Clinical and experimental immunology最新文献

{"title":"Amlexanox targeted inhibition of TBK1 regulates immune cell function to exacerbate DSS-induced inflammatory bowel disease.","authors":"Lu Hui, Meng-Ke Huang, Qing-Kai Dai, Cheng-Lin Miao, Yun-Long Yang, Chen-Xi Liu, Ting Liu, Yong-Mei Jiang","doi":"10.1093/cei/uxae082","DOIUrl":"10.1093/cei/uxae082","url":null,"abstract":"<p><p>Amlexanox (ALX) is a small-molecule drug for the treatment of inflammatory, autoimmune, metabolic, and tumor diseases. At present, there are no studies on whether ALX has a therapeutic effect on inflammatory bowel disease (IBD). In this study, we used a mouse model of dextran sulfate sodium-induced colitis to investigate the effect of ALX-targeted inhibition of TBK1 on colitis. We found that the severity of colitis in mice was correlated with TBK1 expression. Notably, although ALX inhibited the activation of the TBK1-NF-κB/TBK1-IRF3 pro-inflammatory signaling pathway, it exacerbated colitis and reduced survival in mice. The results of drug safety experiments ruled out a relationship between this exacerbating effect and drug toxicity. In addition, ELISA results showed that ALX promoted the secretion of IL-1β and IFN-α, and inhibited the production of cytokines IL-6, TNF-α, IL-10, TGF-β, and secretory IgA. Flow cytometry results further showed that ALX promoted T-cell proliferation, activation, and differentiation, and thus played a pro-inflammatory role; also, ALX inhibited the generation of dendritic cells and the polarization of macrophages to M1 type, thus exerting anti-inflammatory effect. These data suggest that the regulation of ALX on the function of different immune cells is different, so the effect on the inflammatory response is bidirectional. In conclusion, our study demonstrates that simply inhibiting TBK1 in all immune cells is not effective for the treatment of colitis. Further investigation of the anti-inflammatory mechanism of ALX on dendritic cells and macrophages may provide a new strategy for the treatment of IBD.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11771202/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nck1 regulates the in vitro development of human regulatory T cells through AKT pathway.","authors":"Aussanee Nuiyen, Donruedee Sanguansermsri, Jarun Sayasathid, Kanthachat Thatsakorn, Siraphop Thapmongkol, Jatuporn Ngoenkam, Sutatip Pongcharoen","doi":"10.1093/cei/uxaf011","DOIUrl":"10.1093/cei/uxaf011","url":null,"abstract":"<p><p>T cell receptor (TCR) signalling is crucial in determining the fate of thymocyte differentiation in the thymus. The high-avidity interaction between TCR and self-peptide-MHC complexes induces development of regulatory T cells (Tregs), lineage commitment for which is controlled by expression of transcription factor Forkhead box P3 (FoxP3). The non-catalytic region of the tyrosine kinase (Nck) comprises two members, Nck1 and Nck2, with Nck1 playing a dominant role in TCR-mediated T cell activation and function. Nck's role, while established in thymocyte development, remains unelucidated in development of Tregs. In this study, we aimed to determine the function of Nck1 in the in vitro development and differentiation of human thymocytes. Human thymocytes were transfected with shRNA plasmid to silence Nck1 expression. The number of FoxP3+ Tregs decreased noticeably in Nck1 knockdown thymocytes after co-cultivation with myeloid dendritic cells (mDCs) and thymic epithelial cells for 14 days. Furthermore, decreased phosphorylation of AKT and FoxO1 was observed in Nck1-silenced thymocytes, in association with reduced FoxO1 nuclear localization. Taken together, these findings identify the pivotal role of Nck1 in Treg development.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11923542/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intratumoral injection of R848 and poly(I:C) synergistically promoted antitumor immune responses by reprogramming macrophage polarization and activating DCs in lung cancer.","authors":"Shuanghui Chen, Linzhao Li, Haohua Yuan, Huan Gui, Quan Wan, Mengjiao Wang, Hang Lv, Chenglv Wang, Lan Zhu, Yingjie Nie, Xiangyan Zhang","doi":"10.1093/cei/uxae110","DOIUrl":"10.1093/cei/uxae110","url":null,"abstract":"<p><strong>Introduction: </strong>Immunotherapy has rapidly become a primary treatment option for many lung cancer patients because of its success in treating this prevalent and deadly disease. However, the success of immunotherapy relies on overcoming the immunosuppressive tumor microenvironment, making remodeling this environment a potential strategy for lung cancer therapy. Research suggests that Toll-like receptor (TLR) agonists can impede tumor growth by promoting the conversion of tumor-associated macrophages into an M1-like state or enhancing dendritic cell development. However, there is insufficient research on the combined use of TLR agonists for treating lung cancer.</p><p><strong>Methods: </strong>In this study, we examined how TLR agonists such as resiquimod (R848) and poly(I:C) impact lung cancer treatment when used alone or in combination. In vitro, the regulatory functions and mechanisms of R848 and poly(I:C) were analyzed in primary macrophages, RAW264.7 cells, and primary dendritic cells (DCs). Tumor treatment efficacy was assessed in vivo with a Lewis lung carcinoma (LLC) mouse model.</p><p><strong>Results: </strong>The combination of R848 + poly(I:C) enhances the transformation of macrophages from the M2 phenotype to the M1 phenotype by increasing inflammatory cytokine levels. The percentage of mature DCs expressing MHC-II+CD11c+ and CD86+ cells was significantly higher in the R848 + poly(I:C) group compared with the other groups. Intratumoral injection of the synergistic combination of R848 + poly(I:C) suppressed tumor growth by increasing the M1:M2 ratio in TAMs, activating DCs, and attracting CD4+ and CD8+ T cells.</p><p><strong>Conclusion: </strong>R848 + poly(I:C) synergistically induces M1-like polarization of macrophages, activates DCs, and promotes effective antitumor immunity in mice with subcutaneous LLC tumors.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12062569/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Experimental induction of anti-muscarinic type-3-receptor extracellular loop antibodies by immunization with 4-hydroxy-2-nonenal modified Ro60 and unmodified Ro60.","authors":"Biji T Kurien, Devavrat Dave, Martha Tsaliki, Syed M S Quadri, Valerie M Lewis, Robert Hal Scofield","doi":"10.1093/cei/uxae114","DOIUrl":"10.1093/cei/uxae114","url":null,"abstract":"<p><strong>Objective: </strong>Sjögren's Disease (SjD) subjects have decreased lacrimal/salivary gland function. Studies have proposed that autoantibodies targeting G-protein-coupled muscarinic acetylcholine-type-3-receptor (M3R) are potential clinical markers for SjD. We hypothesized that rabbits/mice immunized with 4-hydroxy-2-nonenal (HNE)-modified/unmodified Ro60 will develop an autoimmunity, specifically a SjD phenotype, thus expressing increased levels of anti-M3R antibodies.</p><p><strong>Methods: </strong>We immunized two rabbits each with 10 mM HNE-modified Ro60/unmodified Ro60 antigen or Ro274-290/Ro413-428/Ro500-517 Ro60 peptides. Two rabbits each were immunized with either M3R second extracellular loop (ECL2) or M3R ECL3 peptide. Finally, five groups of BALB/c mice were immunized as follows-Group-I immunized with Ro60, Groups-II-IV immunized with Ro60 modified with 0.4 mM (low), 2 mM (medium), and 10 mM (high) HNE, respectively and Group-V-Freund's adjuvant. Serum antibodies to M3R ECL2/ECL3/Ro60/La or Sm were detected by ELISA. Functional assays were also performed.</p><p><strong>Results: </strong>Immunization with HNE-modified Ro60/unmodified Ro60 antigen or Ro274/Ro 413/Ro500 peptides induced a rapid intermolecular epitope spreading to M3R ECL2/ECL3, especially to M3R ECL3 in HNE-Ro immunized rabbits. These animals did not bind to scrambled M3R peptides. Ro60-immunized rabbit IgG inhibited M3R activity in a functional assay. Rabbits immunized with ECL2/ECL3 developed high reactivity to Ro60 but not against Sm/RNP. We found a differential antibody-induction against M3R ECL2 with Group-3 mice developing significant reactivity.</p><p><strong>Conclusion: </strong>Our data show induction of increasing anti-M3R antibodies in rabbits immunized with Ro60/HNE-Ro60 or Ro60 peptides and differential induction of these antibodies in mice immunized with Ro60 modified with increasing HNE. These findings suggest that M3R ECL2/ECL3 are involved in SjD autoimmunity progression.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11748001/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142806241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery and Phase 1 study of a novel monoclonal antibody against human IL-1β for the treatment of IL-1β-mediated diseases.","authors":"Minseon Cho, Susan H Tam, Lihua Shi, Isa Fung, Mark Tornetta, Gabriela A Canziani, Man-Cheong Fung, Mark L Chiu, Chao Han, Di Zhang","doi":"10.1093/cei/uxaf009","DOIUrl":"10.1093/cei/uxaf009","url":null,"abstract":"<p><p>Interleukin-1β (IL-1β) is a key mediator of innate immunity against pathogen infections. However, dysregulated IL-1β activity is associated with various autoinflammatory, autoimmune, degenerative, atherosclerotic diseases, and cancers. Biologic drugs that neutralize excess IL-1β activity, such as canakinumab, have been effective in treating IL-1β-mediated diseases. This article reports the discovery and development of a novel humanized anti-IL-1β antibody, designated as TAVO103A, which exhibited potent binding affinities to human and monkey IL-1β. TAVO103A demonstrated more potent neutralization of IL-1β activities compared to canakinumab in multiple assays, including tests on the IL-1β-driven signal transduction cascade, inflammatory cytokine release from MRC-5 cells, chemokine release from A549 cells, and the proliferation of D10.G4.1 helper T cells. Ex vivo studies showed that TAVO103A effectively neutralized IL-1β-mediated release of pro-inflammatory cytokines from peripheral blood mononuclear cells. In addition, TAVO103A exhibited dose-dependent efficacy in a knee joint inflammation mouse model. TAVO103A underwent Fc engineering to reduce binding to Fcγ receptors, increase affinity to FcRn receptors, and enhance its resistance to proteolytic degradation. In a Phase 1 study, TAVO103A was found to be safe, well tolerated, and demonstrated a median half-life of 63 days in healthy subjects. By recognizing a different epitope, TAVO103A provided more potent neutralization of IL-1β activities, a longer circulating half-life, and improved safety profiles compared to canakinumab, positioning it to be a potential best-in-class therapeutic option for various IL-1β-mediated diseases.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11923543/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"sB7-H4 is a diagnostic biomarker in epithelial ovarian cancer and correlates to platinum resistance.","authors":"Ying Zhou, Jingluan Tian, Yu Shen, Hansi Liang, Youguo Chen, Juan Wang, Yanzheng Gu","doi":"10.1093/cei/uxae084","DOIUrl":"10.1093/cei/uxae084","url":null,"abstract":"<p><p>Ovarian cancer (OC), with its high mortality rate among gynecological cancers, is often diagnosed late due to the lack of early diagnostic symptoms and biomarkers. The tumor immune microenvironment has become a focal point in cancer diagnostic and therapeutic research. Among these, B7-H4, a checkpoint protein, plays a crucial role in immune regulation and tumor suppression, contributing to immune evasion within the tumor microenvironment. This study aims to identify the concentration of soluble B7-H4(sB7-H4) in the plasma of patients with OC and to evaluate its clinical significance. Through a comprehensive analysis involving enzyme-linked immunosorbent assay, immunohistochemistry, and multicolor immunofluorescence, we quantified sB7-H4 levels in patient plasma and ascites, correlating these findings with tissue expression and clinical outcomes. Results indicated a strong association between high sB7-H4 levels and advanced disease, surgical outcomes, lymphatic metastasis, and platinum resistance. When compared with traditional biomarkers CA125 and HE4, sB7-H4, especially in conjunction with these markers, enhances the diagnostic accuracy for epithelial ovarian cancer (EOC), offering insights into disease progression and therapeutic efficacy. This comprehensive analysis suggests that sB7-H4 is a promising biomarker for EOC, providing valuable insights into diagnosis, stage differentiation, treatment effectiveness, and prognosis.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11771197/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of vitamin D: a promising pathway to combat neuropsychiatric lupus disorders.","authors":"Thaís Evelyn Karnopp, Gustavo Flores Chapacais, Maria Luísa Gasparini, Natália Garcia Dos Santos, Vinicius da Silva Freitas, Marina Piccoli, Andressa Leite Di Domenico, Lucas Denardi Doria, Nikolas Mateus Pereira de Souza, Alexandre Rieger, Eduarda Correa Freitas, Fernanda Visioli, Odirlei André Monticielo","doi":"10.1093/cei/uxae099","DOIUrl":"10.1093/cei/uxae099","url":null,"abstract":"<p><p>To evaluate neuropsychiatric manifestations in the pristane-induced lupus (PIL) model, as well as to evaluate immunoregulatory effects of vitamin D (vit-D) in the brain of mice with PIL. Eighty female BALB/c mice were divided into six groups with 90 (3 months) and 180 (6 months) days of experimentation: CO3, CO6 (controls), PIL3, PIL6 (pristane-induced lupus), VD3 and VD6 (PIL supplemented with 1,25-dihydroxyvitamin D). Forced-swim, elevated plus maze and Barnes maze were the behavioral tests performed. Expression of pVDR was assessed by immunofluorescence. Brain IgM and IgG deposits were evaluated by double staining fluorescence. Serum IL-6 and IFN-α1 were quantified by ELISA. AUC-ROC curve was also performed for immunoglobulins. PIL and VD showed depressive-like behavior in the forced-swim test and anxious-like behavior in the elevated plus maze test. PIL also presented cognitive and memory impairment in the Barnes maze test. Additionally, PIL and VD presented higher levels of serum IFN-α1, but not IL-6. Mice supplemented with vit-D had reduced IgM and IgG deposits and increased pVDR expression in the brain after 180 days. The AUC-ROC curve demonstrated high sensitivity and specificity for IgM and IgG in the brain. We observed neuropsychiatric manifestations in this model of systemic lupus erythematosus (SLE), strongly corroborating to PIL model being suitable as a neuropsychiatric lupus (NPSLE) model. Vit-D was able to reduce immunoglobulin deposits in the brain and influenced the levels of serum IL-6 in the animals assessed. Also, it improved memory, but it had no effect on depressive and anxious-like behavior.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11773805/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142575496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Response to Letter to the Editor: Type 2 diabetes is associated with the accumulation of senescent T cells.","authors":"Sian M Henson","doi":"10.1093/cei/uxad078","DOIUrl":"10.1093/cei/uxad078","url":null,"abstract":"","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11771188/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9818300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Response to letter to the editor: tubulin beta is not the target of antineutrophil antibodies in primary sclerosing cholangitis.","authors":"Beate Preuß, Reinhild Klein","doi":"10.1093/cei/uxae064","DOIUrl":"10.1093/cei/uxae064","url":null,"abstract":"","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11755840/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141726988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antigen-specific T-cell frequency and phenotype mirrors disease activity in DRB1*04:04+ rheumatoid arthritis patients.","authors":"Cliff Rims, Hannes Uchtenhagen, Kadin Brooks, Bernard Ng, Sylvia E Posso, Jeffrey Carlin, William W Kwok, Jane H Buckner, Eddie A James","doi":"10.1093/cei/uxae102","DOIUrl":"10.1093/cei/uxae102","url":null,"abstract":"<p><p>Rheumatoid arthritis (RA) is associated with high-risk HLA class II alleles known as the \"RA shared epitope.\" Among prevalent shared epitope alleles, study of DRB1*04:04 has been limited. To define relevant epitopes, we identified citrullinated peptide sequences from synovial antigens that were predicted to bind to HLA-DRB1*04:04 and utilized a systematic approach to confirm their binding and assess their recognition by CD4 T cells. After confirming the immunogenicity of 13 peptides derived from aggrecan, cartilage intermediate layer protein (CILP), α-enolase, vimentin, and fibrinogen, we assessed their recognition by T cells from a synovial tissue sample, observing measurable responses to 8 of the 13 peptides. We then implemented a multicolor tetramer panel to evaluate the frequency and phenotype of antigen-specific CD4 T cells in individuals with anti-citrullinated protein antibody-positive RA and controls. In subjects with RA, CILP-specific T-cell frequencies were significantly higher than those of other antigens. The surface phenotypes exhibited by antigen-specific T cells were heterogeneous, but Th1-like and Th2-like cells predominated. Stratifying based on disease status and activity, antigen-specific T cells were more frequent and most strongly polarized in RA subjects with high disease activity. In total, these findings identify novel citrullinated epitopes that can be used to interrogate antigen-specific CD4 T cells and show that antigen-specific T-cell frequency is elevated in subjects with high disease activity.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11754868/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}