Transplant immunology最新文献

{"title":"ELAVL1-stabilized USP22 promotes diabetic nephropathy progression via mediating podocyte injury and death by triggering ACSL4 deubiquitination","authors":"Xin Wang ,&nbsp;Wei Wang ,&nbsp;MengYing Han ,&nbsp;JingYuan Zhang ,&nbsp;YaNan Li","doi":"10.1016/j.trim.2025.102280","DOIUrl":"10.1016/j.trim.2025.102280","url":null,"abstract":"<div><h3>Background</h3><div>Diabetic nephropathy (DN) represents approximately 50 % of all chronic kidney disease cases. Given the established involvement of USP22 in DN progression, this study investigated its underlying regulatory mechanisms.</div></div><div><h3>Methods</h3><div>Mouse podocytes were treated with high glucose (HG), and a diabetic mouse model was established. Podocyte viability and apoptosis were assessed by CCK-8 and TUNEL/flow cytometry, respectively. Ferroptosis markers (Fe²⁺, ROS, MDA, and GSH) and inflammatory cytokines were quantified using ELISA and commercial kits per manufacturers' protocols. The interaction of USP22 with ACSL4 was demonstrated through protein stability and co-immunoprecipitation (Co-IP) assays. Additionally, RNA immunoprecipitation (RIP) and mRNA stability assays were employed to elucidate the ELAVL1/USP22 interaction.</div></div><div><h3>Results</h3><div>In HG-treated podocytes, USP22 silencing enhanced cell viability (<em>P</em> = 0.0018), repressed apoptosis (<em>P</em> = 0.0019), and reduced the release of inflammatory cytokines (IL-1β: <em>P</em> = 0.0002; TNF-α: <em>P</em> &lt; 0.0001) and ferroptosis markers (Fe²⁺: <em>P</em> = 0.0002; ROS: <em>P</em> = 0.0005; MDA: <em>P</em> = 0.0017; GSH: <em>P</em> = 0.0086). Conversely, USP22 overexpression in HG-treated podocytes exhibited the opposite effects (<em>P</em> &lt; 0.05). USP22 increased ACSL4 expression (<em>P</em> = 0.0012) in a deubiquitination-dependent manner. Notably, ACSL4 overexpression rescued USP22 depletion-mediated alterations on cell viability, apoptosis, inflammation, and ferroptosis (<em>P</em> &lt; 0.05). Moreover, ELAVL1 stabilized USP22 mRNA through interaction (<em>P</em> = 0.0075). USP22 silencing alleviated DN progression and reduced inflammation cytokine secretion in a diabetic mouse model (<em>P</em> &lt; 0.05).</div></div><div><h3>Conclusion</h3><div>ELAVL1-stabilized USP22 promotes DN progression by exacerbating podocyte injury and enhancing inflammatory responses and cell death through ACSL4 deubiquitination-dependent mechanisms.</div></div>","PeriodicalId":23304,"journal":{"name":"Transplant immunology","volume":"93 ","pages":"Article 102280"},"PeriodicalIF":1.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145034192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characteristics linking ischemia-reperfusion to chronic lung allograft dysfunction in lung transplantation: A single-cell bioinformatics analysis","authors":"Peng Zhang ,&nbsp;Zhendong Qiao ,&nbsp;Song Zhao ,&nbsp;Kai Wu","doi":"10.1016/j.trim.2025.102326","DOIUrl":"10.1016/j.trim.2025.102326","url":null,"abstract":"<div><h3>Background</h3><div>Lung transplantation offers a life-saving procedure to patients with end-stage lung diseases with 85–89 % one year and 60 % five-year survival rates. Lung transplants are complicated by early ischemia/reperfusion injury (IRI) and late chronic lung allograft dysfunction (CLAD). However, the cellular and molecular links between IRI and CLAD remain unclear.</div></div><div><h3>Materials and methods</h3><div>We integrated single-cell RNA-seq results from <span><span>GSE220797</span><svg><path></path></svg></span> and <span><span>GSE224210</span><svg><path></path></svg></span> data sets. After quality filtering, we performed Louvain clustering and UMAP visualization. We applied Augur method to prioritize cell populations by transcriptional responsiveness to IRI and CLAD. We also performed dynamic trajectory analyses to map pseudotemporal transitions. Pathway activity was characterized by differential expression analysis and module scoring. Intercellular communication was assessed using CellChat and MEBOCOST analyses. Regulon inference was performed with pySCENIC analysis.</div></div><div><h3>Results</h3><div>Overall, epithelial cells showed progressive metabolic suppression and activation of cuproptosis, a programmed cell death (PCD) triggered by excessive copper accumulation within cells. Club cells, found in the small airways of the lungs, exhibited developmental plasticity and predictive potential across IRI and CLAD conditions. Among myeloid populations, M1 proinflammatory (AM_M1TM) macrophages underwent macrophage-to-myofibroblast transition (MMT) and produced excessive extracellular matrix (ECM) supporting a network of proteins surrounding cells. Metabolite and cell–cell communication analyses revealed declining macrophage/epithelial metabolic crosstalk and differential signaling flux from normal through IRI to CLAD transition.</div></div><div><h3>Conclusions</h3><div>The integrated single-cell atlas delineates interaction of multiple cells and their signaling pathways linking IRI to CLAD processes. These findings require further verification through studies in animal models and clinical samples.</div></div>","PeriodicalId":23304,"journal":{"name":"Transplant immunology","volume":"93 ","pages":"Article 102326"},"PeriodicalIF":1.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145514175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pre-donation statin therapy to improve solid organ transplant outcomes","authors":"Juhi R. Patel ,&nbsp;John Dark ,&nbsp;Daniel Harvey ,&nbsp;Kulwant Dhadwal","doi":"10.1016/j.trim.2025.102283","DOIUrl":"10.1016/j.trim.2025.102283","url":null,"abstract":"<div><h3>Background</h3><div>Inflammatory injury in organ donors, particularly after brain death and during ischemia-reperfusion, contributes to graft dysfunction, rejection, and reduced survival. Statins, beyond their lipid-lowering role, exert pleiotropic anti-inflammatory and immunomodulatory effects, including IL-6 suppression, NF-κB inhibition, immune cell modulation, and potential alteration of exosome secretion.</div></div><div><h3>Methods</h3><div>Building upon this background, this narrative review synthesises preclinical and clinical evidence on pre-donation statin therapy in solid organ transplantation. Specifically, we examine mechanistic pathways, such as cytokine signalling, vascular protection, and exosome modulation, alongside clinical data from heart, liver, lung, and kidney transplantation.</div></div><div><h3>Results</h3><div>In terms of outcomes, preclinical models consistently demonstrate reduced inflammatory burden, preserved microvascular integrity, and improved graft function with donor statin therapy. Moving to clinical studies, limited randomised controlled trials suggest early biochemical and haemodynamic benefits, such as reduced cardiac biomarkers, lower ALT in liver recipients, and reduced primary graft dysfunction in lung recipients. However, evidence for improved long-term graft survival, rejection rates, or mortality is inconsistent. Most trials are underpowered, single-centre, and lack mechanistic endpoint analysis, and data on donation after circulatory death and living donors remain sparse.</div></div><div><h3>Conclusions</h3><div>Pre-donation statin therapy is biologically plausible, safe in early studies, and supported by robust mechanistic rationale, yet definitive clinical benefit remains unproven. Large, multi-centre trials incorporating mechanistic and clinical endpoints, such as the ongoing SIGNET study, are essential to determine whether this strategy should be integrated into standard donor management.</div></div>","PeriodicalId":23304,"journal":{"name":"Transplant immunology","volume":"93 ","pages":"Article 102283"},"PeriodicalIF":1.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145021006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PD-1 inhibitor use for skin malignancies in patients with solid organ and bone marrow transplants: Graft rejection, treatment responses, and survival","authors":"Lily M. Parker ,&nbsp;Kate E. Beekman ,&nbsp;Meredith E. Thomley ,&nbsp;Rahul Mhaskar ,&nbsp;Kenneth Tsai ,&nbsp;Lilia M. Correa-Selm","doi":"10.1016/j.trim.2025.102287","DOIUrl":"10.1016/j.trim.2025.102287","url":null,"abstract":"<div><h3>Importance</h3><div>Solid organ transplant recipients face a markedly increased risk of aggressive skin cancers. Programmed cell death protein-1 (PD-1) inhibitors have significantly improved outcomes for advanced melanoma, squamous cell carcinoma (SCC), and Merkel cell carcinoma (MCC), but their use in transplant patients is limited by the risk of graft rejection. Data in this population remain scarce.</div></div><div><h3>Objective</h3><div>To evaluate rates of graft rejection, treatment responses, and survival among transplant recipients treated with PD-1 inhibitors for advanced skin malignancies.</div></div><div><h3>Methods</h3><div>We identified 16 solid organ transplants patients (14 kidney, 2 liver) and 5 allogeneic bone marrow transplant patients. Skin cancer types included 14 squamous cell carcinomas, 2 melanomas, and 5 Merkel cell carcinomas.</div></div><div><h3>Results</h3><div>Among 16 solid organ transplant recipients (14 kidney, 2 liver), 4 developed graft rejection. Three occurred prior to PD-1 initiation, leaving only one rejection attributable to therapy. Median survival following PD-1 initiation was longer in patients with rejection (8.3 months) compared with those who died of cancer progression (3.0 months). No bone marrow transplant recipients experienced rejection.</div></div><div><h3>Conclusions and relevance</h3><div>In our data (the largest reported cohort to date), most transplant recipients tolerated PD-1 inhibitors without graft rejection. Although rejection remains a serious risk, these findings suggest that PD-1 immunotherapy may be considered as a salvage option for carefully selected patients with advanced skin cancer.</div></div>","PeriodicalId":23304,"journal":{"name":"Transplant immunology","volume":"93 ","pages":"Article 102287"},"PeriodicalIF":1.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145047117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Subtype-specific progression of post-transplant lymphoproliferative disease (PTLD) in children: Implications for age-based surveillance and early intervention strategies","authors":"Sujie Wang ,&nbsp;Zhipeng Zong ,&nbsp;Li Li ,&nbsp;Yu Zeng ,&nbsp;Jianchen Fang","doi":"10.1016/j.trim.2025.102321","DOIUrl":"10.1016/j.trim.2025.102321","url":null,"abstract":"<div><div>Post-transplant lymphoproliferative disorder (PTLD) represents a major cause of mortality in pediatric liver transplant recipients. However, data on clinicopathological risk factors across its subtypes remain limited.</div><div>An analysis of 33 pediatric liver transplant recipients revealed significant differences in the time to onset among PTLD subtypes: monomorphic PTLD developed significantly later than non-destructive/polymorphic PTLD, with higher tacrolimus blood concentration at diagnosis in the latter, consistent with the immunosuppressive tapering protocols. Among monomorphic PTLD cases, patients with Burkitt lymphoma (BL-PTLD) had a younger transplant age and higher early tacrolimus blood concentration than those with diffuse large B-cell lymphoma (DLBCL-PTLD), indicating that younger transplant age and more intense immunosuppression may promote Burkitt lymphomagenesis. Notably, among monomorphic PTLD, patients transplanted at &lt;1 year showed a significantly prolonged interval from transplantation to diagnosis than those transplanted at 1–18 years. Universal EBV-encoded RNA (EBER) positivity confirmed Epstein-Barr virus (EBV) as a key pathogenic factor, while the blood EBV DNA load at diagnosis showed no significant differences across subtypes, suggesting it does not influence PTLD subclassification.</div><div>These findings suggest that the time interval from transplantation to PTLD, immunosuppression intensity, and age at liver transplantation play a more determinant role in PTLD subtype progression.</div></div>","PeriodicalId":23304,"journal":{"name":"Transplant immunology","volume":"93 ","pages":"Article 102321"},"PeriodicalIF":1.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145410074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immune mediators as therapeutic targets in GvHD; cytokines, growth factors, chemokines, and co-stimulation /co-inhibition","authors":"Amir Rastegari ,&nbsp;Fatemeh Mohebbi","doi":"10.1016/j.trim.2025.102328","DOIUrl":"10.1016/j.trim.2025.102328","url":null,"abstract":"<div><div>Allogeneic hematopoietic stem cell transplantation (allo-HSCT) and emerging allogeneic T cell–based immunotherapies offer curative potential for hematologic malignancies, solid tumors, and selected non-malignant disorders through graft-versus-tumor (GvT) and immune reconstitution effects mediated by donor immune cells. However, their clinical success is constrained by graft-versus-host disease (GvHD) and other immune-mediated toxicities resulting from donor–host alloreactivity. Therefore, a central challenge is to develop personalized, safer allogeneic cellular therapies that preserve potent anti-tumor and immune-restorative functions while minimizing tissue injury. This review integrates the current understanding of acute and chronic GvHD immunopathogenesis, covering cytokine and chemokine networks, growth-factor signaling, and co-stimulatory/co-inhibitory pathways, and links these mechanisms to therapeutic strategies for selective immune modulation. Drawing on translational insights, we propose a framework for next-generation allogeneic cell-based therapies that are precision-tuned to donor/recipient biology, advancing individualized anticancer and immune-reconstitution outcomes with improved safety.</div></div>","PeriodicalId":23304,"journal":{"name":"Transplant immunology","volume":"93 ","pages":"Article 102328"},"PeriodicalIF":1.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145516906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hemophagocytic Lymphohistiocytosis with onset of mental and behavioral disorders following allogeneic hematopoietic stem cell transplantation: A case report","authors":"Heng Liu,&nbsp;Yaozhu Pan,&nbsp;Wu Tao,&nbsp;Dongfeng Mao,&nbsp;Hongjuan Tian,&nbsp;Feng Xue,&nbsp;Miao He","doi":"10.1016/j.trim.2025.102314","DOIUrl":"10.1016/j.trim.2025.102314","url":null,"abstract":"<div><div>Hemophagocytic lymphohistiocytosis (HLH) is a rare but highly fatal complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT), with central nervous system involvement (CNS-HLH) being exceptionally uncommon in adults and posing significant diagnostic challenges. This report details a 24-year-old male with acute myeloid leukemia (AML-M5) who developed CNS-HLH on +50 day after haploidentical allo-HSCT. The patient achieved complete donor chimerism post-transplant with no active infections but subsequently presented with acute neuropsychiatric symptoms, including short-term memory impairment, hypersomnia, reduced verbal output, and psychomotor retardation, rapidly progressing to coma. Laboratory findings revealed pancytopenia, hyperferritinemia (4301 μg/L), hypertriglyceridemia, and elevated CD8⁺ T lymphocytes (58 %). Cerebrospinal fluid analysis showed increased pressure (220 mmH₂O) and markedly elevated protein (1350.3 mg/L), while cranial MRI demonstrated bilateral hippocampal and amygdaloid hyperintensities. Bone marrow examination confirmed hemophagocytosis, fulfilling the HLH-2004 criteria and modified post-HSCT HLH diagnostic criteria for secondary HLH. Despite aggressive interventions—high-dose methylprednisolone, intravenous immunoglobulin, plasma exchange, and ruxolitinib combined with intrathecal therapy—the patient remained comatose and succumbed to multi-organ failure. This case underscores the unique clinical trajectory of post-HSCT CNS-HLH, where neuropsychiatric manifestations precede classical hematologic abnormalities and conventional immunosuppressive therapies exhibit limited efficacy. The findings emphasize the imperative for heightened clinical suspicion of HLH in transplant recipients with unexplained neurological deterioration accompanied by progressive cytopenias and biomarker derangements. Furthermore, this report highlights the urgent need for optimized early diagnostic strategies and targeted therapeutic approaches for CNS-HLH. The case provides critical insights into the clinical management and mechanistic understanding of post-transplant HLH.</div></div>","PeriodicalId":23304,"journal":{"name":"Transplant immunology","volume":"93 ","pages":"Article 102314"},"PeriodicalIF":1.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145303680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhancement of allograft acceptance by combined dexmedetomidine and rapamycin","authors":"Chen-Fang Lee ,&nbsp;Chih-Hsien Cheng ,&nbsp;Hui-Hsin Chuang ,&nbsp;Hao-Chien Hung ,&nbsp;Wei-Chen Lee ,&nbsp;Hsiang-Sheng Wang","doi":"10.1016/j.trim.2025.102313","DOIUrl":"10.1016/j.trim.2025.102313","url":null,"abstract":"<div><h3>Background</h3><div>Dexmedetomidine, an α2-adrenoceptor agonist, is known for its sedative effects and unique pharmacological mechanism. Research increasingly emphasizes its potential to modulate immune responses. Further investigation is needed to fully understand how dexmedetomidine influences T cell differentiation and its potential synergy with tolerance-promoting agents. This study aims to explore a new approach to enhance allograft acceptance by combining dexmedetomidine with the mTOR inhibitor rapamycin.</div></div><div><h3>Methods</h3><div>The effects of both drugs on T cell proliferation, regulatory T cell preservation, and allograft survival were examined through both in vitro and in vivo animal experiments, including a fully MHC-mismatched mouse skin transplantation model. The study also evaluated the effect of combined drugs on immune memory via retransplantation surgery.</div></div><div><h3>Results</h3><div>Our data demonstrate that combining dexmedetomidine with rapamycin effectively inhibits T cell proliferation. This combination also increases the frequency of regulatory T cells, thereby preserving immune regulation. Furthermore, dual therapy significantly extends the median survival time (MST) of the skin compared to dexmedetomidine, or rapamycin alone or no treatment (20 vs. 12 days, <em>p</em> &lt; 0.001; 20 vs. 16 days, <em>p</em> &lt; 0.05; 20 vs. 7 days, <em>p</em> &lt; 0.0001). Similarly, mice treated with the combination therapy have notably prolonged MST of the second allogenic graft, compared to no treatment (11 days versus 7.5 days, <em>p</em> &lt; 0.001).</div></div><div><h3>Conclusion</h3><div>Our findings highlight the potential of combining dexmedetomidine with mTOR inhibitors to enhance graft acceptance and reduce memory responses.</div></div>","PeriodicalId":23304,"journal":{"name":"Transplant immunology","volume":"93 ","pages":"Article 102313"},"PeriodicalIF":1.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145309318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Linking autophagy to endothelial cell immunogenicity in transplant-associated ischemia-reperfusion injury","authors":"Meredith E. Taylor ,&nbsp;Dinesh Jaishankar ,&nbsp;Krishnaraju Madavaraju ,&nbsp;Simseok A. Yuk ,&nbsp;Kaijie Zhang ,&nbsp;Hongzhang Mei ,&nbsp;Connor W. Lantz ,&nbsp;Luisa H. Andrade da Silva ,&nbsp;Yu Min Lee ,&nbsp;Jacqueline A. Burke ,&nbsp;Carl Atkinson ,&nbsp;Bowen Wang ,&nbsp;Evan A. Scott ,&nbsp;Satish N. Nadig","doi":"10.1016/j.trim.2025.102315","DOIUrl":"10.1016/j.trim.2025.102315","url":null,"abstract":"<div><h3>Background</h3><div>Cold storage (CS) and ischemia-reperfusion injury (IRI) are inevitable consequences of heart transplantation (HTx), primarily affecting the microvascular endothelial cells (ECs) of donor hearts. The nutrient deprivation and oxidative stresses sustained by ECs during CS and IRI activate and trigger alloimmune recognition. ECs adapt to these conditions by utilizing autophagy to maintain cellular homeostasis. Whether autophagy plays a role in EC activation and immunogenicity during CS and IRI in HTx remains unknown.</div></div><div><h3>Methods</h3><div>Autophagy in murine microvascular cardiac endothelial cells (MCEC) was modulated by genetic (knockout of the autophagy-related gene 5 (Atg5) by CRISPR/Cas9 technology) or pharmacological (rapamycin to induce autophagy and chloroquine to inhibit autophagy) approaches or by nanocarriers encapsulating rapamycin. MCECs were subjected to a previously established cold storage-warm reperfusion (CS-WR) model to mimic CS and IRI. We evaluated a) changes in autophagy by immunoblotting and confocal imaging, b) MCEC activation via pro-inflammatory cytokine and chemokine secretion by ELISA, and c) MCEC immunogenicity by determining T-cell activation in EC-T-cell co-cultures with MCEC-sensitized CD8⁺ T cells. The human relevance of EC autophagy was demonstrated by reanalyzing a recently published single-nucleus RNA sequencing dataset obtained from baseline and cold-preserved human donor hearts.</div></div><div><h3>Results</h3><div>Autophagy was reduced in MCECs when subjected to CS alone in organ preservation solution and increased early on during WR. The absence of the autophagic machinery in Atg5^−/− MCECs significantly increased MCEC activation and immunogenicity, while pharmacological induction of autophagy with rapamycin significantly mitigated this effect. Additionally, treating MCECs with an organ preservation solution supplemented with rapamycin-loaded nanocarriers during hypothermic CS demonstrated a protective effect in mitigating MCEC immunogenicity. Reanalysis of the single-nucleus RNA sequencing dataset in EC subclusters revealed that cold storage induced an activated EC state characterized by reduced expression of autophagy-related genes, aligning with our in vitro findings.</div></div><div><h3>Conclusions</h3><div>A novel role of autophagy in MCEC immunogenicity during CS and IRI is implicated. A viable preconditioning approach has also been demonstrated to bolster MCEC autophagy with nanocarriers during CS and mitigate its immunogenicity.</div></div>","PeriodicalId":23304,"journal":{"name":"Transplant immunology","volume":"93 ","pages":"Article 102315"},"PeriodicalIF":1.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145287165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transplant outcomes after de novo donor specific antibody (DSA) development correlate with persistence of DSA","authors":"A. Jaffer ,&nbsp;O. Shaw ,&nbsp;D. Stringer ,&nbsp;A. Dorling ,&nbsp;S. Shah","doi":"10.1016/j.trim.2025.102312","DOIUrl":"10.1016/j.trim.2025.102312","url":null,"abstract":"<div><h3>Background</h3><div>The OuTSMART trial confirmed <em>de novo</em> DSAs were associated with an increased risk of graft loss and rejection. In this post-hoc analysis, outcomes were analysed in 132 patients who had a DSA at the point of randomisation and compared between patients who had persistent DSA (DSA+/+) with those in whom the DSA was not detected on subsequent samples (DSA+/−).</div></div><div><h3>Methods</h3><div>Serial serum samples were collected post-enrolment until 2016. Those who had their final visit after 2018, had repeat HLA antibody testing ≥32 months post-randomisation. 115 of the 132 DSA+ patients had 2 or more samples available for analysis. 39/115 patients were persistently DSA+ and in 76/115 the DSA became undetectable at 12–32 months post enrolment.</div></div><div><h3>Results</h3><div>Both groups were well matched in sex, ethnicity, immunosuppression, and DSA status at transplant. The total Mean Fluorescence Intensity (MFI) of baseline DSA was significantly higher in the DSA+/+ <em>vs</em> DSA+/− (11,568 v 6518, <em>P</em> &lt; 0.01) with a predominance of class II HLA. Significantly higher rates of antibody mediated rejection (ABMR) and death censored graft failure (GF) were seen in DSA+/+ <em>vs</em> in DSA+/− (15.4 % v 2.6 %, <em>P</em> = 0.02 and 20.5 % v 6.6 %, <em>P</em> = 0.03 respectively). In Cox regression analysis, persistent DSA and having both HLA classes were associated with increased risk of ABMR (HR 6.05, CI 1.2–30.0, P = 0.03 and HR 14.7, CI 1.33–162, P = 0.03 respectively). Additionally, persistent DSA was associated with higher GF rates (HR 3.4, 1.1–10.4, P = 0.03).</div></div><div><h3>Conclusions</h3><div>Persistent <em>de novo</em> DSA, after kidney transplantation, is associated with higher MFI and increased risk of ABMR and GF.</div></div>","PeriodicalId":23304,"journal":{"name":"Transplant immunology","volume":"93 ","pages":"Article 102312"},"PeriodicalIF":1.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145267894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}