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关键词： 带状疱疹后神经痛   SB-204900   小胶质细胞   p38 MAPK/CREB/TNF-α信号通路  

摘要： 目的 探究p38 MAPK抑制剂SB-204900对带状疱疹后神经痛（PHN）大鼠疼痛反应的影响，并分析其机制。方法 采用带状疱疹病毒接种建立PHN大鼠模型，鞘内注射SB-20490021天后检测大鼠机械痛阈值和热痛阈值；HE染色观察大鼠脊髓病理形态变化；TUNEL实验检测大鼠脊髓细胞凋亡水平；免疫荧光观察大鼠脊髓中Iba1阳性细胞数；Western blot检测大鼠脊髓组织中p-p38 MAPK、p38 MAPK、p-CREB和CREB蛋白表达；ELISA检测大鼠脊髓组织中TNF-α含量。结果 给予SB-204900降低PHN大鼠热痛阈值并增加大鼠机械痛阈值，改善大鼠脊髓组织病理损伤并抑制脊髓组织细胞凋亡，降低大鼠脊髓组织中Iba1阳性细胞数，下调大鼠脊髓组织中p-p38 MAPK和p-CREB蛋白表达以及TNF-α含量。结论 SB-204900降低PHN大鼠热痛阈值并增加大鼠机械痛阈值，改善大鼠脊髓组织病理损伤并抑制脊髓组织细胞凋亡和小胶质细胞激活，其机制可能与抑制p38 MAPK/CREB/TNF-α信号通路有关。

关键词： common genes   such as SNAP25   AQP4   SV2B   KCND3   ABCA2   CD163   CD14  

摘要： Tumor necrosis factor receptor-associated factors (TRAFs) are crucial intracellular signaling proteins in bone homeostasis. TRAFs mediate pathways associated with bone remodeling, particularly in response to inflammatory stimuli, influencing osteoclast differentiation and function. Dysregulation of TRAF-mediated signaling contributes significantly to osteoporosis, a condition marked by increased bone resorption and fragility. Natural products, with their anti-inflammatory and antioxidant properties, offer promising therapeutic potential by targeting TRAF-associated pathways to inhibit excessive osteoclast activity and promote bone formation. This review explores the mechanisms by which natural compounds modulate TRAF signaling in osteoclastogenesis and osteoblastogenesis, providing insights into their potential for osteoporosis treatment.

摘要： On August 1, 2024, the FDA granted accelerated approval to afamitresgene autoleucel, a melanoma-associated antigen-A4 (MAGE-A4)-directed genetically modified autologous T-cell immunotherapy, for the treatment of adults with unresectable or metastatic synovial sarcoma (SS) who have received prior chemotherapy, are HLA-A*02:01P, -A*02:02P, -A*02:03P, or -A*02:06P positive, and whose tumors express MAGE-A4 as determined by FDA-approved or cleared companion diagnostic devices. Approval was based on results from the phase 2, single-arm, open-label, multicenter Study ADP-0044-002. Patients received a single dose of afamitresgene autoleucel following lymphodepleting chemotherapy. Of the 44 efficacy evaluable patients, the overall response rate was 43.2% (95% CI: 28.4, 59.0), with complete response in two patients (4.5%). The median duration of response was 6.0 months (95% CI: 4.6, not reached [NR]) with a median follow-up of 21.9 months. Among the 44 patients, cytokine release syndrome occurred in 75% (Grade ≥3, 2%) warranting a Boxed Warning. Grade ≥3 infections occurred in 14% of patients and prolonged severe cytopenias also occurred. One patient developed Grade 1 immune effector cell-associated neurotoxicity and one patient developed Epstein-Barr virus-positive lymphoproliferative disease. Notably, during review of this application, FDA identified issues with data quality and study conduct that prompted an independent re-review of imaging assessments. The results of the re-review were the basis for FDA's determination of substantial evidence of effectiveness. This represents the first FDA approval of a T-cell receptor gene therapy. It is also the first FDA approval specifically for SS, representing a new treatment modality for this rare population who lack effective therapies.

关键词： Caspase-8   TNFR1   Duodenal Pathology   T Cell Imbalance   Intestinal Epithelial Layer  

摘要： RIPK1 is a crucial regulator of cell survival, inflammation and cell death. Human RIPK1 deficiency leads to early-onset intestinal inflammation and peripheral T cell imbalance, though its role in alpha beta T cell-mediated intestinal homeostasis remains unclear. In this study, we demonstrate that mice with RIPK1 ablation in conventional alpha beta T cells (Ripk1 Delta CD4) developed a severe small intestinal pathology characterized by small intestinal elongation, crypt hyperplasia, and duodenum-specific villus atrophy. Using mixed bone marrow chimeras reveals a survival disadvantage of alpha beta T cells compared to gamma delta T cells in the small intestine. Broad-spectrum antibiotic treatment ameliorates crypt hyperplasia and prevents intestinal elongation, though villus atrophy persists. Conversely, crossing Ripk1 Delta CD4 with TNF receptor 1 Tnfr1-/- knockout mice rescues villus atrophy but not intestinal elongation. Finally, combined ablation of Ripk1 triangle CD4 and Casp8 triangle CD4 fully rescues intestinal pathology, revealing that alpha beta T cell apoptosis in Ripk1 triangle CD4 drives the enteropathy. These findings demonstrate that RIPK1-mediated survival of alpha beta T cells is essential for proximal small intestinal homeostasis. In Ripk1 triangle CD4 mice, the imbalanced T cell compartment drives microbiome-mediated intestinal elongation and TNF-driven villus atrophy.

关键词： MHC-II macrophages   tumor-associated macrophage   DNA methylation   monocyte-to-macrophage transition   Arg1 macrophages   prostaglandin E2   EP2   lung metastasis   macrophage differentiation  

摘要： Monocytes differentiate into macrophages (Mops) to facilitate lung metastasis, but the monocyte-to-Mop transition during this process is not well understood. To investigate, we performed bulk RNA sequencing on Mops isolated from the lungs of mice bearing Lewis lung carcinoma tumors and from naive lungs. Our results showed impaired differentiation of monocytes into major histocompatibility complex (MHC) class II+ Mops, with an upregulation of PGE2-inducible genes, including Arg1, in tumor-associated Mops (TAMs). In vitro experiments confirmed that prostaglandin E2 (PGE2) inhibits the differentiation of MHC class II+ Mops while promoting Arg1+ Mops via the E prostanoid 2 (EP2) receptor, accompanied by DNA methylation. Whole-genome bisulfite sequencing revealed that PGE2-EP2 signaling drives the hypermethylation and downregulation of gene sets related to myeloid cells in non-neoplastic tissues. Our study highlights PGE2-EP2-driven DNA methylation in the monocyte-to-TAM transition, suggesting potential therapeutic avenues for lung metastasis.

关键词： immune-related diseases   inflammatory diseases   type III interferon  

摘要： Type III interferons (IFN-lambda), which include IFN-lambda 1 (or interleukin [IL]-29), IFN-lambda 2 (IL-28A), IFN-lambda 3 (IL-28B) and IFN-lambda 4, exert their effects through a unique receptor complex composed of interferon lambda receptor 1 (IFNLR1) and IL-10 receptor subunit beta (IL-10R2). Studies have highlighted their critical role in modulating immune response, particularly in the context of autoimmune diseases, viral infections and cancer. Unlike type I IFNs, which are broadly expressed, IFN-lambda displays a more tissue-specific expression pattern, predominantly acting on epithelial cells and certain immune cell types, such as neutrophils and B cells. This specificity allows IFN-lambda to play a pivotal role in mucosal immunity, particularly at barrier sites, such as the respiratory and gastrointestinal tracts. Emerging evidence suggests that IFN-lambda has a dual role in both enhancing antiviral immunity and regulating inflammation, thus offering a promising therapeutic strategy for diseases like systemic lupus erythematosus, rheumatoid arthritis, asthma and various cancers. However, the precise mechanisms by which IFN-lambda influence immune modulation and disease progression remain an area of active investigation. This review aims to provide an overview of the structure, function and signalling pathways of IFN-lambda, exploring their role in immune-related diseases and discussing potential avenues for therapeutic intervention.

关键词： CP: Immunology   CP: Microbiology   Heligmosomoides   helminth   HpARI   HpBARI   IL-33   immunomodulation   nematode   parasite   vaccine  

摘要： The murine intestinal nematode Heligmosomoides polygyrus bakeri (Hpb) modulates the host immune response via the Hpb alarmin release inhibitor (HpARI) family (HpARI1/2/3), which acts on interleukin (IL)-33, and the Hpb binds alarmin receptor and inhibits (HpBARI) family (HpBARI and HpBARI_Hom2), which acts on the IL-33 receptor ST2. Here, we find that this immunomodulation is evident only in the first week of infection and affects local and distal tissues. Vaccination with HpARI or HpBARI proteins raises antibody responses that block their immunomodulatory activities: HpARI2 vaccination results in significantly increased type 2 innate lymphoid cells (ILC2s), T helper (Th)2, and serum IL-4 and IL-5 responses, while HpBARI + HpBARI_Hom2 vaccination reverses infection-mediated ST2 suppression and increases Th2 immunity. A cocktail of HpARI2 + HpBARI + HpBARI_Hom2 gives robust protection against infection, associated with stunting of adult parasites, reduced egg burden, increased type 2 immune responses, and intestinal goblet cell expansion. Therefore, vaccination with immunomodulatory proteins can protect the host against infection and can be used as a tool for blocking the effects of specific parasite-derived proteins. © 2025 The Author(s)

摘要： Oligodendroglia expressing major histocompatibility complex (MHC) molecules have become of central interest in multiple sclerosis (MS) research, but their role in aging is still being elucidated. Using MHC class I and II reporter mice, we compared oligodendroglial MHC expression in neonatal, young adult (8-16 weeks), and aging (52 weeks) mice at baseline and after stereotactic delivery of AAV-GFAP-IFN gamma. We found that MHC class I-expressing oligodendroglia were present in both the na & iuml;ve brain and spinal cord, while MHC class II-expressing oligodendroglia were seen only in the spinal cord of aging mice at baseline. After AAV injection, MHC expression in oligodendroglia increased, recapitulating pathology seen in MS mouse models and in MS post-mortem tissue. After IFN gamma-AAV injection, the abundance of MHC class I-expressing oligodendroglia did not vary with age, whereas MHC class II-expressing oligodendroglia were more abundant in aging mice than neonatal and young adult mice. Our results suggest that MHC class II-expressing oligodendroglia are more prevalent with aging, which may contribute to the mechanisms underlying progressive MS and other age-related neurodegenerative diseases with central nervous system inflammation.

关键词： Natural killer (NK) cells   Cryopreservation   Good manufacturing practice (GMP)   Cell therapy   Immunotherapy   Advanced therapy medicinal product (ATMP)  

摘要： The adoptive transfer of natural killer (NK) cells represents a promising cancer therapy due to their intrinsic ability to distinguish between malignant and healthy cells in an allogeneic context, enabling off-the-shelf manufacturing possibilities. On demand availability of cryopreserved advanced therapy medicinal products (ATMPs) could promote enrolment in clinical trials and eventually commercialization with repeated dosing possibilities. However, NK cells are considered highly sensitive to cryopreservation-induced defects, including impaired viability, anti-tumor cytotoxicity, and in vivo expansion capacity. Here, we present the GMP-compliant manufacturing of an off-the-shelf NK cell product (RNK001), derived ex vivo from CD34+ hematopoietic stem and progenitor cells (HSPCs). To facilitate scalability and reduce hands-on time, the production process was adapted to a G-rex bioreactor, yielding high numbers of a pure CD56+CD3- NK cell product. Cryopreservation of HSPC-NK cells using an optimized freeze-thaw protocol resulted in a consistently high post-thawing viability of mature and differentiated cells. Surviving HSPC-NK cells post-thawing exhibited enhanced proliferative capacity compared to fresh cells in vitro and their persistence in vivo was similar to that of fresh cells when administrated intravenously or intraperitoneally in NOD/SCID/IL2Rgnull mice. Moreover, cryopreserved HSPC-NK cells had robust anti-tumor functionality, efficiently killing tumor spheroids embedded in a 3D collagen matrix and maintaining degranulation and interferon-gamma production capacity comparable to fresh cells following in vivo infusion. Together, these findings show the potential of cryopreserved HSPC-NK cells with potent effector functions, allowing the manufacturing of an off-the-shelf therapeutical NK cell product for hematological and solid malignancies.

关键词： 高摄入红肉   TLR4/MyD88/NF-κB通路   炎症细胞因子   溃疡性结肠炎  

摘要： 目的 观察高摄入红肉对溃疡性结肠炎(ulcerative colitis，UC)小鼠结肠组织中TLR4/MyD88/NF-κB信号通路及炎症细胞因子的影响。方法 40只断乳Balb/c小鼠随机分为4组：分别是对照组、红肉组、UC组和红肉+UC组，每组10只，对照组、UC组给予普通纯化型饲料，红肉组、红肉+UC组给予含有高红肉的饲料，均饲养8周；在这8周的最后9d对UC组、红肉+UC组小鼠给予3% DSS诱导小鼠UC。采用实时荧光定量PCR检测UC小鼠结肠中TLR4、MyD88及NF-κB mRNA的表达，检测UC小鼠结肠中IL-1β、IL-6、TNF-α和iNOS mRNA的表达。结果 与UC组相比，红肉+UC组小鼠结肠组织中TLR4、MyD88及NF-κB mRNA的表达显著升高；与UC组相比，红肉+UC组小鼠结肠组织中IL-1β、IL-6、TNF-α和iNOS mRNA表达显著升高。结论 高摄入红肉可能是通过激活UC小鼠TLR4/MyD88/NF-κB信号通路并促进炎症细胞因子大量释放加重小鼠UC。