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关键词： chronic antibody-mediated rejection (AMR)   donor-specific antibodies (DSA)   graft fibrosis   immunosuppression   operational tolerance  

摘要： Pediatric liver transplantation, while life-saving, poses long-term challenges in immunosuppression (IS) management. We retrospectively studied 26 pediatric recipients who underwent living donor liver transplantation between 1990 and 1994 and retained their original grafts for over 30 years. Based on IS status at the final follow-up, patients were categorized as IS-free (n=8), IS-resumption (n=9), or IS-continued (n=9). We analyzed liver allograft fibrosis score (LAFSc, range 0-9), donor-specific antibodies (DSA), and liver function tests. At the last follow-up, liver function tests showed no significant differences across groups. The IS-free group had a median IS cessation period of 22.8 years (range: 14.2-26.7) and demonstrated minimal fibrosis (median LAFSc=1) and low DSA prevalence, suggesting potential operational tolerance. The IS-resumption group resumed IS after a median cessation period of 7.9 years (range: 1.3-15.7) due to fibrosis progression and exhibited the highest fibrosis burden (median LAFSc=4) and frequent DSA positivity. Notably, some patients showed a tendency for fibrosis progression despite the restart of IS, suggesting possible subclinical antibody-mediated injury. The IS-continued group experienced fluctuating fibrosis (median LAFSc=1) and multiple late-onset T cell-mediated rejection episodes. Across all groups, high DSA positivity (mean fluorescence intensity >20,000) significantly correlated with advanced fibrosis. In conclusion, the IS-free group's favorable histology and antibody profile support the possibility of durable immune tolerance. Conversely, persistent fibrosis in the IS-resumption group highlights the limitations of conventional IS strategies. Serial histological evaluations and antibody monitoring would be helpful for long-term IS management in pediatric liver transplant recipients.

关键词： HLA   eplet   kidney transplantation   molecular mismatch   organ allocation  

摘要： HLA molecular matching in solid organ transplantation in the form of eplets, solvent-accessible amino acids or PIRCHE-II has been proposed as a more granular method than HLA matching on the antigen level. While many studies have shown the association between molecular mismatches and de novo donor-specific antibody formation, rejection and graft loss, evidence for prospective molecular matching in allocation is currently lacking, and the actual practical implementation and feasibility of molecular matching remains unclear. In this review the various potential applications of molecular matching in transplantation are discussed, including 1) organ allocation in deceased donor programs, 2) living donor selection, 3) increasing the transplantability of highly sensitized patients and 4) risk stratification to facilitate personalized immunosuppressive management, along with the challenges and gaps in current knowledge regarding these approaches. While clinical application of molecular mismatch analysis in solid organ transplantation holds promise, the fundamentals of HLA-specific antibody biology and epitope-paratope interactions should be further elucidated. This will aid in unraveling the factors that affect the relative immunogenicity of HLA molecular mismatches in order to start using molecular matching in clinical transplantation.

关键词： Epitope prediction   Epitope presentation   Helper T cells   SARS-CoV-2   Spike protein  

摘要： Early in the COVID-19 pandemic, multiple studies used prediction methods to identify candidate peptides to be included in prospective vaccines. While subsequent studies identified epitopes from convalescent and vaccinated subjects, few studies have compared the predicted to identified epitopes. Here we used three methods to predict SARS-CoV-2 spike protein helper T cell epitopes and compared the results to experimentally determined peptide binding as well as published epitopes. The correspondence between the predicted and experimental binding results and published epitopes depended more on the HLA being investigated than the prediction method used. Lastly, these observations were used to predict peptides which bind to the most HLAs. These peptides were previously identified and predicted to maintain HLA binding in the current variants of interest. This study highlights which prediction methods and conditions lead to the most reliable prediction results which would be of great interest for improving the design of future vaccines.

关键词： HLA novel allele   italic>HLA-E*01:154   nanopore sequencing   PolyseqOne sequencing  

摘要： HLA-E*01:154 differs from HLA-E*01:01:01:01 by a single nonsynonymous nucleotide substitution in codon 199 of exon 3.

关键词： Oncolytic virus   Cancer immunotherapy   Interleukin-12   Interleukin-17   PD-L1  

摘要： Cancer immunotherapy has recently achieved a breakthrough status, however, it is not effective in all cancer types. Genetically engineered oncolytic viruses (OVs) with immunomodulators are promising new therapeutic modalities for cancer. CARG-2020 is an engineered trivalent oncolytic viral construct that specifically expresses three immune modulators that inhibit IL-17RA signaling and regulate PD-L1 expression by shRNAs, along with the cytokine IL-12 which activates multiple tumoricidal pathways. Previous work showed that intratumoral (i.t.) injection of CARG-2020 exhibits robust efficacy against established colorectal cancer (CRC). In this study, we report that systemic delivery of CARG-2020 via the intravenous (i.v.) route can successfully control CRC growth. To further expand the scope of CARG-2020 as a pan-cancer candidate, we also show that CARG-2020 works in two additional mouse models of melanoma and triple-negative breast cancer. Administration of CARG-2020 resulted in increased accumulation of CD8+ T lymphocytes in the tumors, and depletion of these T cells results in poor tumor regression mediated by CARG-2020. Overall, our study shows a broad-spectrum efficacy of CARG-2020 in solid tumors and demonstrates the potential of CARG-2020 to be developed as a clinical candidate for the treatment of multiple human cancers that are surgically accessible.

关键词： apoptosis   angiogenesis   inflammation   ovarian ischemia/reperfusion   pirfenidone  

摘要： Objective Ovarian ischemia/reperfusion (I/R) injury is a common gynecological emergency, typically caused by ovarian torsion. Pirfenidone (PFN) has demonstrated potential therapeutic benefits due to its antioxidant, anti-inflammatory, and antiapoptotic properties. This research aimed to investigate the protective effects of PFN in alleviating ovarian I/R injury in female *** Female rats received PFN (300 mg/kg/day) for 3 consecutive days, either with or without the induction of ovarian I/R. The study assessed markers of ovarian oxidative stress, inflammation, apoptosis, and the levels of hypoxia-inducible factor-1 alpha and vascular endothelial growth factor-A (VEGF-A). Ovarian histology was analyzed, along with immunohistochemical staining for Toll-like receptor 4 (TLR4) and p38 mitogen-activated protein kinase (p38 MAPK).Key findings I/R injury resulted in increased oxidative stress, inflammation, apoptosis, and a significant reduction in ovarian VEGF-A levels. Histological examination revealed ovarian damage, with increased expression of TLR4 and p38 MAPK. PFN treatment significantly improved the hormonal balance and mitigated oxidative stress, inflammatory, and apoptotic markers to normal levels. In addition, PFN improved ovarian tissue morphology and decreased TLR4 and p38 MAPK *** The findings suggest that PFN may offer protective effects against ovarian I/R injury through its antioxidant, anti-inflammatory, and antiapoptotic properties, as well as by promoting angiogenesis in the ovary.

关键词： Clear cell renal cell carcinoma (ccRCC)   Interleukin-2 Receptor Subunit Gamma (IL2RG)   Long non-coding RNAs (lncRNAs)   Biomarkers   Immune response   Tumor microenvironment (TME)  

摘要： Interleukin-2 Receptor Subunit Gamma (IL2RG) has been implicated in various cancers, but its role in clear cell renal cell carcinoma (ccRCC) remains unclear. This study aimed to explore IL2RG expression, its relationship with IL2RG -related lncRNAs (IRLs). Gene expression and clinical data for ccRCC were obtained from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus(GEO) database. The IRL signature was constructed using Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis. Clinical data validated the diagnostic value of the signature. The prognostic value of the signal was assessed using Kaplan-Meier analysis and Receiver Operating Characteristic (ROC) curves. The prognostic value of the nomogram was further evaluated through calibration curves, ROC curves, and Decision Curve Analysis (DCA). Gene set enrichment analysis (GSEA), single-sample GSEA (ssGSEA), CIBERSORT algorithms, and TISCH2 database were applied to analyze immune function and immune cell infiltration in different risk groups. Clinical treatment differences among populations with varying risks and susceptibilities were predicted using R packages. The expression of IL2RG and key lncRNAs was validated by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). IL2RG was significantly upregulated in ccRCC tissues and correlated with advanced clinical stages (p < 0.001). High IL2RG expression was linked to worse overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) (p < 0.05). A 6-IRLs signature was identified, and the resulting model accurately predicted survival outcomes. Immune-related pathways were enriched in high-risk patients, and drug sensitivity analysis indicated that high-risk patients were more responsive to sunitinib and temsirolimus. IL2RG and its related 6-IRLs are potential biomarkers for ccRCC progression. The 6-IRLs model provides a robust tool for predicting prognosis and guiding

关键词： IL-15 superagonist   mouse model   nonsmall-cell lung cancer   PD-1/PD-L1 inhibitors   SHR-1501  

摘要： BackgroundInterleukin-15 (IL-15) is a pleiotropic cytokine recognized as a promising therapeutic agent in cancer immunotherapy. IL-15 superagonists have shown efficacy across various cancers, yet their effects in lung cancer immunotherapy remain *** study evaluated the antitumor effects of SHR-1501 through intratumoral injection in two murine lung cancer models: Lewis lung carcinoma (LLC) and Kras G12D/p53-/- (KP). We employed flow cytometry to assess immune cell populations in the tumor microenvironment (TME) and systemic circulation. Immunohistochemistry (IHC) was used to analyze TME changes in tumor tissues, while single-cell RNA sequencing provided insights into TME modulation following SHR-1501 treatment. Additionally, we assessed the synergistic potential of combining SHR-1501 with PD-1 monoclonal antibody (mAb) therapy and explored the abscopal effect of ***-1501 significantly inhibited tumor growth in both KP and LLC models at 5 mu g and 15 mu g doses (p = 0.0022 and p = 0.0002, respectively, for KP;p = 0.0508 and p = 0.0131, respectively, for LLC). Flow cytometry revealed increased infiltration of CD8+ T cells, effector memory CD8+ T cells (TEM), and natural killer (NK) cells in the TME. SHR-1501 also enhanced systemic immune responses, increasing CD8+ T cells and TEM populations in peripheral blood and spleen, with an early NK cell elevation on day 7 post-treatment. Single-cell analysis indicated that SHR-1501 promoted the activity of macrophages, increasing M1 macrophage proportions. Moreover, SHR-1501 enhanced the antitumor immune response by promoting pro-inflammatory changes across multiple cell types within the TME, including neutrophils, fibroblasts, and endothelial cells. When combined with PD-1mAb, SHR-1501 exhibited potent synergistic antitumor effects. The combination therapy significantly prolonged overall survival with no significant toxicity observed. Furthermore, SHR-1501 may have the ability to induce an

关键词： HLA-B*40:542   next-generation sequencing   novel allele  

摘要： HLA-B*40:542 differs from the HLA-B*40:23 allele by two nucleotide substitutions in exon 3.

关键词： endometrial carcinoma   histopathological parameters   HLA-I   immune phenotype   molecular classification   risk stratification   tumour microenvironment  

摘要： Aims: This study aims to define and characterize human leukocyte antigen class I (HLA-I) expression in a consecutive series of molecularly classified endometrial carcinomas (ECs), and to evaluate its association with clinicopathologic features, spatial cancer-immune phenotypes and patient prognosis, with a focus on the NSMP (no specific molecular profile) subtype. Methods and results: HLA-I expression was assessed by immunohistochemistry on whole tissue sections from 208 ECs, classified into POLE-mutated, MMR-deficient (MMRd), p53-abnormal (p53abn) and NSMP subtypes. Loss of HLA-I was identified in 31% of cases and was associated with adverse features including high-grade, aggressive histotypes, deep myometrial invasion, substantial lymphovascular space invasion (LVSI), extensive tumour necrosis and an 'excluded' immune phenotype. While HLA-I loss showed no significant prognostic impact in POLE, MMRd or p53abn tumours, it significantly correlated with worse disease-free survival in NSMP tumours (P < 0.001). Multivariate analysis confirmed HLA-I loss as an independent prognostic factor in early-stage NSMP ECs, in addition to substantial LVSI, presence of lymph node metastases and spatial cancer-immune phenotypes. Integration of HLA-I status improved the performance of predictive models over time. Conclusions: HLA-I loss defines a biologically aggressive subgroup within NSMP ECs and is associated with adverse clinicopathologic and immune features. Assessment of HLA-I expression could refine risk stratification in NSMP ECs, a group traditionally lacking robust prognostic markers and may help identify patients who could benefit from intensified clinical surveillance and future immunomodulatory treatment strategies.