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摘要： Recipients' age has emerged as a key factor that impacts on acute renal allograft rejection and graft survival. Age-related functional and structural changes in the immune system have been observed, yet the precise influence of aged immunity on kidney transplant remains unclear. In an initial retrospective analysis of clinical data gathered from two major centers in China and Germany, we found a correlation between aging and mitigated rejection outcomes in kidney recipients. To study the mechanism, we performed kidney transplantation on mice and observed attenuated allograft rejection in senescent recipients. Single-cell transcriptome analysis of allograft kidneys indicated a protective role of p21high macrophages in aged mice. Supernatant collected from p21high macrophage primary culture inhibited the cytotoxic function and proliferation of CD8+ T cells. Zfp36 is highly expressed in senescent p21high macrophages. To determine its role in renal allograft rejection, we studied mice with Zfp36 conditionally deleted in macrophages (Zfp36-cKO). These mice developed exacerbated allograft rejection with enhanced IL-27 production and CD8+ T cell hyperactivation. Inhibition of IL-27 with neutralizing antibody or deletion of IL-27 receptor on CD8+ T cells reversed acute renal allograft rejection in Zfp36-cKO mice. Moreover, in vitro silencing Zfp36 with siRNA led to impaired degradation of IL-27 p28 mRNA and a subsequent increase of IL-27 in p21high macrophages. In conclusion, senescent macrophages protect renal allograft rejection by suppressing CD8+ T cells via a Zfp36/IL-27-dependent mechanism. These findings may provide innovative therapeutic strategies for addressing kidney allograft rejection.

关键词： Medical risk factors   Immune suppression   Graft survival   Renal transplantation   Antigens   Diabetes mellitus   Immunology   Transplantation immunology  

摘要： Background HLA-DQ antibodies are the most prevalent de novo donor-specific antibodies (dnDSAs) after kidney transplantation (KT). The immunogenicity and impact of each HLA-DQ mismatch on graft outcomes can vary considerably. Methods This retrospective cohort study investigated the prevalence and risk factors for dnDSA development in patients who underwent KT at Siriraj Hospital between 2006 and 2020 and had HLA-DQB1 mismatches. Our center employed a protocol for post-KT dnDSA surveillance. The impact of dnDSAs on late rejection and graft survival was evaluated. Results In our cohort of 491 KT recipients, 59 (12.02%) developed dnDSAs to HLA-DQB1 at a median time of 4.2 years after KT. The risk of dnDSA occurrence was significantly higher among recipients with HLA-DQ7 mismatch (HR: 2.8;95% CI: 1.21-6.52;P = 0.017) and HLA-DQ9 mismatch (HR: 2.63;95% CI: 1.11-6.27;P = 0.028). Recipients who developed dnDSAs were younger (P = 0.009), had higher rates of medication nonadherence (P = 0.031), had pre-KT panel reactive antibody levels above 20% (P = 0.044), and received non-tacrolimus immunosuppression (P < 0.001) compared to those without. Recipients who developed dnDSAs to HLA-DQ exhibited a significantly higher incidence of late graft rejection (HR: 7.76;95% CI: 5-12.03;P < 0.0001) and inferior death-censored graft survival than those without dnDSAs (log rank P < 0.001). Conclusion The patients with HLA-DQ7 and HLA-DQ9 mismatches exhibit the highest risk of developing dnDSAs. Individualized immunosuppression adjustment and kidney allocation based on specific HLA-DQ mismatch may enhance long-term graft survival.

关键词： 犬细小病毒2c型   病原分离   原核表达   单克隆抗体  

摘要： 本研究从病死北极狼体内分离并鉴定犬细小病毒（CPV），将该株病毒暂时命名为CPV-JL-23。并制备该毒株的中和活性单克隆抗体。本研究以病死北极狼的临床症状、分子检测和病原分离结果为依据，分离鉴定对北极狼为高致病性的CPV病毒，通过序列分析进行亚型鉴定；以病毒基因组DNA为模板，利用PCR扩增VP2基因，通过原核系统表达VP2蛋白，以纯化后的蛋白为抗原对BALB/c小鼠进行免疫；取免疫后的脾细胞与SP2/0进行细胞融合。以VP2蛋白或病毒悬液为包被抗原，利用间接ELISA、Western-blot和IFA检测方法筛选CPV单抗，并在细胞水平进行中和活性分析。经鉴定，本研究分离到CPV-2c型病毒1株，筛选到15株识别CPV的单克隆抗体；其中4B1和5F1两株单克隆抗体具有中和活性。

关键词： Cellular immune response   Genetic diseases   Genetics   Immunology  

关键词： Cell biology   Immunology   Immunotherapy   Therapeutics   Urology  

摘要： Tumor cells often employ many ways to restrain type I IFN signaling to evade immune surveillance. However, whether cellular amino acid metabolism regulates this process remains unclear, and its effects on antitumor immunity are relatively unexplored. Here, we found that asparagine inhibited IFN-I signaling and promoted immune escape in bladder cancer. Depletion of asparagine synthetase (ASNS) strongly limited in vivo tumor growth in a CD8⁺ T cell–dependent manner and boosted immunotherapy efficacy. Moreover, clinically approved L-asparaginase (ASNase),synergized with anti–PD-1 therapy in suppressing tumor growth. Mechanistically, asparagine can directly bind to RIG-I and facilitate CBL-mediated RIG-I degradation, thereby suppressing IFN signaling and antitumor immune responses. Clinically, tumors with higher ASNS expression show decreased responsiveness to immune checkpoint inhibitor therapy. Together, our findings uncover asparagine as a natural metabolite to modulate RIG-I–mediated IFN-I signaling, providing the basis for developing the combinatorial use of ASNase and anti–PD-1 for bladder cancer. © 2025, Wei et al.

关键词： IDO1   immunohistochemistry   TMA   metabolic reprogramming  

摘要： Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous and malignant disease with a limited number of biomarkers and insufficient targeted therapies. The current therapeutic landscape is challenged by low response rates, underscoring the need for new therapeutic targets. The success of immunotherapy in HNSCC has highlighted the importance of the immune microenvironment, and since metabolic reprogramming, especially altered tryptophan metabolism, is an important aspect in immune evasion, the interplay of the two enzymes IDO1 and IL4I1 was investigated in HNSCC to assess their immunosuppressive roles and potential as prognostic biomarkers. The immunohistochemical expression of IDO1 and IL4I1 was evaluated by an experienced head and neck pathologist in a tissue microarray (TMA) of 402 patients with HNSCC. Clinical and pathological data were retrieved, and the overall survival of the patients was calculated. In this study, IDO1 and IL4I1 were expressed by HNSCC tumor cells in the TMA of 402 patients. The overall survival analysis of the clinical data of the patients revealed that high IL4I1 expression was significantly associated with worse OS (p = 0.0073), while IDO1 expression did not reach statistical significance (p = 0.087). The combination of both markers led to a clinically significant stratification of patients. Especially p16-negative OPSCC with a high IL4I1 expression demonstrated poor survival. Immunologic differences between IDO1 and IL4I1 were detected in a TMA of 403 patients, with IDO1 and IL4I1 being expressed by HNSCC. A low IL4I1 expression in HNSCC led to a significantly better OS in this study, while IDO1 expression did not have a significant effect. Additional studies are necessary to investigate the complex interplay in the metabolic reprogramming of tumor cells.

关键词： Epoxy resin   MXene   PBA   Fire safety   Ionic Liquid   Mechanical property  

摘要： Epoxy resins (EP) are renowned for their chemical stability, ease of processing, and cost-effectiveness, which has led to their extensive utilisation. However, their flammability and associated fire risks impose significant limitations on their broader application. Developing effective flame retardants to enhance the fire safety of EP remains a pressing need. In this study, a flame-retardant nanohybrid MXene@PBA@IL (MPL) with excellent fire safety properties for EP was developed by modifying MXene with a trimetallic Prussian blue analogue (PBA) incorporated with Ionic Liquid (IL). MPL demonstrated good compatibility with EP and effectively enhanced its flame retardancy, smoke suppression, durability, and mechanical properties at very low addition levels. Specifically, the EP-2 %MPL sample, containing 2 wt% MPL, achieved a UL-94 V-0 rating and a high limiting oxygen index of 30.8 %. Moreover, compared to pure EP, the peak heat release rate (pHRR), total heat release (THR), peak smoke production rate (pSPR) and total smoke production (TSP) of EP-2 %MPL were reduced by 39.18 %, 23.16 %, 44.09 %, and 50.22 %, respectively. The synergistic carbonization effect of MXene, PBA, and IL played a key role in enhancing the flame retardancy of EP-2 %MPL. Additionally, the flexural strength, impact strength, and water contact angle of EP-2 %MPL increased by 21.82 %, 39.18 %, and 61.76 %, respectively, compared to pure EP. This study offers a promising strategy for the development of multifunctional polymeric nanocomposites based on MXene derivatives.

关键词： 肠致病性大肠杆菌   脂多糖   O-抗原   血清型   结构鉴定  

摘要： O-抗原是细菌脂多糖最外层的组成部分， 其结构的复杂性与多样性对细菌的免疫逃逸、致病性及宿主相互作用具有重要影响。本研究开展了肠源性大肠杆菌EPEC080菌株脂多糖O-抗原的提取纯化。通过分子量测定、单糖组分分析、红外光谱分析以及核磁共振谱分析完成了该细菌脂多糖O-抗原化学结构的解析。该O-抗原的平均分子量为14.3 kDa， 由五糖重复单元→4)-[α-D-GalpNAc-(1→3)]-α-L-Rhap-(1→2)-[β-D-GalpNAc-(1→3)]-α-L-Rhap-(1→2)-α-L-Rhap-(1→构成， 其化学结构与已知的大肠杆菌各血清型O-抗原结构均不同， 表明EPEC080菌株是一种新的大肠杆菌血清型。本研究结果可为肠致病性大肠杆菌的致病机制探索， 以及相关疾病的预防和治疗方法研发提供基础。

关键词： AGT/AGTR1a/IL-1 beta axis   extracellular matrix metabolism   osteoarthritis   renin-angiotensin system   SEMA6D  

摘要： The tissue-localized renin-angiotensin system (tRAS) plays a pivotal role in the crosstalk between cardiovascular factors and osteoarthritis (OA). Semaphorin 6D (SEMA6D), a cardiovascular neuroeffector, may contribute to chondrocyte homeostasis;however, its cartilage-specific functions remain unclear. Chondrocytes with altered SEMA6D expression were established via gene transfection. RNA sequencing was performed to identify SEMA6D-related genes and pathways, with preliminary validation in human OA samples. Furthermore, biochemical methods were employed to investigate the role of the AGT/AGTR1a/IL-1 beta axis in mediating SEMA6D-associated extracellular matrix metabolism (ECM). An AAV5-based lentiviral vector was used to generate OA rat models overexpressing SEMA6D, followed by radiological and histological analyses. SEMA6D overexpression significantly enhanced ECM homeostasis, marked by increased Aggrecan, COL2A1 and decreased COL10A1, MMP13, and Runx2 expression. These SEMA6D-induced genes were enriched in the tRAS pathway, with AGT, AGTR1a, and IL-1 beta identified as critical targets. Furthermore, the AGT/AGTR1a/IL-1 beta axis activated ECM degradation in chondrocytes, while SEMA6D overexpression effectively suppressed this signaling. In the OA rat model, elevated SEMA6D expression significantly reduced cartilage degradation. SEMA6D confers chondroprotective effects in OA by modulating the tRAS pathway, likely through inhibition of the AGT/AGTR1a/IL-1 beta axis, thereby regulating ECM metabolism and chondrocyte hypertrophy. These findings enhance our understanding of cardiovascular influences on cartilage health and reveal tissue-specific regulatory mechanisms in OA.