Transplant immunology最新文献

{"title":"De novo donor specific antibody (dnDSA) development with tacrolimus versus Belatacept based regimens in kidney transplant recipients","authors":"Cayla Kass ,&nbsp;Goni Katz-Greenberg ,&nbsp;Jason Bodner ,&nbsp;Scott Sanoff ,&nbsp;Alice Parish ,&nbsp;Alaattin Erkanli ,&nbsp;Jennifer Byrns","doi":"10.1016/j.trim.2025.102297","DOIUrl":"10.1016/j.trim.2025.102297","url":null,"abstract":"<div><h3>Purpose</h3><div>Belatacept has been associated with less de novo specific antibody (dnDSA) development, but few publications have compared the incidence of dnDSA development between tacrolimus and belatacept-based immunosuppression regimens. The purpose of this study was to investigate the differences in dnDSA development and clinical outcomes between these two maintenance regimens in kidney transplant.</div></div><div><h3>Methods</h3><div>This was a retrospective, single center, cohort study of patients transplanted between 2013 and 2019 who received a de novo belatacept or tacrolimus-based immunosuppression regimen. The primary outcome was the incidence of dnDSA development (MFI ≥ 1000) at 36 months. Secondary outcomes included renal function, biopsy proven rejection (BPAR), and patient/graft survival.</div></div><div><h3>Results</h3><div>Ninety patients met inclusion criteria. The primary outcome occurred in 4 (8.9 %) belatacept patients and 6 (13.3 %) tacrolimus patients, with an overall median time to dnDSA of 300 days (<em>p</em> = 0.51). Class II dnDSA development occurred in 3 (6.7 %) belatacept patients and 6 (13.3 %) tacrolimus patients. Belatacept patients had a lower, but not significantly different, rate of developing BPAR (4.4 % vs 13.3 %, <em>p</em> = 0.13) and had superior renal function at 36 months (median 66 ml/min vs 53 ml/min, <em>p</em> &lt; 0.01). Overall, there was excellent patient/graft survival at 36 months post-transplant.</div></div><div><h3>Conclusion</h3><div>De novo belatacept use did not result in a statistically significant difference in the development of dnDSAs but did show a numerically lower class II dnDSA and BPAR development. Overall, belatacept was associated with improved renal function as compared to tacrolimus-based regimens.</div></div>","PeriodicalId":23304,"journal":{"name":"Transplant immunology","volume":"93 ","pages":"Article 102297"},"PeriodicalIF":1.4,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081726","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":"Assessing the influence of isolation techniques on NK cell transcriptomic profiles","authors":"Rana ElNouty ,&nbsp;Ahmed Moustafa ,&nbsp;Maha Mostafa ,&nbsp;Amged Ouf ,&nbsp;Khaled Abou-Aisha ,&nbsp;Mona Rady","doi":"10.1016/j.trim.2025.102298","DOIUrl":"10.1016/j.trim.2025.102298","url":null,"abstract":"<div><div>Natural Killer (NK) cells are vital components of the innate immune system, playing a crucial role in defending the body against tumors and virally infected cells. While various methods exist for their isolation, the profound impact of these techniques on NK cell biology remains poorly characterized.This study presents a comprehensive analysis of the transcriptomic profiles of NK cells isolated using different positive selection methods; anti-CD56, anti-CD7 (with two distinct lineage depletion protocols), and a combination of anti-CD16 and anti-CD56 antibodies, compared to negative selection using immunomagnetic beads. Our integrated analysis of RNA-Seq datasets revealed that the isolation method is a dominant source of transcriptomic variation, accounting for 68.6 % of the total dataset variance, with technical factors being inextricably confounded with this biological signal. We identified extensive method-specific transcriptional signatures, with minimal overlap (&lt;0.1 %) in differentially expressed genes (DEGs) across techniques. Functional enrichment analysis demonstrated that these signatures correspond to starkly different functional states: anti-CD16/anti-CD56 selection enriched for a highly activated, cytotoxically competent NK cell population with upregulated pathways in cytotoxicity and immune surveillance, while one anti-CD7-based method captured NK cells in a suppressed state, showing significant downregulation of lymphocyte activation and cytotoxicity pathways. Marker expression analysis further revealed extreme inter-study heterogeneity, with fold-changes in key cytotoxic genes exceeding 70,000-fold between methods. These findings highlight that the choice of isolation technique is not neutral but fundamentally determines the transcriptional and functional identity of the studied NK cell population. Our results highlight the critical importance of methodological standardization in NK cell research and provide essential guidance for selecting isolation strategies tailored to specific research or therapeutic applications.</div></div>","PeriodicalId":23304,"journal":{"name":"Transplant immunology","volume":"93 ","pages":"Article 102298"},"PeriodicalIF":1.4,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145076088","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":"Case report: Recipient-derived, late-onset post-transplant lymphoproliferative disorder involving a transplanted liver","authors":"Dongmei Zou ,&nbsp;Qiang Ma ,&nbsp;Dandan Wang ,&nbsp;Dongdong Lin ,&nbsp;Hong Zhao ,&nbsp;Wanling Sun","doi":"10.1016/j.trim.2025.102299","DOIUrl":"10.1016/j.trim.2025.102299","url":null,"abstract":"<div><h3>Introduction</h3><div>Post-transplant lymphoproliferative disorders (PTLD) are severe complications of transplantation associated with poor outcomes. Compared to early-onset PTLDs, late-onset PTLDs are much less associated with allograft localization. Herein, we report a case of Epstein-Barr virus (EBV)-negative lymphoma involving a graft 7 years after liver transplantation.</div></div><div><h3>Case presentation</h3><div>A 45-year-old man presented with hepatomegaly 7 years after liver transplantation. Liver puncture biopsy revealed B-cell lymphoma with a high proliferation index and a germinal center B-cell-like subtype. Tissue and other donor information were unavailable. Next-generation sequencing was performed on the tumor and recipient tissues, and the single nucleotide polymorphism (SNP) sites were identical, thereby confirming the recipient origin. The patient received a reduction in immunosuppression and six cycles of rituximab, reduced doses of cyclophosphamide, doxorubicin, vincristine, and prednisone, and achieved complete remission after the fourth cycle of treatment. The patient remained in good condition for 7 months after the last chemotherapy dose.</div></div><div><h3>Conclusion</h3><div>This rare case report describes a late-onset EBV-negative recipient-derived PTLD involving a transplanted liver. SNP analysis is a useful method for determining tumor origin in situations where donor tissue is unavailable.</div></div>","PeriodicalId":23304,"journal":{"name":"Transplant immunology","volume":"93 ","pages":"Article 102299"},"PeriodicalIF":1.4,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145065259","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":"Racial and ethnic disparities in kidney transplantation","authors":"Macrae Kozody ,&nbsp;Roberta Buccilli ,&nbsp;Giovanni Faddoul ,&nbsp;Jorge Ortiz","doi":"10.1016/j.trim.2025.102289","DOIUrl":"10.1016/j.trim.2025.102289","url":null,"abstract":"<div><div>Social determinants of health, bias and genetic predisposition contribute to racial inequities in chronic kidney disease (CKD) and kidney transplant (KTX) allocation. Recognizing and addressing these complex factors leads to improvement in outcomes. This narrative review aims to discuss the current state of racial disparities surrounding KTX and identify where future efforts should be concentrated. The discussion focuses on data from the past 10 years (2015–2025). Overall mortality and graft loss is lowest in Hispanics and Asians and highest in Native Americans, perhaps due to the unique protective or detrimental social factors in these populations. Blacks have equal to better mortality than Whites, but worse graft survival. In an effort to identify paucities in the current literature, KTX outcomes by specific CKD etiologies are reviewed, including: diabetic nephropathy, focal segmental glomerulosclerosis, membranous nephropathy, lupus nephritis, vasculitis and polycystic kidney disease. Graft survival and mortality patterns for disease specific kidney transplant generally mirrors that of all cause KTX, but available data is limited. In recent years, racial disparities in CKD and transplant have improved, but still persist, representing the need for continued investigation and improvement. Future work should focus on continued identification and implementation of successful mitigation strategies and investigation where current literature is insufficient, such as diabetic nephropathy.</div></div>","PeriodicalId":23304,"journal":{"name":"Transplant immunology","volume":"93 ","pages":"Article 102289"},"PeriodicalIF":1.4,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145055869","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":"2025-09-10","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":"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":"2025-09-08","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":"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":"2025-09-06","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":"Pre-transplant compatibility testing: Transition from CDCXM to flow cytometry in India","authors":"Kashyap Shubham,&nbsp;Aseem K Tiwari,&nbsp;Chauhan Rajni,&nbsp;Mehra Simmi,&nbsp;Bhardwaj Gunjan,&nbsp;Rani Neha,&nbsp;Kahlon Simran","doi":"10.1016/j.trim.2025.102281","DOIUrl":"10.1016/j.trim.2025.102281","url":null,"abstract":"<div><div>Over 60 % of kidney transplant candidates are non-sensitised while remaining 40 % are sensitised because of previous exposure to human alloantigens during previous transplants, blood transfusions, and pregnancy in women. Pre-transplant compatibility testing is mandatory prior to renal transplantation for detecting the presence of donor-specific antibodies (DSAs), which are associated with early hyperacute/acute and later chronic rejections. Initially, complement-dependent cytotoxicity crossmatch (CDCXM) was used as a traditional method for detecting preformed DSAs. However, its limited sensitivity fails to detect low-level antibodies, and all non-complement-binding antibodies lead to early graft rejection despite a negative CDC-XM result. Flow cytometry crossmatch (FCXM), introduced in 1983, addresses these limitations by offering superior sensitivity in detecting DSAs. FCXM uses indirect immunofluorescence to differentiate T cell (expressing class I HLA) and B cell (expressing class I/II HLAs) reactivities providing a more precise assessment of DSAs, significantly decreasing the risk of rejection. Studies demonstrate that positive FCXM results, even with negative CDC-XM, correlate with higher rejection rates and reduced graft survival. Various modifications, including pronase treatment and especially streamlined Halifax and Halifaster protocols, have improved the test's specificity and speed. Despite its advantages, FCXM is also susceptible to potential false-positive and false-negative results because of non-HLA antibodies, cross-reactivity with therapeutic agents, and other technical factors. Nonetheless, FCXM remains a gold standard in modern transplantation immunology, enhancing safety of graft outcomes through better identification of immunologically significant DSAs. This review outlines the transition from CDCXM to FCXM in the Indian context, emphasizing its impact on pre-transplant testing and clinical decision-making.</div></div>","PeriodicalId":23304,"journal":{"name":"Transplant immunology","volume":"93 ","pages":"Article 102281"},"PeriodicalIF":1.4,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145016240","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":"Fxyd5 downregulation protects the heart from ischemia/reperfusion injury by suppressing myocardial inflammation","authors":"Lei Zhang ,&nbsp;Junjie Xu ,&nbsp;Fujiang Cui ,&nbsp;Jin Jin ,&nbsp;Liwen Liu ,&nbsp;Lei Wang ,&nbsp;Yuxia Gao","doi":"10.1016/j.trim.2025.102282","DOIUrl":"10.1016/j.trim.2025.102282","url":null,"abstract":"<div><h3>Background</h3><div>Myocardial ischemia/reperfusion (I/R) injury is a common cause of death. FXYD domain-containing ion transport regulator-5 (Fxyd5) is a type I membrane protein that plays a significant role in mediating cellular functions. However, the expression and function of Fxyd5 in myocardial I/R injury remain unclear.</div></div><div><h3>Methods</h3><div>Male C57BL/6 mice (8–10 weeks) were subjected to myocardial I/R by ligating the left anterior descending coronary artery. Preventive intervention was performed using adeno-associated virus 9 (AAV9)-mediated Fxyd5 knockdown. An in vitro hypoxia/reoxygenation (H/R) in H9c2 cardiomyoblasts was used for validation.</div></div><div><h3>Results</h3><div>Myocardial I/R injury significantly upregulated Fxyd5 expression (<em>p</em> &lt; 0.01). Silencing Fxyd5 markedly improved cardiac function, as evidenced by a 58.0 % increase in EF (<em>p</em> &lt; 0.01) and a 54.5 % reduction in infarct size (<em>p</em> &lt; 0.01). Fxyd5 knockdown also attenuated myocardial apoptosis and inflammation, demonstrated by decreased cleaved caspase-3 expression and reduced levels of IL-6 (−44.2 %) and TNF-α (−42.7 %) (<em>p</em> &lt; 0.01). Mechanistically, Fxyd5 silencing suppressed NF-κB activation, and these protective effects were confirmed in vitro in H/R-treated cardiomyocytes.</div></div><div><h3>Conclusion</h3><div>Fxyd5 silencing significantly attenuated I/R-induced myocardial injury, reduced infarct size, and improved cardiac function, while also decreasing apoptosis and inflammatory cytokine expression (<em>p</em> &lt; 0.01). These findings indicate that Fxyd5 contributes to the pathogenesis of myocardial I/R injury and that its inhibition confers cardioprotective effects, partly through suppression of the NF-κB pathway.</div></div>","PeriodicalId":23304,"journal":{"name":"Transplant immunology","volume":"93 ","pages":"Article 102282"},"PeriodicalIF":1.4,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006616","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":"IL-6 amplifies corneal transplant alloimmunity by inducing dysfunctional IFN-γ- secreting Treg through the VEGFA-VEGFR1 axis","authors":"Seokjoo Lee,&nbsp;Akitomo Narimatsu,&nbsp;Neda Heydarian,&nbsp;Mark Krauthammer,&nbsp;Shilpy Bhullar,&nbsp;Yihe Chen,&nbsp;Sunil K. Chauhan,&nbsp;Thomas H. Dohlman,&nbsp;Reza Dana","doi":"10.1016/j.trim.2025.102284","DOIUrl":"10.1016/j.trim.2025.102284","url":null,"abstract":"<div><h3>Background</h3><div>Corneal allografts generally exhibit high acceptance due to the immune-privileged ocular microenvironment. Regulatory T cells (Treg) promote graft tolerance; however, in a vascularized milieu, they may acquire a pro-inflammatory phenotype. We investigated how dysfunctional Treg contribute to graft rejection through the VEGFA–VEGFR1 axis.</div></div><div><h3>Methods</h3><div>Treg were treated with IL-6 and VEGFA, and their phenotype—including FoxP3, IL-10, and IFN-γ—was evaluated with or without a VEGFR1 antagonist (αVEGFR1) using PCR, immunoblotting, ELISA, and flow cytometry. Suppressive function was assessed by T-cell proliferation assays, corneal cell death by Annexin V staining, and graft survival by adoptive transfer of dysfunctional Treg into a transplantation model.</div></div><div><h3>Results</h3><div>IL-6 reduced FoxP3 (<em>p</em> &lt; 0.0001) and upregulated VEGFR1 (<em>p</em> &lt; 0.001). IL-6 plus VEGFA further decreased FoxP3 (<em>p</em> &lt; 0.0001) and IL-10 (<em>p</em> &lt; 0.0001) while increasing IFN-γ (p &lt; 0.0001). αVEGFR1 reversed these effects, restoring FoxP3 (p &lt; 0.0001) and IL-10 (<em>p</em> &lt; 0.05) while reducing IFN-γ (<em>p</em> &lt; 0.001). Functionally, IL-6/VEGFA-pretreated Treg showed impaired suppression of effector T-cell proliferation (<em>p</em> &lt; 0.0001), an effect partially rescued by αVEGFR1 (<em>p</em> &lt; 0.001). In ex vivo assays, fresh Treg prevented, whereas dysfunctional IFN-γ–secreting Treg induced, corneal cell death (<em>p</em> &lt; 0.0001). In vivo, grafts injected with dysfunctional Treg were rejected within 3–7 weeks, while those with αVEGFR1-treated Treg showed improved survival and reduced cell death (<em>p</em> &lt; 0.0001).</div></div><div><h3>Conclusion</h3><div>IL-6 impairs Treg via VEGFR1 upregulation, driving IFN-γ secretion through the VEGFA–VEGFR1 axis and promoting corneal cell death and graft rejection.</div></div>","PeriodicalId":23304,"journal":{"name":"Transplant immunology","volume":"93 ","pages":"Article 102284"},"PeriodicalIF":1.4,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144996996","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}