Frontiers in Immunology最新文献

In kidney transplant workups, supplementing flow cytometry crossmatches (FCXMs) with solid-phase assays (SPAs) helps differentiate between true positive from false positive results, which can prevent unnecessary waitlist delays. This study presents an analysis of three discordant cases characterized by positive B-cell FCXM results and the absence of detectable donor-specific antibodies (DSAs). Peripheral blood samples were obtained from both recipients and donors for HLA typing, FCXM, antibody screening, and surrogate crossmatches, with expanded single antigen bead assays at One Lambda laboratory to detect unidentifiable antibodies. Initial FCXM positivity did not correlate with SPA-confirmed DSAs. However, surrogate crossmatch results varied: Recipient 1 had unacceptable antigen leading to a halted transplant, Recipient 2's negative results allowed the transplant to proceed, and Recipient 3's mixed results led to the decision not to proceed with the transplant due to an unacceptable antigen. The findings suggest that a positive FCXM, in the absence DSAs, may be interpreted as false positive, underscoring the necessity for comprehensive testing in the pre-transplant evaluation process. Employing multiple diagnostic techniques ensures more accurate risk assessments, improves transplant outcomes, and expands the pool of suitable donors, emphasizing the critical role of thorough HLA and non-HLA antibody evaluations.

Antiphospholipid syndrome (APS) is an autoimmune disorder defined by persistent antiphospholipid antibodies (aPL), thrombosis, and/or pathological pregnancy. Its phenotypic spectrum is heterogeneous and its pathogenesis remains incompletely understood. The incidence of APS increases year by year. Due to the constraints on human studies, animal models have become indispensable tools for dissecting the mechanisms of APS. The animal models accelerate the drug discovery and refine the therapeutic strategies in APS. Over the past decades, substantial methodological and translational advances have been achieved in APS animal models. In this review, we systematically summarize the current construction paradigms in thrombotic and obstetric APS animal models and highlight their respective advantages and limitations.

T-bet is a transcription factor predominantly expressed in immune cells, and it has been associated with a range of physiological and pathological processes, including the differentiation of various immune cell types, the development of immune-related diseases, and tumor progression. Despite notable advancements in the field, current research on T-bet remains fragmented, primarily concentrating on functional studies within specific cell types or the progression of particular diseases. This review aims to provide a comprehensive synthesis of the most recent findings regarding the role of T-bet in various diseases, with an emphasis on elucidating its molecular mechanisms and potential clinical applications. We underscore the involvement of T-bet in the pathogenesis of systemic diseases, including autoimmune disorders, infectious diseases, allergic conditions, endocrine disorders, psychiatric illnesses, and chromosomal abnormalities. Furthermore, we summarize its role in the development of various malignant tumors, such as esophageal cancer, gastric cancer, breast cancer, colon cancer, prostate cancer, and hematological malignancies. Additionally, we discuss the impact of T-bet on several critical processes in tumor biology, including tumor cell proliferation, apoptosis, epithelial-mesenchymal transition (EMT), metastasis, immune cell infiltration, and iron-induced apoptosis. We also assess the potential of T-bet as a prognostic and therapeutic target for tumors. In conclusion, T-bet may serve as a significant biomarker for the diagnosis and treatment of immune disorders and cancer, as well as a target for innovative immunotherapeutic strategies aimed at addressing tumors and immune-related diseases.

Introduction: Pre-existing comorbidities prior to allogeneic hematopoietic stem cell transplantation (HSCT), significantly affects outcomes. Prior hepatic impairment is included in classic prognostic scores like HCT-CI, without taking into consideration modern assessment techniques such as liver stiffness (LS) measurement. We aimed to evaluate the value of LS using Fibroscan (FS) to predict transplant outcomes and hepatic complications in patients undergoing allo-HSCT using post-transplant cyclophosphamide (PTCY) for graft-versus-host disease (GVHD) prophylaxis.

Methods: We conducted a single-center, prospective, observational study to evaluate the utility of LS measurement performed prior to transplantation and on day +14 to predict transplant outcomes, between October 2021 and March 2024. ROC curves were used to identify cut-off points for LS values for the development of hepatotoxicity, veno-occlusive disease (VOD), and hepatic acute and chronic GVHD. Logistic regression was used to analyse the impact of LS on overall survival (OS), event-free survival (EFS), non-relapse mortality (NRM) and graft-versus-host-disease and relapse-free survival (GRFS) .

Results: One hundred eight patients were included. Median follow-up was 12.5 months. OS, EFS, GRFS, cumulative incidence of relapse and NRM at 12-months were 75%, 68%, 55%, 22% and 9%, respectively. Cumulative incidences of grade II-IV acute GVHD at day 180 and moderate-severe chronic GVHD at 12 months were 14% and 12%, respectively. Five patients (4.6%) developed VOD. LS variation (FSΔ) from baseline LS to day +14 was significantly increased in those patients who developed VOD compared to those who did not (p=0.048; AUROC 0.8). Logistic regression univariate analysis showed FS+14>6KPa to be predictive for worse OS and EFS (p<0.05). Multivariate analysis found FS+14>6 KPa to be predictive for worse EFS.

Discussion: In our experience, increase in LS between baseline and day +14 was predictive for VOD. In addition, a measurement of FS+14>6Kpa was predictive for the outcome of allo-HSCT, with an independently predictive value for worse EFS. Thus, FS+14>6 KPa should be considered in future prognostic models used for PTCY-based HSCT.

Introduction: Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a global health crisis, with drug resistance and immune evasion complicating control efforts. Mtb subverts macrophage function to establish persistent infection, but the role of exosomes in immune regulation remains poorly understood.

Methods: This study employed iTRAQ-based proteomics to dissect strain-specific immune modulation strategies of virulent H37Rv (RV) and attenuated H37Ra (RA) through macrophage and exosome profiling.

Results: We revealed distinct survival strategies of Mtb in Macrophages: RV maintained host cell viability and intracellular proliferation, while RA induced apoptosis. Human proteomic profiling identified significantly more upregulated host proteins in RA-infected macrophages than in RV-infected cells, with RA robustly activating antigen presentation pathways. Conversely, exosomes from infected macrophages exhibited overall protein downregulation, particularly for RV. Strikingly, 24 of the top 25 enriched pathways were upregulated intracellularly but downregulated in exosomes, indicating bidirectional immune dysregulation. Bacterial proteomics revealed that functional proteins were preferentially sorted into exosomes. RV-exosomes were enriched in dormancy regulators (e.g., DevS) and immunosuppressive effectors, while RA-exosomes carried immunogenic antigens leading to robust cytokines releasing such as THF-a, IL-1a and IL-6.

Discussion: Conclusively, Mtb exploits exosomes as "virulence vectors" to deliver RhoGDI and death signals (e.g., Caspse-9), paralyzing systemic immunity while optimizing intracellular survival. Virulence-specific cargo sorting informs novel diagnostics and therapies against TB. However, given the limitations of the in vitro model, future research should incorporate in vivo models and clinical trials to validate these findings.

[This corrects the article DOI: 10.3389/fimmu.2025.1729525.].

Based on the hypothesis that neovascularization was required for tumor growth, the search for angiogenesis inhibitors attracted considerable attention, leading to the development of the monoclonal antibody bevacizumab against vascular endothelial growth factor (VEGF) which is currently standard treatment in several types of cancer. However, and despite encouraging preclinical data, clinical trials frequently failed to translate into benefits for patients due to limited efficacy, resistance and toxicity. Resistance mechanisms include triggering of alternative proangiogenic pathways, non-angiogenic vascularization, and the unforeseen heterogeneity of tumor endothelial cells. Early efforts to disrupt key interactions between extracellular matrix and endothelial cells via integrin or metalloproteinase inhibitors also had modest clinical outcomes, mainly due to poor selectivity and compensatory mechanisms. Similarly, the promise of endogenous angiogenesis inhibitors like endostatin and angiostatin did not led to durable clinical responses. Recent studies have shown that VEGF contributes to immune suppression, and therefore anti-VEGF therapy can not only normalize vasculature, improving immune infiltration, but also help to reshape tumor microenvironment. This has led to successful combinations of antiangiogenic agents and immune checkpoint inhibitors, now approved in several indications, including renal cell and hepatocellular carcinomas. Based on these results, bispecific antibodies targeting simultaneously VEGF and PD-(L)1 are emerging as promising therapeutic agents, with several worldwide phase 3 trials ongoing. Globally, around twenty bispecifics and trispecifics are in clinical development. In this review, we recapitulate previous successes and failures of anti-angiogenic strategies, and explore the potential of VEGF x PD-(L)1 antibodies as a new paradigm in cancer treatment.

Background: The immunoglobulin level following vaccination against SARS-CoV-2 results from a multifaceted immunological process involving cells and molecules that determine its efficacy and protect us against severe infection outcomes. The observed heterogeneity in the immune response to vaccination is partly attributable to host genetic factors; however, this genetic contribution has only been partially explored.

Methods: To elucidate the mechanisms underlying the antibody response elicited by the Pfizer-BioNTech vaccine, we conducted a genome-wide association study on anti-spike immunoglobulin G levels measured in 1,968 Italian individuals who received two doses of the vaccine, selected from a larger cohort of 7,169 volunteers characterized for 8 million genetic variants. Sex, age, body mass index, smoking habit, and time elapsed between vaccine administration and blood draw were accounted as covariates in the linear regression model.

Results: We identified a novel signal of association on chromosome 3 in the intronic region of the CMTM8 gene and confirmed one previously identified at the HLA locus close to the HLA-B gene. The lead SNP in the CMTM8 gene, rs7643677 (p-value = 2.095×10^-8), is associated with anti-S IgG levels and with the expression level of CD66b on granulocytic/polymorphonuclear myeloid-derived suppressor cells.

Conclusions: These findings support a role for CMTM8 in regulating the suppressive activity of specific immune cells, and suggest a potential interplay among genetic, humoral, and cellular mechanisms underlying the immune response to SARS-CoV-2 vaccination.

N6-methyladenosine (m⁶A) is the most abundant post-transcriptional modification in eukaryotic mRNA, extensively involved in RNA splicing, export, stability, and translation. In recent years, accumulating evidence has demonstrated that m⁶A modification plays a critical role in regulating the differentiation and function of immune cells. Among these, myeloid-derived suppressor cells (MDSCs), as a key immunosuppressive population within the tumor microenvironment (TME), accelerate tumor progression by inhibiting T cell activity and promoting immune evasion and therapy resistance. Emerging studies indicate that m⁶A modification modulates the development, accumulation, and immunosuppressive function of MDSCs, thereby contributing to tumor initiation and progression. This review provides a narrative overview of the current evidence regarding the crosstalk between m⁶A modification and MDSCs, with a focus on the underlying molecular mechanisms and their potential implications for cancer immunotherapy. Furthermore, we discuss future research directions and the challenges associated with clinical translation.