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关键词： Asthma   Benralizumab   Mepolizumab  

摘要： CASE REPORT: A 24-year-old woman with asthma (2013) and allergic rhinitis (2014) was treated for 3 years with subcutaneous immunotherapy, inhaled salmeterol/fluticasone, and external antihistamines. She presented to our department (2019). Upon admission, her asthma persisted with uncontrolled asthma, daily use of a rescue inhaler, and persistent moderate-severe rhinitis. Asthma treatment was adjusted according to guidelines, reaching step 4 of treatment, with persistent lack of control (ACT 16 points), meeting criteria for starting Benralizumab 30 mg (July 26, 2024). Two doses were completed with clinical improvement (ACT). However, during two doses, the patient presented with fever, headache, myalgia, and arthralgia, so treatment was discontinued. Symptoms worsened. A decision was made to switch from the biotechnological agent to mepolizumab (February 4, 2025), with adverse effects after the third dose. CONCLUSION: A percentage of patients with asthma presented with severe symptoms, 80% with an eosinophilic phenotype, associated with difficult control and increased exacerbations. Monoclonal antibodies are indicated in these patients. Benralizumab, which targets IL-5Rα, induces eosinophil depletion through antibody-mediated cytotoxicity. Several studies (MELTEMI) have been conducted to evaluate the safety of long-term use. The most common non-serious adverse effects include upper respiratory tract viral infections (47.3%), while less common adverse effects are headache and arthralgia, which account for 20.9% and 6.4%. Biotechnological agents reduce exacerbations, reduce corticosteroid use, and improve control and quality of life. However, they are not exempt from adverse effects, and even the less common ones should be identified to assess continued treatment.;REPORTE DE CASO: Mujer de 24 años, con asma(2013) y rinitis alérgica(2014), tratada con inmunoterapia subcutánea durante 3 años, salmeterol/fluticasona inhalado y antihistamínicos por unidad externa. Acude a n

关键词： DNA vaccine   immune response   neoantigen   recombinant IL-7   breast cancer  

摘要： Cancer neoantigens are tumor-specific antigens considered to be promising targets for cancer immunotherapy. Neoantigens typically arise from genetic alterations in protein-coding regions, but they can also originate from disordered post-transcriptional and post-translational modifications, aberrant RNA splicing, or proteasomal misprocessing [1,2,3,4,5]. Unlike tumor-associated antigens (e.g., PSA, HER2, MUC1), neoantigens are not expressed in normal tissues and are therefore not subject to central mechanisms of immune tolerance, making them highly attractive targets for immunotherapy [5,6]. Various bioinformatic approaches exist to identify candidate neoantigens for personalized vaccine therapy [3,7,8,9]. Research from our group and others has validated these approaches both in pre-clinical and clinical settings [4,5,7,10]. Personalized cancer vaccines (PCVs) possess the ability to expand T cell populations toward specific target antigens, have proven to be safe in clinical translation, and in initial studies, are associated with prolonged survival in cancer patient populations [1,7,10].Female C57BL/6 mice (stock number 000664) were purchased from The Jackson Laboratory (Bar Harbor, ME, USA). All experiments were performed on animals 6–10 weeks of age. Animal studies were approved by the Institutional Animal Studies Committee of Washington University School of Medicine. Masking or blinding was not implemented in this study.E0771 is a murine breast cancer cell line of C57BL/6 (H-2b) origin [25]. The cell line was carried in RPM1640 media (Gibco, Billings, MT, USA) supplemented with 10% FBS (Atlanta Biologicals, Oakwood, GA, USA), 1% penicillin-streptomycin, L-glutamine, sodium pyruvate, and non-essential amino acid (Gibco, Billings, MT, USA).Neoantigens were identified and cloned into the mammalian expression plasmid pcDNA 3.1(+) as previously described [26]. Polyepitope plasmid DNA was amplified in Escherichia coli DH5α (Invitrogen, Waltham, MA, USA) and purified us

关键词： Arthritis   Autoimmunity   Cell biology   Proteoglycans   Rheumatology  

摘要： Rheumatoid arthritis (RA) is a common systemic autoimmune disorder. Fibroblast-like synoviocytes (FLS) have emerged as an attractive target for non-immunosuppressive RA therapy, but there are no approved drugs targeting FLS. The receptor protein tyrosine phosphatase sigma (PTPRS) negatively regulates FLS migration and has been proposed as a target for FLS-directed RA therapy. Here we examined the impact of sequence variations on efficacy of an FLS-targeted biologic comprised of Fc-fused PTPRS immunoglobulin (IgG)-like domains Ig1 and Ig2 (Ig1&2-Fc). Engineering the linker and Fc tag improved effectiveness of human Ig1&2-Fc in assays of FLS migration and a mouse model of arthritis. Treatment of mice with Ig1&2-Fc over four months revealed no signs of toxicity or organ pathology. Finally, we show potential of Ig1&2-Fc co-administration in combination or as a bispecific fusion with a tumor necrosis factor alpha inhibitor (TNFi). Combination treatment of mouse tumor necrosis factor receptor 2 (mTnfr2) with Ig1&2-Fc resulted in increased efficacy in suppressing arthritis beyond single agent treatment. When administered as a dual-action bispecific, Ig1&2 fused to mTnfr2 proved more efficacious at suppressing arthritis than mTnfr2 alone. This study illustrates the potential of Ig1&2-Fc as a combination or bispecific therapy with DMARDs to improve patient outcomes in RA.

关键词： adoptive T cell therapy   cancer immunotherapy   T cell engineering   T cell receptor (TCR) T cell therapy  

摘要： Adoptive T cell therapies have shown limited efficacy against solid tumors due in part to immunosuppressive cues such as from TGF-β and insufficient survival/proliferative signals within the tumor microenvironment (TME). We engineered chimeric immunomodulatory fusion proteins (IFPs) that convert immunosuppressive TGF-β signals into proliferative/survival Interleukin 2 (IL-2) signals in T cells. Chimeric TGF-βR/IL-2R IFPs were constructed by fusing extracellular domains of the TGF-β receptor chains with intracellular domains of IL-2Rβ and IL-2Rγ to enable TGF-β binding to trigger STAT5 phosphorylation and activate the downstream IL-2 pathway. In human primary CD8+ T cells, select IFP designs robustly induced p-STAT5 upon exposure to TGF-β1, and simultaneously reduced canonical SMAD2/3 signaling. IFP-expressing T cells proliferated and displayed enhanced viability in response to TGF-β1, effectively leveraging TGF-β-rich conditions to outcompete nontransduced cells. Transcriptomic analyses revealed that IFP signaling promoted T cell activation and allowed maintenance of stemness during culture with TGF-β. Functionally, coexpressing IFPs with a mesothelin-specific T cell receptor improved tumor killing and promoted T cell expansion in the presence of TGF-β1, highlighting both neutralization of TGF-β-mediated suppression and enhanced proliferation. TGF-βR/IL-2R IFPs appear promising for reprogramming the signals T cells receive in the TME and improving efficacy of adoptive T cell therapy in solid tumors.

关键词： chronic inflammatory disease and genetic polymorphism   IL-13   rs20541   SNP  

摘要： Over the years, accumulating evidence has been associating interleukin-13 gene (IL-13) variants with a wide array of chronic inflammatory diseases. Also, recent findings have associated the potential role of a single nucleotide polymorphism (SNP) of IL-13, rs20541, to promote either anti- or pro-inflammatory responses in chronic inflammatory diseases. Although rs20541 has been widely associated with various immune-related and inflammatory conditions, its precise functional relevance in the pathogenesis of human diseases has yet to be fully clarified. Nonetheless, its consistent associations and known effects on IL-13 signalling underscore its potential biological importance. Hence, this meta-analysis aimed to investigate the associations between IL-13 SNP rs20541 with distinct groups of chronic inflammatory diseases. Eligible studies were selected from seven databases including PubMed, EBSCO Host (all databases), Medline, CINAHL Plus, Scopus, SNPedia and GWAS. In total, 45 case-control studies with 16,045 cases and 23,312 controls were categorised into four major groups: atopic, cardiopulmonary and autoimmune diseases as well as cancer and tumour. While no consistent associations emerged for asthma or overall atopic and cardiopulmonary groups, protective associations for psoriasis and glioma were observed across multiple genetic contrasts. The A allele of rs20541 was significantly associated with higher risk of chronic obstructive pulmonary diseases (COPDs) [1.17 (1.03-1.32)] but reduced risk of cardiovascular diseases (CVDs) [0.87 (0.75-1.00)], psoriasis [allele model: 0.71 (0.65-0.77);dominant model: 0.69 (0.62-0.76)], overall cancer [allele model: 0.82 (0.66-0.98);dominant model: 0.82 (0.67-0.98) and glioma [allele model: 0.82 (0.68-0.95);dominant model: 0.72 (0.57-0.87)]. In subgroup analysis and meta-regression, sources of between-study heterogeneity were associated with ethnicity, age, gender and sample size in respective disease groups (p(z) < 0.05, p(res) >

关键词： ANCA   glomerulonephritis   immunotherapy   interleukin-2   T cells  

摘要： Background and hypothesis Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) is a major cause of glomerulonephritis (GN) and kidney failure and current therapies are often limited by significant toxicity and limitations. Regulatory T cells (Tregs) play a crucial role in maintaining immune tolerance, and their dysfunction has been implicated in AAV pathogenesis. Low dose interleukin-2 (IL-2) has emerged as a promising strategy to selectively expand Tregs and restore immune balance in several autoimmune diseases. However, low dose IL-2's therapeutic potential in AAV remains unclear, warranting further investigation into its immunoregulatory effects in experimental AAV *** We tested the therapeutic efficacy of low dose IL-2 therapy (25 000 international units/day) in an experimental murine model of AAV, specifically anti-myeloperoxidase (MPO) GN, using C57BL/6J mice. Both passive and active models of anti-MPO GN were used to assess IL-2's effects across different disease *** In GN induced by passive transfer of anti-MPO antibodies, low dose IL-2 increased intrarenal Treg numbers, limited macrophage recruitment, and reduced macrophage pro-inflammatory phenotype in kidneys, demonstrating anti-inflammatory effects on innate immunity. However, these immunological changes did not translate into improvement in kidney injury. In T-cell mediated active anti-MPO GN induced by MPO immunization and triggered by anti-glomerular basement membrane globulin, preventative IL-2 therapy increased splenic Tregs, attenuated anti-MPO-specific Th1/Th17 responses and limited structural and functional kidney injury. In established autoimmunity, mice treated with low dose IL-2 from 12 days after MPO immunization also expanded splenic Tregs. However, effector T-cell responses were also enhanced and glomerular injury was increased. To more specifically target Tregs and minimize low dose IL-2's potential to promote effector leukocytes, we administered

关键词： entry   HIV   membrane fusion   PLSCR1   restriction factor  

摘要： Human phospholipid scramblase 1 (PLSCR1) is an interferon-stimulated gene (ISG) that inhibits viral infections through various mechanisms. Here, we identify PLSCR1 as a host restriction factor that inhibits HIV-1 entry by impairing membrane fusion mediated by the envelope glycoprotein (Env). Using multiple cell types including the human SupT1 T cell line and purified CD4⁺ T cells, we demonstrate that PLSCR1 inhibits the replication of HIV-1 with diverse tropisms and subtypes, as well as HIV-2 and SIV. Mechanistically, we find that PLSCR1 blocks viral entry and cell-to-cell transmission, in part by restricting HIV-1 virion–cell and cell–cell fusion without affecting CD4 or CXCR4 expression or virus binding to the cell surface. Collectively, these findings establish PLSCR1 as a broad-spectrum lentiviral restriction factor that acts at the membrane fusion stage, thereby expanding our understanding of ISG-mediated antiviral defense. Copyright © 2025 the Author(s).

关键词： 蠲哮汤   支气管哮喘   气道重塑   细胞间黏附分子-1   TGF-β   IL-4  

摘要： 目的：探究不同剂量蠲哮汤对支气管哮喘大鼠气道重塑及TNF-β/IL-4表达的影响。方法：60只大鼠随机分为正常组（10只）和造模组（50只）。造模组使用卵蛋白10 mg+氢氧化铝200 mg致敏，造模第15天给予2%卵清蛋白雾化，进一步刺激大鼠哮喘发作，每天雾化1次，每次30 min，连续干预4周。将造模成功的大鼠随机分为模型组、地塞米松组和蠲哮汤低、中、高剂量组，每组10只。造模第16天，地塞米松组灌胃0.2 mg/kg地塞米松，蠲哮汤低、中、高剂量组灌胃0.36、0.72、1.44 g/kg蠲哮汤水煎液，正常组和模型组大鼠均灌胃等量生理盐水，每日1次，连续6周。ELISA法检测各组大鼠血清中细胞间黏附分子-1(ICAM-1)水平；Masson染色并计算大鼠支气管管壁厚度（W/pi）和支气管平滑肌厚度（S/Pi）;qRT-PCR及免疫印迹检测肺组织中转化生长因子-β(TGF-β)和白细胞介素-4(IL-4)mRNA表达。结果：与正常组比较，模型组给药后第2、6周大鼠血清中ICAM-1含量、W/Pi值、S/Pi值、TGF-β和IL-4水平均升高（P <0.05）；与模型组比较，蠲哮汤低、中、高剂量组和地塞米松组大鼠给药后第2、6周血清中ICAM-1含量、W/Pi值、S/Pi值、TGF-β和IL-4水平表达均显著降低（P <0.05），且蠲哮汤各组呈剂量依赖；与地塞米松组比较，蠲哮汤高剂量组大鼠给药后第2、6周血清中ICAM-1含量、W/Pi、S/Pi值、TGF-β和IL-4表达差异无统计学意义（P> 0.05）。结论：蠲哮汤可降低哮喘大鼠血清中ICAM-1水平和W/Pi、S/Pi值，抑制肺组织中TGF-β、IL-4表达，进而减轻哮喘大鼠气道炎症，延缓哮喘气道重塑。

关键词： Apoptosis   Melanocytes   Oxidative stress   Peripheral blood mesenchymal stem cells   Vitiligo  

摘要： Peripheral blood mesenchymal stem cells (PBMSCs) are a less invasive and more accessible source of adult multipotent stem cells than bone marrow mesenchymal stem cells (BMMSCs), because their collection does not involve anaesthesia and the risk of complications. In the present study, we observed that PBMSCs alone exhibited a higher concentration of IL-10 in the supernatant when cultured independently. Furthermore, the supernatant from the Transwell co-culture system of PBMSCs with HO-induced oxidative stress in B16 melanoma cells, which serves as an in vitro model for vitiligo, demonstrated elevated levels of IL-10. Western blot analysis revealed that the PI3K/AKT signaling pathway was activated in B16 melanoma cells, as evidenced by increased phosphorylation of AKT, enhanced expression of the antioxidant enzyme HO-1 and the anti-apoptotic protein Bcl-2, alongside decreased expression of the pro-apoptotic proteins Bax and Cleaved-Caspase 3. Notably, these effects were inhibited by the IL-10 neutralizing antibody (AB9969) and the PI3K inhibitor (LY294002). Collectively, our findings suggest that PBMSCs may mitigate oxidative damage and apoptosis in B16 melanoma cells through the paracrine activation of the PI3K/AKT signaling pathway by IL-10. This approach offers a novel, readily available, and minimally invasive cellular therapeutic strategy for vitiligo while also providing a theoretical basis for targeting antioxidant pathways in treatment.

关键词： pseudorabies virus   DNA polymerase processivity factor   pUL42   cGAS-STING   interferon  

摘要： Pseudorabies (PR), caused by the PR virus (PRV), is an acute infectious disease in livestock and various wild animals. PRV has developed several immune evasion mechanisms to antagonize the host's antiviral immune response. However, the precise role of PRV-encoded proteins in regulating the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon (IFN) gene (STING) signal for immune evasion remains unclear. In this study, we demonstrate that the PRV UL42 protein (pUL42) inhibited cGAS-mediated antiviral signaling by modulating cGAS recognition of dsDNA. Mechanistically, pUL42 interacts with the DNA-binding domain of cGAS, thereby inhibiting its recognition of double-stranded DNA, leading to the inhibition of its dimerization and oligomerization activation. Furthermore, knocking down the expression of the Ul42 gene in the PRV genome diminishes the antagonistic effect on type I IFN production and inhibits PRV replication. Ultimately, we have established that pUL42 targets cGAS-mediated signaling, thereby inhibiting the production of type I IFN and facilitating viral replication. Overall, our findings suggest that PRV pUL42 functions as an antagonist to evade the host's antiviral response by targeting the cGAS-STING *** GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) axis is essential for host resistance to DNA virus infections by regulating type I interferon production. However, whether pseudorabies virus (PRV) antagonizes the cGAS-STING signaling pathway to immune evasion is not fully investigated. In this study, we clearly demonstrated that the PRV pUL42 protein inhibits the recognition of double-stranded DNA of cGAS, leading to inhibiting the oligomerization and activation of cGAS, thereby suppressing the cGAS-mediated host antiviral immune responses. Taken together, our results reveal a novel strategy employed by PRV to evade host defenses, which will provide theoretical support for the development of anti-PRV drugs for the prevention