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关键词： IL-15   NK cell   NKp30   TriKE   tumor immunotherapy  

摘要： Natural killer (NK) cells represent a promising effector population for tumor immunotherapy. Conventional NK cell engagers (NKCEs), primarily targeting CD16a, show efficacy but face limitations due to receptor polymorphisms and off-target toxicity. Here, we report the development and characterization of a novel trispecific NK cell engager (TriKE) simultaneously targeting the activating receptor NKp30 and the tumor-associated antigen HER2, integrated with a modified interleukin-15 (IL-15 N72D) fused to the IL-15R alpha sushi domain (IL-15R alpha Su) to enhance NK cell proliferation and persistence. Protein expression and affinity analyses confirmed the proper formation of the fusion protein with high-affinity binding to NKp30, HER2, and IL-15 receptor components. Flow cytometry demonstrated dose-dependent binding of the TriKE to primary human NK cells and HER2+ tumor cells. Functionally, the TriKE induced significantly greater NK cell activation, as measured by CD69 expression, compared with a bispecific engager lacking IL-15. Importantly, cytotoxicity assays revealed superior NK-mediated killing of HER2+ tumor cells upon prolonged exposure, highlighting the immunostimulatory effect of the IL-15 moiety. These results establish the alpha NKp30 TriKE as a potent platform to redirect NK cytotoxicity against HER2+ tumors, combining targeted receptor engagement with cytokine-driven activation to enhance NK cell-based cancer immunotherapy. A trispecific NK cell engager targeting HER2 and NKp30 and incorporating IL-15 enhances NK cell activation and cytotoxicity against HER2+ tumors.

关键词： FCV1   NLRP3 inflammasome 2   Cell pyroptosis 3   IL-1 beta 4  

摘要： Feline calicivirus (FCV) poses a significant threat to the health of susceptible animals in the global epidemic. The inflammasome plays a crucial role in the inflammatory process induced by pathogens, functioning in resisting their invasion, responding to cellular damage, and maintaining internal environmental *** infection in cats causes inflammation,and the regulatory mecha-nisms of the NLRP3 inflammasome on inflammatory factors in infected cells urgently require further *** study focuses on this inflammasome as the entry point, focusing on its activation signal that activates IL-1 beta *** cellular experiments, it analyzes the molecular mechanisms and logical relationships between this inflammasome, intracellular environment, pyroptosis, the regulation of IL-1 beta secretion by viral-encoded *** results showed that FCVinfected cells induced the activation and assembly of the NLRP3 inflammasome, thereby activating this signaling. FCV-induced IL-1 beta secretion was dependent on the activation of this inflammasome. In the early stages of infection, the activation of this inflammasome and IL-1 beta secretion were dependent on cellular Ca2 + influx and K+ efflux. IL-1 beta secretion also relied on FCV-induced pyroptosis;The activation of this inflammasome by the FCVencoded protein p32/LC and the subsequent induction of IL-1 beta secretion are contingent upon the function of its in mediating cellular Ca2+ influx and K+ *** summary, this study demonstrates that following FCV infection of cells, its p32 and LC proteins activate the NLRP3 inflammasome activation signal in a manner dependent on Ca2+ influx and K+ efflux,Induce IL-1 beta secretion. In addition, FCV-induced pyroptosis also triggers the secretion of IL-1 beta. The findings of this study elucidate the leading to inflammatory mechanisms of FCV from a novel perspective, providing new drug targets for the design and screening of anti-inflammatory drugs.

关键词： IFN-gamma   Cytokine   Malignancy   Anti-tumor   Immunotherapy  

摘要： Interferon-gamma (IFN-gamma) is recognized for its ability to inhibit cell growth, promote programmed cell death, and stimulate immune responses against tumor progression. However, cancerous cells exploit IFN-gamma by producing factors that suppress anti-tumor immune responses. Exploring the diverse functions of IFN-gamma can offer fresh perspectives for cancer research and the development of immune-based therapies. IFN-gamma plays a multifaceted role in the immune system, which includes aiding in boosting the effectiveness of cancer immunotherapy, particularly immune checkpoint inhibitor therapy, by triggering the expression of checkpoint molecules like PD-L1 on tumor cells. Conversely, it can also diminish the effectiveness of immunotherapy by contributing to tumor resistance. Moreover, the level of IFN-gamma present inside the microenvironment of the tumor appears to dictate whether IFN-gamma acts as a pro-tumor or anti-tumor response. Therefore, enhanced comprehension of IFN-gamma's multifaceted actions can revolutionize approaches to cancer biology and intervention strategies targeting the immune system. This review provides an overview of the regulatory roles of IFN-gamma in cancer and immunology.

关键词： Orthodontic tooth movement   Periodontal ligament   PDL fibroblasts   Tumor necrosis factor   Osteogenic differentiation   Kieferorthop & auml   dische Zahnbewegung   Parodontalligament   PDL-Fibroblasten   Tumornekrosefaktor   Osteogene Differenzierung  

摘要： AimsTo investigate the effect of tumor necrosis factor (TNF) on the growth of human periodontal ligament (PDL) cells, their osteogenic differentiation and modulation of their matrix secretion in *** influence of 10 ng/ml TNF on proliferation and metabolic activity of PDL cells was analyzed by cell counting (DAPI [4',6-diamidino-2-phenylindole] staining) and the MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay. In addition, cells were cultured under control conditions and osteogenic conditions (media containing 10 mM beta-glycerophosphate). Quantitative expression analysis of genes encoding the osteogenic markers alkaline phosphatase (ALP), collagen type I alpha 1 chain (COL1A1), osteoprotegerin (OPG), and osteopontin (OPN) was performed after 7 and 14 days of cultivation. Calcium deposits were stained with alizarin *** studies showed that 10 ng/ml TNF did not affect the survival and metabolic activity of PDL cells. Quantitative expression analysis revealed that long-term cultures with TNF impaired osteogenic cell fate at early and late developmental stages. Furthermore, TNF significantly reduced matrix secretion in PDL *** present data confirm TNF as a regulatory factor of proinflammatory remodeling that influences the differentiation behavior but not the metabolism and cell proliferation of the periodontium. Therefore, TNF represents an interesting target for the regulation of orthodontic remodeling processes in the periodontium. ZieleIn-vitro-Untersuchung des Einflusses von Tumornekrosefaktor (TNF) auf das Wachstum humaner PDL(Parodontalligament)-Zellen, ihre osteogene Differenzierung und die Modulation ihrer *** Einfluss von 10 ng/ml TNF auf Proliferation und metabolische Aktivit & auml;t der PDL-Zellen wurde anhand der Zellz & auml;hlung (DAPI [4',6-Diamidino-2-Phenylindol]-F & auml;rbung) und des MTS (3-(4,5-Dimethylthiazol-2-yl)-5-(3-Carboxymetho

关键词： Ulcerative colitis   Interleukin-23   Interleukin-17   Mirikizumab  

摘要： Interleukin-17 (IL-17) has been suggested to have a protective effect on the intestinal mucosa. The administration of an anti-IL-17 receptor monoclonal antibody has been associated with the onset of inflammatory bowel disease. We present a case of ulcerative colitis caused by secukinumab, an anti-IL-17 receptor A monoclonal antibody, that was treated with mirikizumab, a p19-directed antibody against IL-23. A man in his 20 s with psoriasis vulgaris was administered secukinumab at the dermatology department of our hospital. After the induction of secukinumab therapy, he gradually developed diarrhea, and after 4 months, bloody stools were observed. The patient was diagnosed with left-sided ulcerative colitis based on the findings of a colonoscopic examination. Secukinumab was discontinued and prednisolone was started;however, there was little improvement. His symptoms improved with the introduction of mirikizumab, and the condition is now clinically and endoscopically stable. In this case, an anti-IL-23 antibody was effective against ulcerative colitis induced by an Il-17A antibody agent. Although IL-23 exists upstream of the Th17 system, mirikizumab, an anti-IL-23 antibody preparation, has been shown to have the potential to alleviate UC.

关键词： Rheumatoid arthritis   TNF-alpha   IL-6R   Fenobody   GelMA microneedle  

摘要： Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease characterized by inflammatory imbalance. The cytokine-targeted therapy is a non-traditional form of RA treatment that is mighty effective but poses the challenge of pharmaceutical storage conditions, professional injection, frequent injection administrations and poor patient adherence, and due to individual differences in sensitivity to TNF-alpha and IL-6R, monotherapy with a single antibody is effective in fewer than 30 % of cases. Hence, to address these issues, we have developed a macromolecule polymer GelMA microneedle sustained-release platform for transdermal delivery of a dual-specific fenobody targeting TNF-alpha and IL-6R in an arthritic rat model. The results demonstrated that the IL-6R-TNF-alpha-fenobody exhibited enhanced specificity and affinity and an extended half-life. IL-6R-TNF-alpha-fenobody effectively neutralizes rhTNF-alpha-induced cytotoxicity in L929 cells, while inhibiting the phosphorylation of I kappa B alpha and p65 in the classical NF-kappa B signaling pathway, and significantly blocks JAK-dependent phosphorylation of STAT3, thereby exerting its anti-inflammatory effects via multiple signaling pathways. The GelMA hydrogel microneedle sustained-release platform facilitates controlled cargo delivery to alleviate the inflammatory environment and reduce over-activated synoviocyte activity, thus promoting bone and joint regeneration. In collagen-induced arthritis (CIA) rats, cross-linked gelatin microneedles demonstrated high mechanical strength, facilitating the effective delivery of fenobodies to the dermis for optimal microcirculation, reduced levels of inflammatory factors, this strategy significantly inhibited the progression of RA. Overall, the IL-6R-TNF-alpha-Fenobody therapy promoted bone and joint regeneration by synergistic inflammation-resolving, osteogenesis. Excitingly, the microneedle group showed comparable treatment outcomes to the injection group, providing a