIUrl":"10.1016/j.ajt.2025.04.018","url":null,"abstract":"<div><div><span><span>Lipoprotein<span> glomerulopathy (LPG) is an ultrarare </span></span>kidney disorder caused by pathogenic variants in the </span><em>APOE</em><span><span> gene. Although kidney biopsy presents typical findings, such as dilated capillary loops containing lipoprotein </span>thrombi, definitive diagnosis requires molecular genetic analysis of </span><em>APOE</em><span>. There is no specific treatment for the disease, and, in the scenario of a disorder with glomerular lipoprotein deposition, it may recur after kidney transplantation. Herein we reported 4 cases of post-transplant recurrence of LPG in Brazilian patients, including 1 case of early relapse (in the first year following transplantation) and 3 cases of late relapse. Two of the patients had the </span><em>APOE</em> Kyoto variant, while 2 harbored the <em>APOE</em><span> Osaka/Kurashiki variant. As in previously described cases, the clinical response was heterogeneous despite the use of statins and antiproteinuric agents, with proteinuria<span> remission or persistence and progression to different stages of chronic kidney disease<span>. Such cases strongly support the molecular genetic investigation of cases suspected of LPG, even in a Latin American population. A confirmed diagnosis can raise the likelihood of disease recurrence in the kidney graft and provide valuable information for selecting a potential living kidney donor.</span></span></span></div></div>","PeriodicalId":123,"journal":{"name":"American Journal of Transplantation","volume":"25 9","pages":"Pages 2017-2022"},"PeriodicalIF":8.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143897319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Tacrolimus prolongs corneal allograft survival and prevents dendritic cell infiltration in a myeloid-derived suppressor cell–dependent manner FK506以依赖mdsc的方式延长异体角膜移植存活并阻止树突状细胞浸润。

IF 8.2 2区医学

American Journal of Transplantation Pub Date : 2025-09-01 DOI: 10.1016/j.ajt.2025.05.018

Yingyi Liu , Yuerong Ren , Runxi Luo , Xiujuan Li , Limin Xie , Huanmin Kang , Yang Li , Xiaonan Dong , Yan He

{"title":"Tacrolimus prolongs corneal allograft survival and prevents dendritic cell infiltration in a myeloid-derived suppressor cell–dependent manner","authors":"Yingyi Liu , Yuerong Ren , Runxi Luo , Xiujuan Li , Limin Xie , Huanmin Kang , Yang Li , Xiaonan Dong , Yan He","doi":"10.1016/j.ajt.2025.05.018","DOIUrl":"10.1016/j.ajt.2025.05.018","url":null,"abstract":"<div><div>Tacrolimus (also known as FK506) is one of the most widely used immunosuppressive drugs in the postsurgery management of transplantation. To date, the cellular mechanism by which FK506 suppresses immune activation and elongates allograft survival remains largely unclear. Here, we employed a mouse model for corneal penetrating keratoplasty to interrogate this critical question. Administration of FK506 led to increased expansion myeloid-derived suppressor cells (MDSC) in recipient mice and prolonged survival of corneal allografts. In contrast, antibody-mediated depletion of MDSC abolished the FK506-mediated beneficial effects, which are associated with increased dendritic cell (DC) activation and recruitment to the graft bed and allografts. Of note, unlike continuous depletion and temporary early depletion (in the first week), delayed depletion of MDSC that started on day 8 posttransplant failed to disrupt the FK506-induced elongation of corneal allograft survival. Single-cell RNA sequencing analysis and immunofluorescence staining of corneal grafts reveal that FK506 reduced graft infiltration of immune cells, including DC and T cells, in an MDSC-dependent and temporal fashion. Moreover, depletion of MDSC reverted the FK506’s suppression of DC maturation in the draining lymph node on day 7. Taken together, these findings indicate that FK506 prolongs allograft survival through induction of MDSC-mediated suppression of early DC activation.</div></div>","PeriodicalId":123,"journal":{"name":"American Journal of Transplantation","volume":"25 9","pages":"Pages 1870-1883"},"PeriodicalIF":8.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144114216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mouse orthotopic liver transplantation: Challenges, achievements, and applications 小鼠原位肝移植：挑战、成就和应用

IF 8.2 2区医学

American Journal of Transplantation Pub Date : 2025-09-01 DOI: 10.1016/j.ajt.2025.06.011

Shinichiro Yokota , Wei Li , Pierre A. Clavien , Jerzy W. Kupiec-Weglinski , Angus W. Thomson

{"title":"Mouse orthotopic liver transplantation: Challenges, achievements, and applications","authors":"Shinichiro Yokota , Wei Li , Pierre A. Clavien , Jerzy W. Kupiec-Weglinski , Angus W. Thomson","doi":"10.1016/j.ajt.2025.06.011","DOIUrl":"10.1016/j.ajt.2025.06.011","url":null,"abstract":"<div><div>The surgically challenging mouse orthotopic liver transplant model has provided numerous insights into liver immunobiology, cellular and molecular regulation of liver transplant ischemia-reperfusion injury, liver regeneration, the influence of major histocompatibility complex antigens on transplant outcome, spontaneous transplant tolerance, and regulation of allograft immunity. Nonarterialized and arterialized models have been established. Reduced-size liver transplant models have also been developed and used to determine critical mass and factors that determine tissue injury and regeneration. Since its first description 3 decades ago, the surgical demands of the model have limited its application to a relatively small number of centers focused on basic liver transplant research. Dissemination of and commitment to acquisition of the required technical skills will facilitate the application of cutting-edge experimental approaches to which the mouse model is well-suited and allow important key basic and translational questions in transplant immunology to be addressed.</div></div>","PeriodicalId":123,"journal":{"name":"American Journal of Transplantation","volume":"25 9","pages":"Pages 1830-1842"},"PeriodicalIF":8.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144289833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

High body mass index at liver transplantation: A retrospective single-center analysis of blood product utilization and postoperative outcomes. 肝移植的高BMI：血液制品使用和术后结果的回顾性单中心分析。

IF 8.2 2区医学

American Journal of Transplantation Pub Date : 2025-08-27 DOI: 10.1016/j.ajt.2025.08.018

Sebastian Zeiner, Rishi P Kothari, Mallika Reddy, Nicholas V Mendez, Garrett R Roll, Hillary J Braun, Michael P Bokoch, Kerstin Kolodzie, Oliver Kimberger, Matthieu Legrand, Dieter Adelmann

{"title":"High body mass index at liver transplantation: A retrospective single-center analysis of blood product utilization and postoperative outcomes.","authors":"Sebastian Zeiner, Rishi P Kothari, Mallika Reddy, Nicholas V Mendez, Garrett R Roll, Hillary J Braun, Michael P Bokoch, Kerstin Kolodzie, Oliver Kimberger, Matthieu Legrand, Dieter Adelmann","doi":"10.1016/j.ajt.2025.08.018","DOIUrl":"10.1016/j.ajt.2025.08.018","url":null,"abstract":"<p><p>Obesity, generally defined as high body mass index (BMI), is increasingly prevalent in liver transplant recipients, but its impact on perioperative management is still not understood. This study aimed to examine intraoperative transfusion as a marker of surgical complexity, alongside blood loss, ventilation duration, and intensive care unit length of stay. We conducted a retrospective single-center analysis of adult liver transplant recipients between June 1, 2012, and March 31, 2024. Data were extracted from electronic medical records and stratified by BMI to compare demographics, clinical characteristics, intraoperative variables, and postoperative outcomes. Among 1444 recipients, patients with a BMI of ≥40 kg/m<sup>2</sup> required significantly more units of blood products (median, 20 units; IQR, 12-32 units) than normal/overweight patients (median, 12 units; IQR, 6-20 units; P < .001). They had greater blood loss, longer ventilation times, and extended intensive care unit stays (all P < .001). This is the first study to assess granular intraoperative data on blood product use, acute kidney injury, and extubation in liver transplant recipients with a BMI of ≥40 kg/m<sup>2</sup>. It shows that a BMI of ≥40 kg/m<sup>2</sup> is linked to increased perioperative resource utilization and longer hospital stays. Importantly, patients with a BMI of ≥40 kg/m<sup>2</sup> have equivalent long-term outcomes after liver transplant. BMI should be used with extreme caution in candidacy decisions.</p>","PeriodicalId":123,"journal":{"name":"American Journal of Transplantation","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937032","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Donor Heart Preservation at 10°C After Thoracoabdominal Normothermic Regional Perfusion Lowers Rates of Severe Primary Graft Dysfunction and Improves Recipient Transplant Outcomes. 胸腹常温区域灌注后10°C供体心脏保存可降低严重原发性移植物功能障碍的发生率并改善受体移植结果。

IF 8.2 2区医学

American Journal of Transplantation Pub Date : 2025-08-27 DOI: 10.1016/j.ajt.2025.08.027

Aaron M Williams, John M Trahanas, Awab Ahmad, Swaroop Bommareddi, Brian Lima, Kevin McGann, Mark Petrovic, Chen Chia Wang, Eric Quintana, Hasan K Siddiqi, Kaushik Amancherla, D Marshall Brinkley, JoAnn Lindenfeld, Jonathan Menachem, Henry Ooi, Dawn Pedrotty, Stacy Tsai, Lynn Punnoose, Aniket S Rali, Suzanne Sacks, Mark Wigger, Sandip Zalawadiya, Stephen A DeVries, Joshua Lowman, Clifton D Keck, Shelley R Scholl, Matthew Bacchetta, Kelly Schlendorf, Ashish S Shah

{"title":"Donor Heart Preservation at 10°C After Thoracoabdominal Normothermic Regional Perfusion Lowers Rates of Severe Primary Graft Dysfunction and Improves Recipient Transplant Outcomes.","authors":"Aaron M Williams, John M Trahanas, Awab Ahmad, Swaroop Bommareddi, Brian Lima, Kevin McGann, Mark Petrovic, Chen Chia Wang, Eric Quintana, Hasan K Siddiqi, Kaushik Amancherla, D Marshall Brinkley, JoAnn Lindenfeld, Jonathan Menachem, Henry Ooi, Dawn Pedrotty, Stacy Tsai, Lynn Punnoose, Aniket S Rali, Suzanne Sacks, Mark Wigger, Sandip Zalawadiya, Stephen A DeVries, Joshua Lowman, Clifton D Keck, Shelley R Scholl, Matthew Bacchetta, Kelly Schlendorf, Ashish S Shah","doi":"10.1016/j.ajt.2025.08.027","DOIUrl":"https://doi.org/10.1016/j.ajt.2025.08.027","url":null,"abstract":"<p><p>This study compares a novel static cold storage (SCS) method using 10°C preservation to conventional ice following thoracoabdominal normothermic regional perfusion (TA-NRP) in donation after circulatory death (DCD) heart transplantation. We retrospectively analyzed adult recipients at a single center from October 2020 to October 2024, excluding congenital and multi-organ transplants. A total of 147 recipients met inclusion criteria (Ice = 96; 10°C = 51). Donors in the 10°C group were older, had higher BMI, and were more often female. Their allografts experienced longer total and warm ischemic times. Inverse probability of treatment weighting (IPTW) was applied to balance baseline differences, and multivariable regression adjusted for warm ischemic time. After adjustment, 10°C preservation was associated with a significantly reduced risk of severe primary graft dysfunction, post-bypass severe right ventricular depression, lower vasoactive inotropic scores at 24 hours, decreased incidence of recipient renal replacement therapy, shorter intensive care unit length of stay, and reduced 6-month mortality. This represents the largest comparison of 10°C versus ice preservation following TA-NRP and suggests that 10°C may offer superior early post-transplant outcomes. These findings warrant further validation in larger, prospective, multicenter studies to confirm the observed benefits.</p>","PeriodicalId":123,"journal":{"name":"American Journal of Transplantation","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Tolerogenic lung allograft microenvironment suppresses pathogenic tissue remodeling following respiratory virus infection in mice. 耐受性肺移植微环境抑制呼吸道病毒感染后小鼠致病性组织重塑。

IF 8.2 2区医学

American Journal of Transplantation Pub Date : 2025-08-26 DOI: 10.1016/j.ajt.2025.08.021

Ítalo de Araújo Castro, Yuriko Terada, Yuhei Yokoyama, Amit I Bery, Wenjun Li, Junedh M Amrute, Charles R Liu, Yun Zhu Bai, Victoria Gnazzo, Hēth R Turnquist, Kory J Lavine, Alexander S Krupnick, Andrew E Gelman, Jon H Ritter, Joshua A Blatter, David Wang, Carolina B López, Daniel Kreisel

{"title":"Tolerogenic lung allograft microenvironment suppresses pathogenic tissue remodeling following respiratory virus infection in mice.","authors":"Ítalo de Araújo Castro, Yuriko Terada, Yuhei Yokoyama, Amit I Bery, Wenjun Li, Junedh M Amrute, Charles R Liu, Yun Zhu Bai, Victoria Gnazzo, Hēth R Turnquist, Kory J Lavine, Alexander S Krupnick, Andrew E Gelman, Jon H Ritter, Joshua A Blatter, David Wang, Carolina B López, Daniel Kreisel","doi":"10.1016/j.ajt.2025.08.021","DOIUrl":"10.1016/j.ajt.2025.08.021","url":null,"abstract":"<p><p>Tolerance after lung transplantation is associated with the induction of Foxp3<sup>+</sup> regulatory T cell-enriched bronchus-associated lymphoid tissue, which suppresses local and systemic alloimmune responses. How this tolerogenic graft environment shapes responses to respiratory viral infections, a known contributor to adverse outcomes after lung transplantation, remains unknown. Using a mouse model of a seasonally circulating parainfluenza virus, we found that acute infection of tolerant lung allografts results in temporary reductions of both bronchus-associated lymphoid tissue size and abundance of graft-resident Foxp3<sup>+</sup> cells but does not trigger rejection. At late time points, pathologic chronic type 2 inflammatory responses characteristic of severe parainfluenza virus infection decreased and Krt5<sup>+</sup> and Krt8<sup>+</sup> lesions were reduced in tolerant allografts when compared with infected native lungs or syngeneic grafts. This reduction in dysplastic alveolar regeneration in tolerant allografts was associated with an increase in amphiregulin-expressing Foxp3<sup>+</sup> cells. Furthermore, type II alveolar epithelial cells in lung allografts upregulated genes related to injury when recipient Foxp3<sup>+</sup> cells were deficient in amphiregulin. These findings shed new light on how immune pathways that are established in tolerant lung allografts, in addition to preventing rejection, protect against aberrant tissue repair after a clinically relevant respiratory viral infection.</p>","PeriodicalId":123,"journal":{"name":"American Journal of Transplantation","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Suppression of cardiac allograft vasculopathy by a macrophage efferocytosis receptor. 巨噬细胞Efferocytosis受体抑制同种异体心脏移植血管病变。

IF 8.2 2区医学

American Journal of Transplantation Pub Date : 2025-08-26 DOI: 10.1016/j.ajt.2025.08.026

Sahil Shah, Aparnaa Ananthakrishnan, Matthew DeBerge, Kristofor Glinton, Rebecca T L Jones, Mallory Filipp, Ivana Shen, Joey Lockhart, Connor W Lantz, Edward B Thorp

{"title":"Suppression of cardiac allograft vasculopathy by a macrophage efferocytosis receptor.","authors":"Sahil Shah, Aparnaa Ananthakrishnan, Matthew DeBerge, Kristofor Glinton, Rebecca T L Jones, Mallory Filipp, Ivana Shen, Joey Lockhart, Connor W Lantz, Edward B Thorp","doi":"10.1016/j.ajt.2025.08.026","DOIUrl":"10.1016/j.ajt.2025.08.026","url":null,"abstract":"<p><p>Cardiac allograft vasculopathy (CAV) remains a major cause of late morbidity following heart transplantation. Although accumulating evidence implicates innate macrophages in the inflammatory progression of CAV, the underlying mechanisms remain incompletely understood. In murine models of CAV, we identified proteolytic cleavage of proto-oncogene tyrosine-protein kinase MER (MERTK), a key anti-inflammatory receptor on macrophages, as a contributing factor to CAV progression. In a model of CAV, MERTK deficiency accelerated allograft rejection and increased intimal leukocyte infiltration. In contrast, mice expressing a genetically cleavage-resistant MerTK exhibited prolonged graft survival, reduced intimal thickening, diminished immune cell infiltration, and decreased circulating effector T cells. Macrophages isolated from cleavage-resistant MerTK allografts had enhanced mitochondrial metabolism, which correlated with the production of anti-inflammatory cytokines, including IL-10. Mechanistically, coculture experiments demonstrated that activated CD8+ T cells, and not CD4+ or naïve CD8+ T cells, induce MERTK cleavage on macrophages, leading to reduced efferocytosis, increased glycolysis, and increased inflammatory cytokine expression. Together, our findings identify MERTK as a critical regulator of macrophage efferocytosis and metabolism in the context of cardiac transplantation. Our data suggest that MERTK activity protects against CAV progression and that activated T cells may promote allograft injury, in part, by driving MERTK proteolysis.</p>","PeriodicalId":123,"journal":{"name":"American Journal of Transplantation","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144936983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Sacubitril suppresses experimental chronic heart allograft vasculopathy. 苏比利抑制实验性慢性同种异体心脏移植血管病变。

IF 8.2 2区医学

American Journal of Transplantation Pub Date : 2025-08-26 DOI: 10.1016/j.ajt.2025.08.009

Andrew G Masoud, Kolden van Baar, Lin Fu Zhu, Olivier Julien, Gavin Y Oudit, Allan G Murray

{"title":"Sacubitril suppresses experimental chronic heart allograft vasculopathy.","authors":"Andrew G Masoud, Kolden van Baar, Lin Fu Zhu, Olivier Julien, Gavin Y Oudit, Allan G Murray","doi":"10.1016/j.ajt.2025.08.009","DOIUrl":"10.1016/j.ajt.2025.08.009","url":null,"abstract":"<p><p>Chronic allograft vasculopathy limits graft and recipient survival after heart transplantation despite modern immune suppression. We examined the effect of sacubitril, an inhibitor of neprilysin neutral endopeptidase activity, on the progression of chronic allograft vasculopathy in HY-antigen-mismatched mouse heart transplantation. We found that sacubitril treatment of the recipient markedly blunted the progressive occlusion of the coronary arterial lumen versus the vehicle control. The proteome of the heart grafts was characterized, and notably identifies differential increased expression of several serine protease inhibitors, decreased transforming growth factor-beta superfamily pathway constituents, and matrix proteins among sacubitril-treated recipients. We observed reduced immune cell infiltration of the allograft, associated with suppression of graft vascular endothelial cell Cx3cl1 and Vcam1 expression among the sacubitril-treated recipients. Further, graft expression of proreparative apelin was increased, and endothelial cell-mesenchymal transdifferentiation was suppressed. In vitro, candidate signaling pathways via glucagon-like protein-1 and atrial natriuretic peptide receptor, but not apelin receptor, agonists phenocopied the effect of sacubitril in vivo. The results highlight direct and indirect proteinase inhibitory and favorable anti-inflammatory effects of sacubitril treatment that limit maladaptive repair of the graft vasculature.</p>","PeriodicalId":123,"journal":{"name":"American Journal of Transplantation","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Organ Procurement and Transplantation Network infrastructure: a high value investment for the government 器官获取和移植网络基础设施：政府的高价值投资

IF 8.8 2区医学

American Journal of Transplantation Pub Date : 2025-08-25 DOI: 10.1016/j.ajt.2025.08.025

Klitenic S.B., Sullivan B., Levan M.L., Sidoti C.N., Alcorn J.B., Tietjen A., Ratner L.E.

引用次数: 0