ImmunoTargets and Therapy最新文献

Background: Cyclophosphamide, tacrolimus, and rituximab (RTX) are first-line treatments for idiopathic membranous nephropathy (IMN), regardless of PLA2R status. While the efficacy of RTX in IMN patients with PLA2R-positive has been well-documented, its effectiveness in IMN patients with PLA2R-negative remains understudied. This study aimed to evaluate the efficacy and adverse events of these three treatment regimens in IMN patients with PLA2R-negative.

Methods: This study included 46 PLA2R-negative IMN patients confirmed by renal biopsy and immunofluorescence from the Department of Nephrology, the Second Affiliated Hospital of Nanchang University between September 2021 and October 2023. We compared clinical remission rates, and side effects at 3, 6, and 12 months follow-up in 14 patients who received prednisolone combined with cyclophosphamide (cyclophosphamide group), in 11 patients who treated with prednisolone combined with tacrolimus (tacrolimus group), and 21 patients who treated with rituximab (RTX group).

Results: Baseline characteristics were similar among the three groups. At the 12-month follow-up, the complete response rate was significantly higher in the cyclophosphamide and tacrolimus groups compared to the RTX group (p = 0.029). However, there were no significant differences in cumulative complete remission rates or cumulative composite remission rates among the three groups during the follow-up period (p = 0.192, p = 0.212). Severe adverse events occurred in all groups, but the differences were not statistically significant (p > 0.05).

Conclusion: Cyclophosphamide and tacrolimus appear to offer long-term benefits for PLA2R-negative IMN patients, with tacrolimus demonstrating superior efficacy among the treatment options evaluated. These insights offer important guidance for clinical decision-making in the management of PLA2R-negative IMN. However, further large-scale, multicenter studies with long-term follow-up are necessary to confirm these findings.

Currently, the management of autoimmune disorders still being a challenge in terms of safety, efficiency, and specificity. Cell-based therapeutic strategies have emerged as a novel approach for autoimmune disease treatment, employing different cell therapy platforms, including tolerogenic dendritic cells, regulatory T cells, conventional and regulatory chimeric antigen receptor-T cells, mesenchymal and hematopoietic stem cells, each with their biological features. Here, we discuss the different cell therapy platforms, their immunological mechanisms of action, their therapeutic potential and benefits in autoimmune diseases, and challenges related to their production, scaling up, risks, and patient safety.

Background: Although anti-GAD65 related epilepsy is rare, it needs more attention because it is refractory to the conventional therapies, has poor outcome and high relapse rate. In this study, we intended to report the efficacy of tocilizumab in the treatment of anti-GAD65 antibodies related refractory epilepsy based on our center's experience and literature review.

Methods: The clinical data of the patients managed with tocilizumab at Xiangya Hospital and those from the literature was collected and analysed.

Results: A female child presented at our center with neuropsychiatric symptoms and generalized tonic-clonic seizures (including status epilepticus) at the age of 3 years. She had positive anti-GAD65 autoantibodies. Her initial electroencephalograph showed multi-focal epileptic discharges and an early brain magnetic resonance imaging demonstrated increased intensity in the bilateral hippocampi and right insular cortex. She received several anti-seizures medications (ASMs) and immunotherapies without significant improvement; however, she experienced significant clinical, electrographic and radiological improvement after receiving four cycles of the tocilizumab. Literature review unveiled two more female cases. The mean age of seizure onset for three cases was 7.72 years, and they presented with refractory seizures (n=3), neuropsychiatric symptoms (n=3), ataxia (n=2), and anti-GAD autoantibodies were elevated in both the serum and cerebrospinal fluid (n=3). All three cases tried several combinations of ASMs and immunotherapies before tocilizumab but they remained with refractory epilepsy. Following several cycles of the tocilizumab, all cases had significant positive changes: seizure freedom (n=1), seizure control (n=2), improved-normal cognition (n=3), improved neuropsychiatry symptoms (n=2) and controlled ataxia (n=2).

Conclusion: Tocilizumab seems to be an effective therapy for the refractory anti-GAD65 related epilepsy as it can control seizures, improve cognition and neuropsychiatric symptoms.

Background: Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide. With the increasing incidence of CRC, there is an urgent need for effective strategies for early diagnosis and treatment. Circadian rhythm, a natural biological clock, regulates various physiological processes, and its disruption has been implicated in the onset and progression of cancer. However, the specific roles of circadian rhythm-related genes (CRDGs) in CRC remain unclear.

Methods: In this study, we analyzed the expression patterns of CRDGs in CRC using single-cell RNA sequencing (scRNA-seq) data and bulk RNA sequencing data from the GSE178318 dataset. We constructed a CRC prognostic model based on CRD scores. Additionally, we explored the potential mechanisms of CRDGs in tumor progression through weighted gene co-expression network analysis (WGCNA) and gene set enrichment analysis (GSEA), and assessed their impact on the response to immune checkpoint inhibitors.

Results: The analysis revealed that CRDGs were significantly upregulated in liver metastasis samples compared to primary CRC samples and were closely associated with several metabolic and immune-related pathways. The prognostic model based on CRD scores indicated that higher CRD scores were associated with poorer outcomes in immunotherapy. These findings were further validated in multiple datasets, underscoring the potential of CRDGs as prognostic indicators in CRC.

Conclusion: This study systematically reveals, for the first time, the expression characteristics of CRDGs in CRC and their relationship with tumor progression and response to immunotherapy. CRDGs may serve as effective prognostic biomarkers and therapeutic targets, offering new strategies for the personalized treatment of CRC.

Background: The treatment of extensive burns requires rapid allogeneic skin transplantation, but HLA diversity poses a significant challenge in finding histocompatible donor-recipient matches.

Methods: In this study, we developed a humanized skin graft model using HLA class I transgenic mice to closely examine the HLA-mediated immune response in skin transplantation. Additionally, this model was used to analyse the response against a human lymphoblastoid cell line, JY, with HLA-B and -C genes knocked out by a single-step CRISPR-Cas9 strategy, retaining the most common HLA class I allele, HLA-A*02:01.

Results: Mice expressing the HLA-A02:01 allele alone or in combination with HLA-B07:02 do not reject the skin of animals expressing only HLA-A02:01. However, skin from HLA-A02:01/B07:02 mice transplanted into HLA-A02:01 mice is rejected, triggering a strong specific CD8 T cell response mediated by the HLA-B*07:02 molecule. In these latter mice, unlike the parental JY cell line, the edited cells did not induce a CD8 T cell response in vitro, suggesting that the selective deletion of HLA-B and -C may contribute to improve skin graft compatibility.

Conclusion: This genetic engineering approach, repeated without modification for the five HLA-A class I most common alleles known to be associated with HLA-B7 and -C7 in the same haplotype, would cover 83.4% of the world population. Our findings offer a scalable HLA-compatible skin graft model, potentially improving practices in burn units worldwide.

Background: Anti-metabotropic glutamate receptor 2 (mGluR2)-related diseases are rare autoimmune disorders of the central nervous system that primarily affect the cerebellum and are occasionally associated with malignancies.

Methods: Data, including demographics, symptoms, blood and cerebrospinal fluid (CSF) tests, and brain magnetic resonance imaging (MRI), were retrospectively collected from two patients with informed consent at Xiangya Hospital from February 2024 to October 2024. Autoantibodies associated with autoimmune encephalitis were tested using cell-based assays. The literature describing anti-mGluR2 antibody-related diseases was searched for in PubMed and five cases were reviewed.

Results: Two cases of anti-mGluR2 antibody-related diseases were reported: one with acute cerebellitis and the other with refractory seizures. Brain MRI showed cerebellar involvement in the cerebellitis patient. Anti-mGluR2 antibodies were detected in the serum but not in the CSF of both cases, and both responded well to immunotherapy. A review of five patients (all female, aged 3-78 years) found four with cerebellar ataxia or cerebellitis and one with immune-related epilepsy. Common symptoms included dysarthria, gait instability, and gaze/nystagmus, while seizures were rare. MRI revealed cerebellar involvement in most cases. Anti-mGluR2 antibodies were present in the serum of all patients but only in the CSF of two. Three patients responded well to immunosuppressive treatment, and two had malignancies.

Conclusion: Anti-mGluR2 antibody-related diseases are autoimmune disorders primarily characterized by ataxic manifestations, though seizures may also occur. The effectiveness of immunosuppressive treatment is uncertain and screening for tumors is necessary.

Background: Recombinant antithrombin (rAT) has been shown to protect lungs from ARDS and modulate immune responses, but its anti-inflammatory mechanisms remain unclear. This study aimed to explore the immunomodulatory effects and mechanisms of rAT in LPS-induced ARDS mice.

Methods: ARDS mouse model was established by intraperitoneally administration of 20 mg/kg LPS. After 3 hours of LPS administration, rAT or PBS was injected intravenously. Lung injury, alveolar permeability, serum inflammatory cytokines, immune cell infiltration in lung tissue, and the proportion of Th17 were assessed 36 hours after rAT administration. The functional roles of the differential expressed genes (DEGs), obtained from LPS-induced ARDS mice treated with or without rAT, were analyzed by GO, KEGG and GSEA enrichment analysis. The activation of NF-κB and NLRP3 inflammasome was evaluated by Western blot and immunofluorescence staining.

Results: We found that rAT alleviated lung injury, reduced pulmonary permeability, decreased serum inflammatory cytokines, and suppressed immune cell infiltration and NLRP3 inflammasome activation. Moreover, rAT decreased the proportion of Th17 cells in lung tissues and peripheral blood, downregulated IL17a expression, and inhibited NF-κB signaling pathway in lung tissues. Additionally, the administration of IL-17A diminished the efficacy of rAT in mitigating lung injury, suppressing the immune response, and inhibiting the activation of the NF-κB signaling pathway in LPS-induced ARDS mice.

Conclusion: The findings of this study suggest that rAT alleviates lung injury and suppresses inflammatory responses by inhibiting the IL17a/NF-κB signaling axis, suggesting that rAT may serve as a potential therapeutic agent for mitigating pulmonary inflammation and improving the prognosis of ARDS induced by sepsis. Furthermore, this study provides important research data and theoretical basis for the clinical translation and application of rAT.

Interleukin 2 (IL2) is a dual-acting cytokine, playing important roles in both immune activation and regulation. The role IL2 plays as a potent activator of CD8 T cells saw IL2 become one of the earliest immunotherapies, used for the treatment of cancer. In more recent years refined understanding of IL2, and the potent capacity it has for Treg stimulation, has seen low-dose IL2 therapy trialled for the treatment of auto-immune and inflammatory conditions. However, despite clinical successes, IL2 therapy is not without its caveats. The complicated receptor biology of IL2 gives rise to a narrow therapeutic window, made problematic by its short half-life. Armed with a better understanding of the structure of IL2 in complex with its receptors, many attempts have been made to create designer IL2 molecules which overcome these problems. A wide range of approaches have been used, resulting in >100 designer IL2 molecules. These include antibody complexes, fusion proteins, mutant IL2 molecules and PEGylation, each uniquely modifying the biological activity in an effort to enhance its therapeutic potential. Collectively, designer IL2 molecules form a blueprint outlining modification pathways available to other immunotherapeutics, paving the way for the next generation of immunotherapy.

Purpose: The peritoneum is a common site of metastasis in gastric cancer (GC), associated with poor prognosis and significant morbidity. The proclivity of GCs to metastasize to the peritoneum has been hypothesized to occur due the latter's immunosuppressive microenvironment, such as stromal infiltration and M2 macrophage enrichment, which are associated with increased risk of PM. As far as we know, a model that can effectively predict the prognosis of patients with GCPM is still lacking. Consequently, we constructed a prognostic risk model based on M2 macrophages associated with gastric cancer peritoneal metastasis, aiming to enhance predictive precision and guide tailored therapeutic interventions.

Methods: M2 macrophage-associated genes were identified in combination with marker genes from single-cell RNA sequencing (scRNA-seq) and modular genes from weighted gene coexpression network analysis (WGCNA). A prognostic model was constructed via LASSO analysis and validated in internal and external cohorts. We further compared the immune microenvironment, immune checkpoints, and chemotherapeutic drug sensitivity between patient groups stratified by risk to clarify the immune landscape in the GCPM.

Results: Our study identified 38 M2 macrophage-related genes via single-cell and bulk RNA sequencing. We developed a prognostic model based on the expression levels of 4 signature genes: DAB2, SPARC, PLTP, and FOLR2. The feasibility of the model was validated with internal and external validation sets (TCGA, GSE62254 and IMvigor210). The model also supported the prediction results of prognosis on the basis of the immunohistochemical results. Notably, patients with higher risk scores had a lower proportion of MSI-H and TMB, a higher prevalence of stages III-IV, and a lower likelihood of responding favorably to immunotherapy.

Conclusion: Our prognostic risk model could effectively predict the prognosis and response to chemo-immune therapy in patients with GCPM. The risk score is a promising independent prognostic factor that is closely correlated with the immune microenvironment and clinicopathological characteristics.

Type 2 Diabetes Mellitus (T2DM) is a rapidly growing global health issue characterized by insulin resistance and chronic inflammation. Beyond regulating glucose homeostasis, insulin plays a pivotal role in modulating immune cell function, linking metabolic dysregulation with immune responses. This review examines the intricate relationship between insulin resistance and immune dysfunction in T2DM, focusing on how impaired insulin signaling pathways, particularly PI3K/Akt and MAPK, contribute to immune cell activation, proliferation, and chronic inflammation. Insulin resistance impacts immune cells such as T cells, B cells, macrophages, and neutrophils, leading to an imbalance between pro-inflammatory and anti-inflammatory responses. Elevated pro-inflammatory cytokines (eg, TNF-α, IL-6) and adipokines (eg, leptin, resistin) exacerbate insulin resistance, promoting a vicious cycle of metabolic and immune dysregulation. This interplay contributes to the chronic low-grade inflammation that underlies T2DM pathogenesis, further impairing insulin signaling and glucose metabolism. Restoration of insulin sensitivity is, therefore, a critical step toward correcting immune imbalance in insulin-resistant states like T2DM. Therapeutic approaches that reduce inflammation could also support improvements in insulin sensitivity, addressing both metabolic and immune disturbances simultaneously. The review also explores therapeutic strategies, including insulin therapy, targeting insulin signaling pathways, and lifestyle interventions. Insulin therapy can reduce pro-inflammatory cytokine production and enhance anti-inflammatory responses, although challenges such as potential immune suppression and hyperinsulinemia remain. Targeting key signaling pathways and transcription factors offers promising avenues for modulating immune responses, while lifestyle interventions, such as dietary modifications, physical activity, and weight management, can improve insulin sensitivity and reduce inflammation. By understanding the dual role of insulin in regulating both metabolic and immune functions, this review underscores the importance of addressing immune dysfunction as part of comprehensive T2DM management. Targeting the interconnected pathways of insulin signaling and immune regulation could lead to more effective therapeutic approaches, ultimately improving patient outcomes and reducing disease complications.