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21 pages, 1616 KB  
Review
The Evolution, Current Landscape, and Future Prospects of Oncolytic Virotherapy in Melanoma: Talimogene Laherparepvec and Beyond
by John Smestad, John Rieth, Douglas Laux and Mohammed Milhem
Cells 2025, 14(20), 1620; https://doi.org/10.3390/cells14201620 - 17 Oct 2025
Viewed by 24
Abstract
Oncolytic viruses represent an emerging class of therapeutic agents that have the potential to transform the care of patients with melanoma. In this narrative review, we describe the evolution of oncolytic virus approaches. We begin by describing early investigations using wild type viruses [...] Read more.
Oncolytic viruses represent an emerging class of therapeutic agents that have the potential to transform the care of patients with melanoma. In this narrative review, we describe the evolution of oncolytic virus approaches. We begin by describing early investigations using wild type viruses and then the development of sophisticated Herpes simplex virus 1 (HSV-1) variant constructs such as talimogene laherparepvec (T-VEC) and vusolimogene oderparepvec (Replimune-1, RP1), which incorporate deletions of viral genes and expression of human or synthetic transgenes to promote tumor selectivity, dendritic cell recruitment, antigen presentation, and stimulation of systemic anti-tumor immune responses. We review the status of clinical trials of oncolytic viruses in melanoma, highlight regulatory challenges, and describe important concepts and key remaining questions within the field. While T-VEC remains the only Food and Drug Administration (FDA)-approved oncolytic virus for melanoma treatment, ongoing research focusing on next-generation viral constructs and combination strategies aims to further improve clinical outcomes and expand the applicability of oncolytic virus therapy in melanoma. Full article
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11 pages, 3735 KB  
Communication
Topical Administration of a Mixed Microbial Culture of Lactobacillus paracasei, Pichia membranifaciens and Saccharomyces cerevisiae Significantly Inhibits the Development of Atopic Dermatitis in a Mouse Model Through IL-10 Overexpression by Dendritic Cells
by Mao Kaneki, Chiharu Ohira, Tensei Magami, Aika Hamauzu, Yukari Inaba, Hideo Togase and Tomoki Fukuyama
Biomedicines 2025, 13(10), 2536; https://doi.org/10.3390/biomedicines13102536 - 17 Oct 2025
Viewed by 24
Abstract
Background/Objectives: In this study, we focused on a mixed microbial culture of Lactobacillus paracasei, Pichia membranifaciens, and Saccharomyces cerevisiae (LS) as a new probiotic and examined the therapeutic and preventive effects of topical treatment with LS in a mouse model [...] Read more.
Background/Objectives: In this study, we focused on a mixed microbial culture of Lactobacillus paracasei, Pichia membranifaciens, and Saccharomyces cerevisiae (LS) as a new probiotic and examined the therapeutic and preventive effects of topical treatment with LS in a mouse model of atopic dermatitis (AD). Methods: Immunomodulatory effects of LS were examined with murine dendritic cell lines (DC2.4) by measuring the interleukin (IL)-10 and tumor necrosis factor (TNF) α levels. The anti-inflammatory effects of LS were evaluated in stimulated human epidermal keratinocytes (HaCaTs) by focusing on the production of IL-8 and thymus and activation-regulated chemokine (TARC). Therapeutic and preventive properties of topical treatment with LS (10%) were finally examined in a mouse model of AD developed by topical sensitization to house dust mite ointment. Clinical symptoms, back skin thickness, and transepidermal water loss (TEWL) were monitored weekly, and the immune responses in the auricular lymph nodes were analyzed after necropsy. Results: LS treatment significantly enhanced the secretions of IL-10 and TNFα by DC2.4 cells. IL-8 and TARC production by stimulated HaCaT cells was significantly decreased by co-culturing with LS. Although there were no significant changes in clinical symptoms, skin thickness, or TEWL in the therapeutic setting of the AD mouse model, the number of IgE-positive B cells and IL-4 levels in the local lymph nodes significantly decreased in the LS treatment group. Preventive treatment with LS significantly decreased AD symptoms compared to those in AD control mice. Conclusions: Our findings indicate that the immunomodulatory and anti-inflammatory effects of LS prevent the development of AD. Full article
(This article belongs to the Section Immunology and Immunotherapy)
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15 pages, 1151 KB  
Article
Dendritic Cell-Based Therapeutic Immunization Induces Th1/Th17 Responses and Reduces Fungal Burden in Experimental Sporotrichosis
by Juliana Aparecida Jellmayer, Adriana Fernandes de Deus, Matheus Ricardo Curti Gonçalves, Lucas Souza Ferreira, Francine Alessandra Manente, Larissa Silva Pinho Caetano, Fernanda Luiza Piccineli, Thais Zamberço dos Reis Genari, Beatriz da Cunha Saçaki, Tarcila Pavicic Catalan de Oliveira Campos, Deivys Leandro Portuondo, Alexander Batista-Duharte and Iracilda Zeppone Carlos
Microorganisms 2025, 13(10), 2351; https://doi.org/10.3390/microorganisms13102351 - 14 Oct 2025
Viewed by 237
Abstract
Sporotrichosis is a globally distributed mycosis caused by thermally dimorphic fungi of the Sporothrix schenckii species complex. In Brazil, sporotrichosis is considered endemic and is usually acquired through zoonotic transmission from infected cats. The clinical manifestations may be cutaneous, lymphocutaneous, or systemic, the [...] Read more.
Sporotrichosis is a globally distributed mycosis caused by thermally dimorphic fungi of the Sporothrix schenckii species complex. In Brazil, sporotrichosis is considered endemic and is usually acquired through zoonotic transmission from infected cats. The clinical manifestations may be cutaneous, lymphocutaneous, or systemic, the latter being more commonly observed in immunosuppressed patients. The limited effectiveness of antifungal treatments against this mycosis, particularly in immunocompromised individuals, has led to the search for more effective and safer therapies. Based on several studies demonstrating the efficient use of dendritic cells as tools for the development of antifungal vaccines, this work aimed to evaluate the protective capacity of bone marrow-derived dendritic cells (BMDCs) activated with cell wall proteins of S. schenckii (SsCWP) in mice infected with S. schenckii sensu stricto. BMDCs were stimulated with SsCWP and analyzed for the surface expression of costimulatory molecules as well as proinflammatory cytokine secretion. Subsequently, mice were vaccinated once or twice to assess immunogenicity, and finally, the therapeutic effect of BMDCs on S. schenckii infection was evaluated. Our results show that SsCWP was able to activate BMDCs. Immunization of healthy mice with SsCWP-stimulated BMDCs induced a balanced Th1/Th17-based immune response. Vaccination of mice previously infected with S. schenckii induced a mixed Th1/Th17 response and reduced fungal burden in the spleen. Overall, these findings demonstrate that therapeutic vaccination with SsCWP-stimulated BMDCs improves fungal control, supporting the notion that dendritic cells represent a promising therapeutic strategy against sporotrichosis. Full article
(This article belongs to the Special Issue New Advances in Sporothrix and Sporotrichosis)
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34 pages, 8250 KB  
Review
From Cytokines to Biomarkers: Mapping the Immunopathology of Inflammatory Bowel Disease
by Sarah Baum, Kamron Hamedi, Caroline Loftus, Gannett Loftus, Emily-Rose Zhou and Sergio Arce
Cells 2025, 14(20), 1589; https://doi.org/10.3390/cells14201589 - 13 Oct 2025
Viewed by 499
Abstract
Inflammatory bowel disease (IBD) is a chronic immune-mediated condition of the gastrointestinal tract, characterized by dysregulated inflammatory responses throughout the gastrointestinal tract. It includes two major phenotypes, Crohn’s disease (CD) and ulcerative colitis (UC), which present with varying gastrointestinal and systemic symptoms. The [...] Read more.
Inflammatory bowel disease (IBD) is a chronic immune-mediated condition of the gastrointestinal tract, characterized by dysregulated inflammatory responses throughout the gastrointestinal tract. It includes two major phenotypes, Crohn’s disease (CD) and ulcerative colitis (UC), which present with varying gastrointestinal and systemic symptoms. The pathophysiology of IBD is multifactorial including genetic predisposition, mucosal and epithelial dysfunction, environmental injury, and both innate and adaptive immune response abnormalities. Several predisposing genetic factors have been associated with IBD explaining the strong hereditary risk for both CD and UC. For example, Caspase Recruitment Domain 9 (CARD9) variant rs10781499 increases risk for IBD, while other variants are specific to either CD or UC. CD is related to loss-of-function mutations in the nucleotide oligomerization domain containing the protein 2 (NOD2) gene and Autophagy-Related 16-like 1 (ATG16L1) gene. UC risk is increased particularly in Chinese populations by the A-1661G polymorphism of the Cytotoxic T-lymphocyte antigen 4 (CTLA-4) gene. This abnormal CTLA-4 interferes with B- and T-cell responses causing predisposition to autoimmune conditions. Previous studies suggested that IBD results from breakdown of the adaptive immune system, primarily of T-cells. However, new evidence suggests that a primary breakdown of the innate immune system in both CD and UC increases susceptibility to invasion by viruses and bacteria, with a compensatory overactivation of the adaptive immune system as a result. When this viral and microbial invasion continues, further damage is incurred, resulting in a downward cycle of further cytokine activation and epithelial damage. Released biomarkers also affect the permeability of the epithelial membrane, including lactoferrin, nitric oxide (NO), myeloperoxidase (MPO) and its activation of hypochlorous acid, matrix metalloproteinases (MMPs), especially MMP-9, omentin-1, and others. Increased macrophage and dendritic cell dysfunction, increased neutrophil activity, increased numbers of innate lymphoid cells, increased T-cells with decreased regulatory T-cells (Tregs), and changes in B-cell populations and immunoglobulin (Ig) functions are all associated with IBD. Finally, treatment of IBD has typically consisted of medical management (e.g., aminosalicylates and corticosteroids) and lifestyle modification, and surgical intervention in extreme cases. New classes of medications with more favorable side effect profiles include anti-integrin antibodies, vedolizumab, etrolizumab, and carotegrast methyl. Additionally, fecal microbiota transplant (FMT) is a newer area of research for treatment of IBD along with TNF-blockers, JAK inhibitors, and S1PR modulators. However, expense and long preparation time have limited the usefulness of FMT. Full article
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12 pages, 1630 KB  
Article
HSP90 Inhibition Disrupts 27-Hydroxycholesterol-Induced Inflammatory Signaling in Monocytic Cells
by Jaesung Kim, Munju Kwon, Dongha Park, Nakyung Kang, Yonghae Son, Ninib Baryawno, Byoung Soo Kim, Sik Yoon, Sae-Ock Oh, Dongjun Lee and Koanhoi Kim
Int. J. Mol. Sci. 2025, 26(20), 9963; https://doi.org/10.3390/ijms26209963 (registering DOI) - 13 Oct 2025
Viewed by 186
Abstract
27-Hydroxycholesterol (27OHChol), a cholesterol metabolite, induces inflammatory responses in monocytic cells and promotes their differentiation into mature dendritic cells. Here, we examined whether inhibition of heat shock protein 90 (HSP90) modulates these responses. Treatment with ganetespib, a selective HSP90 inhibitor, significantly reduced chemokine [...] Read more.
27-Hydroxycholesterol (27OHChol), a cholesterol metabolite, induces inflammatory responses in monocytic cells and promotes their differentiation into mature dendritic cells. Here, we examined whether inhibition of heat shock protein 90 (HSP90) modulates these responses. Treatment with ganetespib, a selective HSP90 inhibitor, significantly reduced chemokine CCL2 expression, lowering monocytic cell migration. It also suppressed matrix metalloproteinase-9 (MMP-9) expression and attenuated the lipopolysaccharide (LPS) response otherwise amplified by 27OHChol. Furthermore, ganetespib decreased mature dendritic cell markers (CD80, CD83, CD88) and restored endocytic activity, indicating a less activated state. These changes suggest that HSP90 regulates 27OHChol-induced pro-inflammatory activation via its client proteins. To explore this mechanism, we examined the phosphorylation status of signaling proteins. 27OHChol enhanced phosphorylation of Akt and its downstream targets, S6 and 4E-BP1 within the Akt/mTORC1 pathway. Ganetespib reduced total and phosphorylated Akt and 4E-BP1, and selectively inhibited S6 phosphorylation without altering total protein level. Collectively, these findings demonstrate that HSP90 inhibition by ganetespib mitigates 27OHChol-driven monocytic cell activation through suppression of the HSP90-Akt/mTORC1 axis. Targeting this pathway may provide a promising therapeutic strategy for metabolic inflammation associated with oxysterols. Full article
(This article belongs to the Special Issue Dialogue Between Inflammation and Immunity: From Mechanism to Therapy)
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29 pages, 1600 KB  
Review
Roles of Tumor-Infiltrating Lymphocytes and Antitumor Immune Responses as Predictive and Prognostic Markers in Patients with Breast Cancer Receiving Neoadjuvant Chemotherapy
by Ryungsa Kim, Takanori Kin and Koji Arihiro
Int. J. Mol. Sci. 2025, 26(20), 9959; https://doi.org/10.3390/ijms26209959 - 13 Oct 2025
Viewed by 279
Abstract
Tumor-infiltrating lymphocytes (TILs) are thought to play important roles in tumor shrinkage and survival prolongation in patients with breast cancer receiving neoadjuvant chemotherapy (NAC). TILs are mononuclear immune cells such as lymphocytes and plasma cells, including CD4+ and CD8+ T cells, natural killer [...] Read more.
Tumor-infiltrating lymphocytes (TILs) are thought to play important roles in tumor shrinkage and survival prolongation in patients with breast cancer receiving neoadjuvant chemotherapy (NAC). TILs are mononuclear immune cells such as lymphocytes and plasma cells, including CD4+ and CD8+ T cells, natural killer cells, B cells, macrophages, regulatory T cells (Tregs), and myeloid/dendritic cells. The pre-NAC presence of more T cells and fewer Tregs in biopsy samples of primary breast tumors is known to contribute to tumor shrinkage and prolonged survival. This review was conducted to elucidate these roles in patients with breast cancer treated with NAC. Publications selected for inclusion in this review were identified by a PubMed search for articles published in English, performed using the terms “breast cancer”, “neoadjuvant chemotherapy”, “tumor-infiltrating lymphocyte”, “pathological complete response”, and “immune response”. The search was completed in July 2024. The functional roles of TILs in the achievement of these outcomes may vary by tumor subtype; increases and decreases in TIL levels before and after NAC have been shown to have conflicting effects. Biomarkers have been reported to predict local responses in the tumor microenvironment (e.g., immune-related gene signatures) and systemic immune responses (e.g., neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios). Immune gene signatures and immune cell infiltration do not appear to be universally associated with tumor response or outcome in patients with breast cancer treated with NAC. The functional roles of TILs in breast tumor response and breast cancer survival may vary by tumor subtype, and conflicting results for the same subtypes may be due to differences in NAC regimens, immune responses, tumor heterogeneity, sample size, and the technical methods used to evaluate TILs in tumor samples. Full article
(This article belongs to the Section Molecular Immunology)
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30 pages, 1356 KB  
Review
Immunology of Hypertension: Pathophysiological and Therapeutic Aspects
by Alexander Manzano, Heliana Parra, Daniela Ariza, Maria Marquina, Pablo Duran, María J. Calvo, Manuel Nava, Omar Ross, Julio César Contreras-Velásquez, Diego Rivera-Porras and Valmore Bermúdez
Int. J. Mol. Sci. 2025, 26(20), 9921; https://doi.org/10.3390/ijms26209921 - 12 Oct 2025
Viewed by 389
Abstract
Hypertension affects over 1.39 billion people globally, causing 9.4 million deaths annually. This paper examines the intricate relationship between the immune system and hypertension, highlighting the contributions of both innate and adaptive immune responses. The innate response, involving natural killer (NK) cells, macrophages, [...] Read more.
Hypertension affects over 1.39 billion people globally, causing 9.4 million deaths annually. This paper examines the intricate relationship between the immune system and hypertension, highlighting the contributions of both innate and adaptive immune responses. The innate response, involving natural killer (NK) cells, macrophages, toll-like receptors (TLRs), and dendritic cells, contributes to organ damage and inflammatory responses, exacerbating hypertension. Adaptive immunity, particularly T cells, further exacerbates vascular and renal dysfunction through the release of cytokines such as IFN-γ, IL-17A, and TNF-α, ultimately leading to multisystem damage. Therapeutic strategies targeting these immune responses are being explored, including immunosuppressants such as mycophenolate mofetil (MMF) and methotrexate (MTX), as well as monoclonal antibodies against IL-1β and TNF-α. While these strategies show promise, further research is needed to evaluate their efficacy and safety. Furthermore, this paper highlights the potential benefits of immunological approaches in managing the root causes of hypertension, offering an alternative to conventional therapies focused on the renin–angiotensin–aldosterone system. In conclusion, this work highlights the immune mechanisms in the hypertension pathogenesis, identifying them as potential therapeutic targets for enhanced management and improved patient outcomes. Full article
(This article belongs to the Section Molecular Immunology)
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38 pages, 8212 KB  
Article
Immunoinformatic Prediction of HIV-1 Glycoprotein gp120 and Nef Epitopes Conjugated to HBsAg-Binding Protein (SBP) to Induce the Humoral and Cellular Immune Response
by Arslan Habib, Xinyi Xu, Jun Xie and Naishuo Zhu
Int. J. Mol. Sci. 2025, 26(19), 9828; https://doi.org/10.3390/ijms26199828 - 9 Oct 2025
Viewed by 478
Abstract
Acquired Immunodeficiency Syndrome (AIDS) is caused by Human Immunodeficiency Virus (HIV), and continues to be responsible for a substantial number of deaths worldwide each year. Development of a robust and efficient HIV-1 vaccine remains a critical priority. Structural analysis of viral proteins provides [...] Read more.
Acquired Immunodeficiency Syndrome (AIDS) is caused by Human Immunodeficiency Virus (HIV), and continues to be responsible for a substantial number of deaths worldwide each year. Development of a robust and efficient HIV-1 vaccine remains a critical priority. Structural analysis of viral proteins provides a foundational approach to designing peptide-based immunogenic vaccines. In the current experiment, we used computational prediction approaches alongside molecular docking and molecular dynamics (MD) simulations to identify potential epitopes within gp120 and Nef proteins. The selected co-epitopes were fused with the HBsAg-binding protein (SBP), a 344-amino acid protein previously identified in our laboratory through screening of a human liver cDNA expression library against HBsAg, to facilitate efficient delivery to and uptake by dendritic cells (DCs), thereby enhancing antigen (Ag) presentation. Flexible linkers are used to connect B cells, Helper T Lymphocytes (HTLs), and Cytotoxic T Lymphocytes (CTLs) in a sequential manner. The assembled vaccine construct comprises 757 amino acids, corresponding to a recombinant protein of 83.64 kDa molecular weight. Structural analysis through docking studies, MD simulations, and 3D structure validation revealed that the designed protein exhibits high structural stability and potential for interaction with Toll-like receptors (TLRs). These findings support the vaccine’s ability to enhance cellular and humoral feedback, including the stimulation of T and B cells and induction of antibody (Ab) production. The results underscore the promise of this in silico designed co-epitope vaccine as a viable candidate for HIV-1 prevention and suggest that such constructs may serve as effective immunogens in future HIV-1 vaccine strategies. Full article
(This article belongs to the Section Molecular Informatics)
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17 pages, 9335 KB  
Article
Overexpression of GitrL in Recombinant Rabies Virus rLBNSE-GitrL Enhances Innate Immunity by Activating Dendritic Cells and Innate Immune-Related Pathways and Genes
by Yufang Wang, Xiao Xing, Zhimin Xiong, Yong Wang, Yaping Liu and Yingying Li
Viruses 2025, 17(10), 1354; https://doi.org/10.3390/v17101354 - 9 Oct 2025
Viewed by 302
Abstract
Rabies, a zoonotic infectious disease causing central nervous system inflammation, remains a threat to public health in regions with limited medical resources. Vaccination effectively reduces rabies incidence and mortality, underscoring the need for vaccines that are cost-effective, immunogenic, protective, and safe. This study [...] Read more.
Rabies, a zoonotic infectious disease causing central nervous system inflammation, remains a threat to public health in regions with limited medical resources. Vaccination effectively reduces rabies incidence and mortality, underscoring the need for vaccines that are cost-effective, immunogenic, protective, and safe. This study constructed a recombinant rabies virus (rRABV)-overexpressing glucocorticoid-induced tumor necrosis factor receptor ligand (GitrL), named rLBNSE-GitrL, using a reverse genetic operating system. rLBNSE-GitrL exhibited similar in vitro phenotypic characteristics and immune safety as the parent RABV (rLBNSE). This recombinant virus stimulated the production of a greater number of activated dendritic cells (DCs) compared to rLBNSE. The enhanced innate immune response induced by rLBNSE-GitrL may be mediated through the activation of innate immune-related signaling pathways, such as the tumor necrosis factor (TNF), and chemokine signaling pathways, and the upregulation of a series of innate immune-related genes, including MMP2, IL-6, CXCL9, TIMP1, IL-17d, and TNF-α. Consequently, rLBNSE-GitrL elicited significantly higher levels of RABV vaccine-induced virus-neutralizing antibodies (VNA), IgG, and IgM compared to rLBNSE as early as 3 days post-immunization (dpi), thereby improving the protective effect in mice. Collectively, the overexpression of GitrL facilitated the induction of early and potent antibody responses following RABV immunization. Full article
(This article belongs to the Special Issue Host Cell-Virus Interaction, 4th Edition)
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31 pages, 1560 KB  
Review
Overcoming Immune Therapy Resistance in Cancer Through Innate Immune Reprogramming
by Giada Mandracci, Nardine Soliman and Nadia El Khawanky
Int. J. Mol. Sci. 2025, 26(19), 9554; https://doi.org/10.3390/ijms26199554 - 30 Sep 2025
Viewed by 772
Abstract
Overcoming immune resistance remains the critical barrier to durable immunotherapy responses. Tumors with non-inflamed, “cold” microenvironments exclude cytotoxic lymphocytes and evade checkpoint blockade. Innate nucleic acid-sensing pathways—including TLRs, RIG-I-like RNA sensors, and the cGAS–STING DNA-sensing axis—can recondition this hostile landscape by licensing dendritic [...] Read more.
Overcoming immune resistance remains the critical barrier to durable immunotherapy responses. Tumors with non-inflamed, “cold” microenvironments exclude cytotoxic lymphocytes and evade checkpoint blockade. Innate nucleic acid-sensing pathways—including TLRs, RIG-I-like RNA sensors, and the cGAS–STING DNA-sensing axis—can recondition this hostile landscape by licensing dendritic cells, restoring antigen presentation, and recruiting effector T and NK cells. In this review, we synthesize mechanistic insights into how these receptors function across tumor and immune compartments and evaluate recent translational advances spanning small-molecule and nucleic acid agonists, engineered delivery systems, and clinical trials. We highlight challenges that have limited clinical impact, including pathway silencing, systemic toxicity, and lack of predictive biomarkers, while emphasizing emerging solutions such as tumor-intrinsic targeting, CAR-T/NK engineering, and biomarker-guided patient selection. By integrating innate activation into rational combination regimens, innate immune reprogramming offers a blueprint to convert resistant disease into one susceptible to durable immune control. Full article
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13 pages, 1961 KB  
Article
A CpG 1018S/QS-21-Adjuvanted HBsAg Therapeutic Vaccine as a Novel Strategy Against HBV
by Zixuan Wang, Jing Wu, Xiaohan Meng, He Weng, Qiang Li, Lin Li, Zhenhao Ma, Sirong Bi, Qiuju Han, Huajun Zhao, Cunbao Liu and Deping Meng
Vaccines 2025, 13(10), 1014; https://doi.org/10.3390/vaccines13101014 - 29 Sep 2025
Viewed by 649
Abstract
Chronic hepatitis B virus (HBV) infection remains a major global health challenge, substantially contributing to liver-related morbidity and mortality. Background/Objectives: Developing therapeutic strategies that overcome immune tolerance and achieve functional cures is an urgent priority. Methods: In this study, we report [...] Read more.
Chronic hepatitis B virus (HBV) infection remains a major global health challenge, substantially contributing to liver-related morbidity and mortality. Background/Objectives: Developing therapeutic strategies that overcome immune tolerance and achieve functional cures is an urgent priority. Methods: In this study, we report a therapeutic vaccine comprising hepatitis B surface antigen (HBsAg) formulated with the dual adjuvant system CpG 1018S and QS-21. The immunogenicity and therapeutic efficacy of this vaccine were systematically evaluated in an rAAV8-HBV1.3-established chronic HBV mouse model. Results: The vaccine elicited a robust Th1-skewed immune response, characterized by elevated anti-HBs IgG2b titers and an increased IgG2b/IgG1 ratio. Notably, immunized mice showed markedly reduced circulating HBsAg levels. Mechanistically, the CpG 1018S and QS-21 adjuvant system enhanced dendritic cell activation, maturation, and antigen presentation, expanded HBV-specific CD4+ and CD8+ T cell populations, and attenuated the expression of the exhaustion markers TIM-3 and TIGIT. Additionally, immunized mice exhibited restored T cell polyfunctionality, with an increased secretion of effector cytokines, including TNF-α and IL-21. These responses collectively contributed to the reversal of T cell exhaustion and breakdown of immune tolerance, facilitating sustained viral suppression. Conclusions: Our findings demonstrate that the CpG 1018S/QS-21-adjuvanted vaccine induces potent humoral and cellular immunity against chronic HBV infection and represents a promising candidate for clinical chronic HBV (CHB) treatment. Full article
(This article belongs to the Section Hepatitis Virus Vaccines)
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17 pages, 10075 KB  
Article
Accelerating Vaccine Adjuvant Screening: Early Follicular Dendritic Cell and Germinal Center B Cell Biomarkers Predict Protective Efficacy
by Yiwei Zhong, Mingyue Chen, Hongzhe Lin, Zhenrui Liu, Shijie Zhang, Yue He and Bin Wang
Vaccines 2025, 13(10), 1011; https://doi.org/10.3390/vaccines13101011 - 28 Sep 2025
Viewed by 397
Abstract
Background: The current assessment method of the protective efficacy of adjuvanted vaccines remains slow and labor-intensive, hindered by prolonged immunization protocols and complex assays. Methods: To overcome this bottleneck, we demonstrate that early segregated cellular biomarkers enable rapid prediction of protection, using [...] Read more.
Background: The current assessment method of the protective efficacy of adjuvanted vaccines remains slow and labor-intensive, hindered by prolonged immunization protocols and complex assays. Methods: To overcome this bottleneck, we demonstrate that early segregated cellular biomarkers enable rapid prediction of protection, using a respiratory syncytial virus (RSV) pre-fusion F (pre-F) protein model with diverse adjuvants in mice. Results: We identified that germinal center (GC) B cell responses (Days 7 and 9 post-immunization) strongly aligned with protective efficacy, except for Alum, which achieved MF59-level protection despite lower GC responses. Crucially, follicular dendritic cell (FDC) abundance at day 7 universally predicted protection across all adjuvants, including Alum, drastically shortening discovery time and effort from at least 4–6 weeks to within 1 week. Conclusions: FDCs and GC B cells serve as complementary early biomarkers that accurately forecast vaccine efficacy. This approach could potentially reduce the need for prolonged immunization regimens by cellular profiling on days 7–9, offering a modest step toward streamlining adjuvant selection and informing vaccine design. Full article
(This article belongs to the Special Issue Immune Correlates of Protection in Vaccines, 2nd Edition)
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11 pages, 2186 KB  
Article
MyD88 Plays an Important Role in UVB-Induced Suppression of Dendritic Cell Activity, T Cell Function, and Cutaneous Immune Response
by Mohammad Asif Sherwani, Carlos Alberto Mier Aguilar, Charlotte McRae, Gelare Ghajar-Rahimi, Aisha Anwaar, Ahmed Omar Jasser, Ariq Chandra, Hui Xu and Nabiha Yusuf
Int. J. Mol. Sci. 2025, 26(19), 9361; https://doi.org/10.3390/ijms26199361 - 25 Sep 2025
Viewed by 366
Abstract
Ultraviolet B (UVB) radiation triggers DNA damage and immune suppression, establishing conditions favorable for skin carcinogenesis. Previous studies have shown that a downstream adaptor for Toll-like receptors (TLRs), myeloid differentiation primary response 88 (MyD88), plays a role in UVB-induced DNA damage and immunosuppression. [...] Read more.
Ultraviolet B (UVB) radiation triggers DNA damage and immune suppression, establishing conditions favorable for skin carcinogenesis. Previous studies have shown that a downstream adaptor for Toll-like receptors (TLRs), myeloid differentiation primary response 88 (MyD88), plays a role in UVB-induced DNA damage and immunosuppression. However, specific mechanisms for the effects on dendritic cells and T cells remain poorly understood. The objective of this study is to determine the role of MyD88 and TIR-domain-containing adaptor inducing interferon-β (TRIF), another key TLR downstream adaptor, in UVB-induced suppression of dendritic cell activity and T cell function. MyD88−/−, Trif−/−, and wild-type (WT) mice were evaluated for UVB-induced effects on dendritic cell, T cells, and contact hypersensitivity responses in skin. MyD88−/− mice exhibited significant resistance to UVB-induced immune suppression, compared to Trif−/− mice and wild-type controls. The MyD88 deficiency significantly reduced UVB-induced Treg cells that were CD4+CD25+Foxp3+ and produced interleukin (IL)-10. Moreover, it significantly inhibited the UVB-induced suppression of IL-12/IL-23 producing CD11c+ dendritic cells. Further experiments confirmed that MyD88 conditional knockout (MyD88fl/flXCD11c.Cre) mice were protected against UVB-induced immune suppression. Dendritic cells from MyD88 genomic or conditional knockout mice were resistant to UVB-induced reduction of major histocompatibility complex (MHC) class II antigens. These findings show that MyD88 plays a key role in UVB-induced immune suppression. The deficiency in the MyD88 gene inhibits UVB-induced suppression of CD11c+ dendritic cell (DC) activity and reduces UVB-induced development of Treg cells. Our studies demonstrate a new mechanism for MyD88-mediated regulation of UVB-induced immune suppression. Full article
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17 pages, 7798 KB  
Article
Dendritic Cell-Cytokine-Induced Killer Cells Co-Loaded with WT1/MUC1/Poly(I:C) Enhance Antitumor Immune Responses In Vitro and In Vivo
by Huimin Liu, Chenlong Wang, Hongtao Chang, Liangliang Dong, Guoqing Yang, Cailing Tong and Lin Mao
Biomolecules 2025, 15(10), 1356; https://doi.org/10.3390/biom15101356 - 24 Sep 2025
Viewed by 484
Abstract
Dendritic cell-cytokine-induced killer (DC-CIK) therapy faces limitations due to antigenic heterogeneity and suboptimal immune activation. In this study, we developed a multi-antigen-loaded DC-CIK (Ag-DC-CIK) system that co-targets Wilms’ tumor 1 (WT1), mucin-1 (MUC1), and the TLR3 agonist poly(I:C) to improve therapeutic outcomes. Utilizing [...] Read more.
Dendritic cell-cytokine-induced killer (DC-CIK) therapy faces limitations due to antigenic heterogeneity and suboptimal immune activation. In this study, we developed a multi-antigen-loaded DC-CIK (Ag-DC-CIK) system that co-targets Wilms’ tumor 1 (WT1), mucin-1 (MUC1), and the TLR3 agonist poly(I:C) to improve therapeutic outcomes. Utilizing umbilical cord blood-derived DC and CIK cells, we demonstrated that Ag-DC-CIK significantly enhanced cytotoxicity, as evidenced by the lactate dehydrogenase (LDH) assay, and increased apoptosis induction, indicated by elevated Bax and reduced Bcl-2 expression, in various tumor cell lines (HeLa, HCT116, MKN45) and organoids generated from a gastric cancer patient. Furthermore, Ag-DC-CIK effectively suppressed tumor cell migration and reduced the viability of the organoid. In MKN45 xenograft models, Ag-DC-CIK treatment inhibited tumor growth without inducing systemic toxicity, as shown by decreased Ki67 cell proliferation. This tripartite strategy synergistically enhances DC-CIK therapy by expanding antigen recognition and augmenting immune responses, presenting a promising translational approach for the treatment of gastric cancer. Full article
(This article belongs to the Section Cellular Biochemistry)
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25 pages, 817 KB  
Review
Pathogenic and Regulatory Roles of Fibrinolytic Factors in Autoimmune Diseases
by Yosuke Kanno
Curr. Issues Mol. Biol. 2025, 47(10), 790; https://doi.org/10.3390/cimb47100790 - 23 Sep 2025
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Abstract
Autoimmune diseases arise from complex interactions of genetic, environmental, and hormonal factors, yet their precise causes remain elusive. Beyond its canonical role in fibrin degradation, the fibrinolytic system is increasingly recognized as both a pathogenic driver and a regulatory modulator in autoimmunity. Key [...] Read more.
Autoimmune diseases arise from complex interactions of genetic, environmental, and hormonal factors, yet their precise causes remain elusive. Beyond its canonical role in fibrin degradation, the fibrinolytic system is increasingly recognized as both a pathogenic driver and a regulatory modulator in autoimmunity. Key factors—plasminogen (Plg), plasmin, α2-antiplasmin (α2AP), tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA), its receptor (uPAR), and plasminogen activator inhibitor-1 (PAI-1)—not only reflect secondary responses to vascular and immune dysregulation but also actively shape innate and adaptive immunity. They influence macrophage activation, dendritic cell maturation, T cell responses, and cytokine production, thereby bridging coagulation, inflammation, and tissue repair. This review integrates current evidence on the dual pathogenic and regulatory roles of fibrinolytic factors, organizing autoimmune diseases into systemic, organ-specific, and secondary syndromes. We further discuss how the imbalance of fibrinolysis can either promote inflammatory persistence or, conversely, facilitate resolution through fibrin clearance and immune homeostasis. By highlighting this bidirectional influence, the review aims to refine our understanding of fibrinolytic components as both contributors to and regulators of autoimmune disease pathogenesis. Full article
(This article belongs to the Section Molecular Medicine)
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