Frontiers in Immunology最新文献

Familial adenomatous polyposis (FAP) is an inherited autosomal dominant disorder caused by germline mutations in the adenomatous polyposis coli (APC) gene. FAP is associated with the development of hundreds of adenomas in the small and large intestines of individuals starting in the teenage years with a near 100% risk of developing colorectal cancer by adulthood. Eventually polyps develop throughout the gastrointestinal tract. Chemoprevention approaches have been somewhat successful in reducing polyp burden, but have not reduced the risk of the development of colorectal cancer or other cancers. The lack of efficacy of more standard drug approaches may be due to limited exposure to the agent only to specific periods while the drug is being metabolized, limited drug penetrance in the colon, and patient adherence to daily dosing and drug side effects. The success of immune therapy for the treatment of invasive cancer has led to research focused on the use of immune based approaches for polyp control in FAP, specifically polyp directed vaccines. Vaccines targeting antigens expressed in FAP lesions may be a superior method to control polyp burden and prevent disease progression as compared to classic chemoprevention drugs. A limited number of vaccines can be administered over a short period of time to generate a lasting immune response. Appropriately primed antigen specific T-cells can traffic to any site in the body where antigen is expressed, recognize, and eliminate the antigen expressing cell. Immunologic memory will allow the immune response to persist and the specificity of the immune response will limit toxicity to the targeted polyp. This review will examine the current state of vaccines directed against FAP lesions and highlight the challenges and opportunities of translating vaccines for cancer interception in FAP to the clinic.

Introduction: Donor lymphocyte infusion (DLI) is a therapeutic approach for relapse after hematopoietic stem cell transplantation (HSCT). Despite their reported efficacy, the evolution of DLI practices over time remains underexplored.

Methods: This study provided a comprehensive analysis of DLI strategies and outcomes over 30 years at a single institution. A retrospective analysis was conducted on 75 patients who underwent DLI for disease relapse between April 1994 and March 2024. The primary endpoint was the 3-year overall survival (OS) rate after DLI. Secondary endpoints included the 100-day complete remission (CR) rate and incidence of acute graft-versus-host disease (GVHD).

Results: The median age at the first DLI was 49 years (range, 20-69 years). The most common underlying diseases in all 75 cases were acute myeloid leukemia (AML, n = 46) and myelodysplastic syndromes (MDS, n = 12). Until 2014, DLI was only performed in patients with AML (n = 14), MDS (n = 2), or chronic myeloid leukemia (n = 5). However, since 2015, patients with various diseases, including lymphoid malignancies, have also undergone DLI. Azacitidine was the most frequently used combination therapy with DLI (n = 34). Regimens including venetoclax and FLT3 inhibitors have been commonly used since 2019 (n = 18). The 3-year OS rate was 29.1% (95% CI, 18.8-40.2%). Factors negatively influencing OS included age ≥50 years and a high or very high refined disease risk index. The 100-day CR rate was 52.1%, and acute GVHD occurred in 25.3% of the patients, with no strong correlation between GVHD incidence and CR achievement. Among 18 patients who underwent three or more DLIs since 2018, 88.9% achieved remission following DLI or second HSCT, with a median follow-up of 949.5 days for survivors.

Conclusion: This study highlighted the evolving trends in DLI practices and the diversification of combination therapies. Future research should focus on further validating these findings and optimizing DLI protocols to improve patient outcomes.

Immunoglobulin M (IgM) and IgM⁺ B cells are key components of the humoral immune system, providing defense against pathogen invasion. While the role of IgM in the systemic and mucosal immune responses of fish to parasites and bacteria has been partially investigated, its function in viral infections remains underexplored. This study successfully developed a largemouth bass (Micropterus salmoides) model for ranavirus immersion infection. Our findings revealed that viral infection caused significant pathological changes in the gill and head kidney tissues, along with a marked upregulation of adaptive immune gene expression. Interestingly, fish that survived an initial viral infection exhibited minimal mortality and low viral loads in the gill and head kidney tissues when exposed to a higher viral concentration. Notably, in these fish with secondary infections, there was a significant increase in IgM protein levels in both the blood and gill mucus, as well as a pronounced accumulation of IgM⁺ B cells in the gill and head kidney tissues. Additionally, the serum contained high levels of virus-specific IgM, which demonstrated the ability to neutralize the virus. These findings highlight the crucial role of IgM in the immune response to viral infections in largemouth bass and suggest its potential as a target for enhancing viral resistance in aquaculture.

Dietary behaviors significantly influence tumor progression, with increasing focus on high-salt diets (HSD) in recent years. Traditionally, HSD has been regarded as a major risk factor for multiple health issues, including hypertension, cardiovascular disease, kidney disease, cancer, and osteoporosis. However, recent studies have uncovered a novel aspect of HSD, suggesting that HSD may inhibit tumor growth in specific pathological conditions by modulating the activity of immune cells that infiltrate tumors and enhancing the effectiveness of PD-1 immunotherapy. This review focused on the duel molecular mechanisms of HSD in cancer development, which are based on the tumor microenvironment, the gut microbiota, and the involvement of sodium transporter channels. The objective of this review is to explore whether HSD could be a potential future oncological therapeutic strategy under specific situation.

Introduction: Breast cancer is among the most prevalent malignant tumors globally, with carboplatin serving as a standard treatment option. However, resistance often compromises its efficacy. DNA damage repair (DDR) pathways are crucial in determining responses to treatment and are also associated with immune infiltration. This study aimed to identify the DDR genes involved in carboplatin resistance and to elucidate their effects on prognosis, immune infiltration, and drug sensitivity in breast cancer patients.

Methods: A 3D-culture model resistant to carboplatin was constructed and sequenced. Co-expressed DDR genes were analyzed to develop a predictive model. Immune infiltration analysis tools were employed to assess the immune microenvironment of patients with varying expression levels of these risk genes. Additionally, drug sensitivity predictions were made to evaluate the efficacy of other DNA damage-related drugs across different risk groups. Molecular assays were performed to investigate the role of the key gene TONSL in breast cancer.

Results: By integrating data from public database, we established a prognostic signature comprising thirteen DDR genes. Our analysis indicated that this model is associated with immune infiltration patterns in breast cancer patients, particularly concerning CD8+ T cells and NK cells. Additionally, it demonstrated a significant correlation with sensitivity to other DDR-related drugs, suggesting its potential as a biomarker for treatment efficacy. Compared to the control group, TONSL-knockdown cell lines exhibited a diminished response to DNA-damaging agents, marked by a notable increase in DNA damage levels and enhanced drug sensitivity. Furthermore, single-cell analysis revealed elevated TONSL expression in dendritic and epithelial cells, particularly in triple-negative breast cancers.

Conclusions: Carboplatin resistance-related DDR genes are associated with prognosis, immune infiltration, and drug sensitivity in breast cancer patients. TONSL may serve as a potential therapeutic target for breast cancer, particularly in triple-negative breast cancer, indicating new treatment strategies for these patients.

This review evaluates in-vitro models for studying how maternal influences during pregnancy impact the development of offspring microglia, the immune cells of the central nervous system. The models examined include primary microglia cultures, microglia cell lines, iPSC-derived microglia, PBMC-induced microglia-like cells, 3D brain organoids derived from iPSCs, and Hofbauer cells. Each model is assessed for its ability to replicate the in-vivo environment of the developing brain, with a focus on their strengths, limitations, and practical challenges. Key factors such as scalability, genetic and epigenetic fidelity, and physiological relevance are highlighted. Microglia cell lines are highly scalable but lack genetic and epigenetic fidelity. iPSC-derived microglia provide moderate physiological relevance and patient-specific genetic insights but face operational and epigenetic challenges inherent to reprogramming. 3D brain organoids, derived from iPSCs, offer an advanced platform for studying complex neurodevelopmental processes but require extensive resources and technical expertise. Hofbauer cells, which are fetal macrophages located in the placenta and share a common developmental origin with microglia, are uniquely exposed to prenatal maternal factors and, depending on fetal barrier maturation, exhibit variable epigenetic fidelity. This makes them particularly useful for exploring the impact of maternal influences on fetal programming of microglial development. The review concludes that no single model comprehensively captures all aspects of maternal influences on microglial development, but it offers guidance on selecting the most appropriate model based on specific research objectives and experimental constraints.

Background: Tumor progression and chronic postsurgical pain (CPSP) in patients with breast cancer are both significantly influenced by inflammation. The associations between immunoinflammatory biomarkers and long-term survival, as well as CPSP, remain ambiguous. This study examined the predictive value of immunoinflammatory biomarkers for both long-term survival and CPSP.

Methods: Data on the clinicopathological characteristics and perioperative peripheral blood immunoinflammatory biomarkers of 80 patients who underwent breast cancer surgery were retrospectively collected. Optimal cut-off values for preoperative immunoinflammatory biomarkers, including the preoperative systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), neutrophil-to-lymphocyte ratio (NLR), and pan-immune-inflammation value (PIV), were established via receiver operating characteristic (ROC) curves. Kaplan-Meier curves and Cox regression analysis were used to evaluate the relationships between preoperative immunoinflammatory biomarkers and long-term survival. The relationships among the perioperative neutrophil count (NEU), monocyte count (MONO), lymphocyte count (LYM), platelet count (PLT), SII, SIRI, NLR, PIV, dynamic changes in peripheral blood cell counts, and CPSP were further assessed using logistic regression analysis.

Results: Kaplan-Meier curves revealed a considerable prolongation of disease-free survival (DFS) and overall survival (OS) in the low preoperative SII, SIRI, NLR, and PIV groups. Multivariate Cox regression analysis revealed that only an elevated preoperative SIRI was an independent risk factor for postoperative DFS (HR=8.890, P=0.038). The incidence of CPSP was 28.75%. Univariate logistic regression analysis revealed that body mass index (BMI), postoperative NEU, MONO, SIRI, and PIV were negatively correlated with the occurrence of CPSP, whereas subsequent multivariate logistic regression analysis revealed that only BMI was independently associated with CPSP (OR=0.262, P=0.023).

Conclusion: Elevated preoperative SIRI was an independent risk factor for poor DFS in breast cancer patients after surgery. In contrast, perioperative immunoinflammatory biomarkers had limited potential for predicting CPSP in patients who underwent breast cancer surgery.

Background: Whole Eye Transplantation (WET) offers potential for vision restoration but is hindered by the complex challenge of immune rejection. Understanding and closely monitoring these immunological responses is crucial for advancing WET. This study delves into the timeline and nature of immune responses in a rodent model of WET without immunosuppression, aiming to elucidate a detailed picture of the immune landscape post-transplantation and establish innovative diagnostic and monitoring methods.

Methods: We employed a multi-faceted approach to analyze immune responses post-WET, including assessments of gross changes in corneal transparency, thickness, and skin condition. Histopathological examinations of both ocular and surrounding skin tissues provided insights into cellular changes, complemented by ocular RT-qPCR for molecular analysis. Serological analysis was employed to quantify cytokines, chemokines, and donor-specific antibodies, aiming to identify potential biomarkers correlating with WET rejection and to validate the presence of antibody-mediated rejection. These methodologies collectively contribute to the development of non-invasive diagnostic and monitoring strategies for WET.

Results: Our study revealed a rapid and acute immune response following WET, characterized by an early innate immune response dominated by complement involvement, and infiltration of neutrophils and monocytes by post-operative day (POD) 2. This was succeeded by an acute T-cell-mediated immune reaction, predominantly involving T helper 1 (Th1) cells and cytotoxic T lymphocytes (CTLs). The presence of donor specific antibody (DSA) and indications of pyroptosis in the early phases of rejection were observed. Notably, the early elevation of serum CXCL10 by POD4, coupled with ocular CD3+ cell infiltration, emerged as a potential early biomarker for WET rejection. Additionally, corneal transparency grading proved effective as a non-invasive monitoring tool.

Conclusion: This study offers a first-time comprehensive exploration of immune responses in WET, unveiling rapid and complex rejection mechanisms. The identification of early biomarkers and the development of non-invasive monitoring techniques significantly advance our understanding of WET rejection. Additionally, these findings establish an essential baseline for future research in this evolving field.

Factor H-related proteins (FHRs) are found in mice, but their equivalence to human FHRs remains uncertain. This study identifies three FHRs in mouse plasma (FHR-B, FHR-C, and FHR-E) and focuses on characterizing FHR-B. Using purified plasma proteins and recombinant mutants, FHR-B was found to form dimers and bind strongly to C3, C3b, iC3b, and C3dg. It also competes with mouse Factor H (mFH) for binding to C3b-coated surfaces and disrupts mFH regulation in hemolysis assays with sheep and guinea pig erythrocytes. These functions are localized to the C-terminal region and are dependent on FHR-B dimerization. Dimerization occurs through the N-terminal region (SCR1-3), which differs from mFH SCR5-7 by only four amino acids and also shares significant homology with human FHR-3 and human FH SCR5-7. In contrast to FHR-1, AUC experiments indicate that FHR-B dimerization is pH-sensitive, reversible and that the monomers in the dimer present the same head to tail orientation. Mutant analyses revealed that mFH SCR5-7 also forms dimers, but less efficiently than FHR-B. Notably, substituting FHR-B Tyr162 (a key residue homologous to the disease-associated Tyr402 in human FH) for His reduces dimerization. We also found that a recombinant FHR-B with a duplicated dimerization domain formed stable dimers but lacked functional activity. Overall, FHR-B shows structural and functional similarities with various human FHRs, suggesting convergent evolution between mouse and human FHRs. Furthermore, this study reveals a novel dimerization domain shared by FHR-B and mouse FH and illustrates the importance of dimerization and monomer orientation in FHRs activity. It also underlines notable differences between human and mice FHRs that should be further explored before modeling FHR-associated human diseases in mice.