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关键词： cancer therapy   cell death   cytokines   immune suppression   lymph node   macrophage   Treg cell  

摘要： Apoptotic cells are immunosuppressive, creating a barrier in cancer treatment. Thus, we investigated immune responses to dying tumor cells after therapy in the tumor draining lymph node (TDLN). A key population responsible for clearing tumor material in the TDLN was medullary sinus macrophages (MSMs). Tumor debris phagocytosis by MSMs induces the cytokine IL-33, and blocking the IL-33 receptor (ST2) or deletion of Il33 in MSMs enhances therapy responses. Mechanistically, IL-33 activates T regulatory cells in TDLNs that migrate to the tumor to suppress CD8⁺ T cells. Therapeutically combining ST2 blockade, targeted kinase inhibitors, and anti-PD-1 immunotherapy increases CD8⁺ T cell activity promoting tumor regression. Importantly, we observe similar activity in human macrophages, and IL-33 expression in sentinel lymph nodes correlates with disease stage and survival in melanoma. Thus, our data identifies an IL-33-dependent immune response to therapy that attenuates therapy-induced anti-tumor immunity. © 2025 Elsevier Inc.

关键词： 疟原虫   免疫逃逸   抗原   表观遗传调控  

摘要： 疟疾是一种由疟原虫感染引起的寄生虫病，主要通过按蚊叮咬传播，是当前严重威胁人类生命健康的重大公共卫生挑战之一。疟原虫为逃避宿主免疫系统的识别和清除，进化出多变的免疫逃逸策略，给疟疾防控工作带来了挑战。本文综述了疟原虫抗原变异、表观遗传调控、拮抗IgM抗体、激活环磷酸鸟苷-腺苷酸合成酶（cyclic GMP-AMP synthase,cGAS）-干扰素刺激基因（stimulator of interferon genes,STING）信号通路、抑制脾脏免疫功能和分子伪装等免疫逃逸机制的研究进展，旨在为疟疾疫苗和抗疟药物研发以及疟疾防治策略制定提供参考。

关键词： knockout   type 1 interferon   IFN beta   ocular infection   eye disease   virus replication   latency   reactivation   CD8   PD-1   exhaustion  

摘要： Type I interferons (IFNs) generate strong antiviral immunity following viral infection in mice and humans. These type I IFNs are encoded by at least 14 IFN alpha genes and a single IFN beta gene. We showed that the absence of one of the IFN alpha genes (IFN alpha 2A-/-) affected latency levels in herpes simplex virus type 1 (HSV-1) ocularly infected mice but not in infected control mice, and the absence of IFN alpha 2A did not affect viral reactivation in ocularly infected mice. Since the role of IFN beta in HSV-1 latency reactivation and the potential effect of latency-associated transcript (LAT) on IFN beta activity is not known, we ocularly infected IFN beta-/- mice with different doses of LAT-plus [LAT(+)] and LAT-minus [LAT(-)] viruses. Wild-type (WT) control mice and IFN beta-/- mice were infected similarly. Virus titers in the eye, viral and cellular transcripts in the eye and trigeminal ganglia (TG) of infected mice on days 3 and 5 post-infection, eye disease, survival, latency-reactivation levels, and T cell exhaustion were measured in latently infected mice. Virus replication and viral and cellular transcripts in the eye of infected IFN beta-/- mice were similar to those in WT mice, while eye disease and survival in IFN beta-/- mice differed significantly from WT mice. WT mice infected with LAT(-) virus showed reduced latency, slower reactivation, and less T cell exhaustion than mice infected with LAT(+) virus. However, using different doses of each virus, latency levels, time of reactivation, and T cell exhaustion were similar between LAT(+) and LAT(-) viruses. These results suggest that the absence of IFN beta expression compensates for the function of LAT with regard to levels of latency, T cell exhaustion, and reactivation but does not affect viral and cellular transcripts during primary *** beta (IFN beta) is a type I interferon that plays an important role in controlling primary herpes simplex virus type 1 (HSV-1) infection

关键词： 心肌梗死   心力衰竭   参蛤散   纤维化   赖氨酰氧化酶样蛋白2/转化生长因子β1/IL-11信号通路   Sprague Dawley大鼠  

摘要： 目的:基于赖氨酰氧化酶样蛋白2(LOXL2)/转化生长因子β1(TGF-β1)/IL-11信号通路探讨参蛤散对心肌梗死后心力衰竭大鼠心肌纤维化的影响。方法:将SD大鼠分为空白对照组、模型对照组、参蛤散小剂量组、参蛤散大剂量组、阳性对照组、参蛤散大剂量+LOXL2激活剂组，每组12只。除空白对照组外，其他组均通过冠状动脉缩窄法构建心肌梗死后心力衰竭模型。建模成功后立即给药，1次/d，持续4周。彩色多普勒超声显像仪检测大鼠左心室短轴缩短率（LVFS）和左心室射血分数（LVEF）;ELISA法分析血清中IL-1β和IL-6水平；Masson染色评估大鼠心肌胶原容积分数（CVF）；免疫组织化学染色检测心肌组织中Ⅰ型胶原蛋白、α平滑肌肌动蛋白（α-SMA）平均光密度值；qRT-PCR检测心肌组织中基质金属蛋白酶9(MMP-9)、基质金属蛋白酶抑制剂1(TIMP-1)mRNA表达；蛋白质印迹法检测心肌组织中LOXL2、TGF-β1、IL-11蛋白表达。结果:与空白对照组比较，模型对照组LVFS、LVEF降低，血清中IL-6和IL-1β水平升高，CVF、心肌组织中Ⅰ型胶原蛋白、α-SMA平均光密度值、MMP-9和TIMP-1 mRNA表达以及LOXL2、TGF-β1、IL-11蛋白表达均增加（均P<0.05）。与模型对照组比较，参蛤散小剂量组、参蛤散大剂量组、阳性对照组LVFS、LVEF升高，血清中IL-6和IL-1β水平降低，CVF、心肌组织中Ⅰ型胶原蛋白、α-SMA平均光密度值、MMP-9和TIMP-1 mRNA表达以及LOXL2、TGF-β1、IL-11蛋白表达减少（均P<0.05）。LOXL2激活剂可逆转大剂量参蛤散对心肌梗死后心力衰竭大鼠心肌纤维化的改善作用。结论:参蛤散可能通过调控LOXL2/TGF-β1/IL-11通路抑制心肌梗死后心力衰竭大鼠心肌纤维化。

关键词： adalimumab   adverse effects   Crohn's disease   dosage   drug interactions   efficacy   Entyvio   guselkumab   Humira   infliximab   lactation   mirikizumab   Omvoh   Otulfi   pregnancy   Pyzchiva   Remicade   Rinvoq   risankizumab   safety   Selarsdi   Skyrizi   Stelara   Steqeyma   TNF inhibitors   Tremfya   upadacitinib   ustekinumab   vedolizumab   Wezlana   Yesintek  

关键词： TNF   TNFR1   TNFR2   Tuberculosis   Anti-TNF therapy  

摘要： Tumor necrosis factor (TNF) is a key immunoregulatory cytokine with a dual role in the host response to Mycobacterium tuberculosis. While essential for granuloma formation, macrophage activation, and containment of latent infection, TNF can also contribute to tissue damage and immune pathology. This review systematically analyzes over 300 peer-reviewed studies published between 1980 and 2024, highlighting the molecular and cellular mechanisms of TNF action in tuberculosis (TB). Particular attention is given to TNF receptor signaling pathways, the balance between protective and pathological immune responses, and the modulation of TNF activity during anti-TNF therapy in patients with autoimmune diseases. We discuss how different TNF inhibitors vary in their capacity to interfere with host defense mechanisms, with monoclonal antibodies carrying a higher reactivation risk than receptor-based agents. To enhance conceptual clarity, we provide newly developed schematic representations that integrate current knowledge on TNF-driven immune dynamics, including its interaction with other cytokines, effects on granuloma stability, and role in intracellular bacterial control. Understanding the pleiotropic functions of TNF in tuberculosis pathogenesis is crucial for developing safe immunomodulatory strategies and optimizing the clinical management of patients at risk of latent TB reactivation.

关键词： 蓝舌病毒   VP5蛋白   截短表达   单克隆抗体  

摘要： 参考GenBank中蓝舌病毒血清1型（BTV-1）标准参考株VP5蛋白氨基酸序列，缺失N端1～79位氨基酸，按照大肠杆菌偏嗜性进行基因密码子优化后，合成编码BTV-1 VP5截短蛋白的基因VP5Δ79aa，将其克隆到表达载体pET-28a-sumo上，构建了重组质粒pET-sumo-VP5Δ79aa。将该重组质粒转化到BL21(DE3)感受态细胞中，用0.5 mmol/L IPTG分别在37 ℃和16 ℃条件下进行诱导表达和可溶性分析，经SDS-PAGE检测，重组VP5Δ79aa蛋白主要以包涵体形式表达。用Ni-NTA亲和层析法纯化重组VP5Δ79aa蛋白，得到与预期大小相符的单一目的条带。纯化后的重组VP5Δ79aa蛋白经不同浓度梯度的尿素透析复性后，将其免疫雌性BALB/c小鼠（6～8周龄），取免疫后脾细胞与骨髓瘤细胞融合，获得能稳定分泌单克隆抗体的杂交瘤细胞株。经间接ELISA、免疫荧光和Western-blot分析，筛选得到2株反应性和特异性良好的单克隆抗体4A10和5H11，其不仅能与重组VP5Δ79aa截短蛋白以及重组全长VP5蛋白反应，而且能特异识别BTV-1感染细胞中的天然VP5蛋白，这为深入研究BTV VP5蛋白的生物学功能及其抗原表位鉴定奠定了基础。

关键词： anti-TNF failure   biological therapy   sequential therapy   ulcerative colitis   inflammatory bowel diseases  

摘要： Background: Many ulcerative colitis (UC) patients require the use of second-line agents after the failure of anti-TNF therapy. Research design and methods: We conducted a multicenter, retrospective study including 683 chronically active, moderate-to-severe UC patients who failed first-line anti-TNFs. The rate of treatment persistence and colectomy-free survival was assessed up to 3 years after the initiation of second-line therapy. Predictors for colectomy and persistence were investigated. Results: After the failure of the first-line anti-TNF, ustekinumab had superior persistence and colectomy-free survival rates compared to tofacitinib (p = 0.05;p = 0.001) and vedolizumab (p = 0.02;p = 0.05), but significant difference was only found in persistence rates in comparison with anti-TNFs (p < 0.001). Regardless of the number of prior anti-TNFs, significantly higher persistence (p = 0.05) and colectomy-free survival rates (p = 0.01) were observed over 2 years with ustekinumab than with vedolizumab or tofacitinib, whereas ustekinumab's superiority over tofacitinib seemed to disappear by the third year. Hypoalbuminaemia (p = 0.002) and shorter disease duration at second-line initiation (p = 0.03) increased, while concomitant immunomodulators (p = 0.05) reduced the risk for colectomy. Shorter disease duration (p = 0.01) and primary non-response to the previously used anti-TNF (p < 0.001) negatively influenced persistence with second-line non-TNF-targeted agents. Conclusion: After first-line anti-TNF failure, switching to a non-anti-TNF agent is worth considering in moderate-to-severe UC.