Search Results (1,356)

Non-muscle invasive bladder cancer (NMIBC) accounts for the majority of bladder cancer diagnoses and remains a clinical challenge due to its high recurrence and progression rates despite intravesical Bacillus Calmette–Guérin (BCG) therapy. In recent years, tumor-infiltrating lymphocytes (TILs) have emerged as promising biomarkers, reflecting the interplay between the tumor and host immune system. However, the evidence regarding their prognostic and predictive role is still conflicting, largely due to methodological heterogeneity, lack of standardized evaluation criteria, and limited prospective validation. This narrative review summarizes the current knowledge on TILs in NMIBC, focusing on their compartmental distribution (stromal, intraepithelial, and tumor–stroma interface), compositional diversity (CD4⁺, CD8⁺, Treg, B cells), and spatial dynamics. Special attention is given to their role in predicting response to BCG immunotherapy, the contribution of tumor-associated macrophages and tertiary lymphoid structures, and the emergence of immune escape pathways, including Programmed Death-Ligand 1 (PD-L1) and the HLA-E/NKG2A axis. Advances in digital pathology, spatial transcriptomics, and integrated immunoscore models provide more accurate metrics compared to simple cell counts, highlighting the importance of functional and spatial signatures. Despite encouraging progress, TILs are not yet ready for routine incorporation into histopathological reporting. Future directions include standardized assessment, integration with molecular biomarkers, and prospective multicenter validation to enable their translation into risk stratification and personalized therapeutic decision-making. Full article

Foxp3+ regulatory T (Treg) cells play a pivotal role in inducing immune tolerance. The expression of Foxp3 in Treg cells depends on the stability of transcription factors that are directly linked to the molecular interplay between Stat5a and cyclin-dependent kinase CDK8/19. In this study, dendritic cells obtained from C57BL/6 male mice were co-cultured with CD4⁺ splenocytes obtained from Balb/c male mice to obtain alloantigen-specific CD4⁺ T cells. Next, these alloantigen-specific CD4⁺ T cells were cultured with the addition of the CDK8/19 inhibitor AS2863619 compound, TGF-β1, and IL-2 to induce their transdifferentiation into alloantigen-specific CD4⁺ Foxp3+ Treg cells. The efficacy of this cocktail in promoting the transdifferentiation of activated CD4⁺ lymphocytes into alloantigen-specific Treg cells (ag-Tregs) was further evaluated using Nanostring gene expression profiling, flow cytometry, ELISA, and in vivo migration assays. The results showed that the addition of the AS2863619 compound along with IL-2 generated effector memory ag-Tregs exhibiting tolerogenic activity, migration properties, and mechanisms for regulating immune homeostasis in the spleen. In conclusion, these findings suggest that the AS2863619-derived effector memory Tregs possess functional properties that support immune tolerance and regulate homeostasis in the spleen, thereby regulating the affinity of naïve T cells to alloantigens, highlighting their potential relevance in transplantology. Full article

Auranofin, an FDA-approved antirheumatic drug and thioredoxin reductase 1 (TXNRD1) inhibitor, has demonstrated anti-tumoral properties, but its immunological effects are not well characterized. Here, we report that auranofin unexpectedly promotes regulatory T cell (Treg) expansion. In a B16F10 melanoma model, auranofin treatment increased lung tumor coverage, IL-10 serum levels, and FOXP3⁺CD44⁺CD4⁺ T cell frequencies. It also altered the proportion of antigen-presenting cells (APCs), increasing B cells and reducing dendritic cells. To test whether Treg expansion occurs independently of tumor antigens, we stimulated T cells ex vivo in lymph node cultures from naïve mice using anti-CD3/CD28, with or without auranofin. Auranofin increased Treg frequency in these cultures, as well as in treated human PBMCs. Similar effects were observed with the TXNRD1 inhibitor TRi-1, suggesting a ROS-dependent mechanism. Using mice with conditional expression of neutrophil cytosolic factor 1 (NCF1), we found that both TXNRD1 inhibition and APC-specific NCF1-NOX2-ROS expression enhanced tumor burden and Treg expansion. Alternatively, sorted T cells from mice harboring conditional TXNRD1 knockouts showed reduced FOXP3 and GITR expression in the naïve state and reduced tumor burden when challenged with B16F10. These data suggest TXNRD1 inhibitors likely drive Treg expansion by elevating ROS levels in APCs during T cell priming and less by intrinsic Treg TXNRD1 blockade. Our findings reveal a paradoxical immunosuppressive effect of TXNRD1 inhibitors that may contribute to their limited efficacy in immunocompetent cancer models. This work provides mechanistic insight and underscores the need to consider Treg-mediated immune suppression when designing TXNRD1-targeted therapies. Full article

Background: The potential of injectable hydrogels as drug depots lies in their ability to achieve local and sustained co-delivery of chemotherapeutic drugs and immunostimulants for combined tumor therapy. Method: In this study, we devised a localized chemo-immunotherapeutic strategy by co-loading the chemotherapeutic drug, oxaliplatin (OXA), and the immune-checkpoint blockade (ICB) antibody, anti-programmed cell death protein ligand 1 (anti-PD-L1), into a matrix metalloproteinase (MMP)-responsive injectable poly(L-glutamic acid) hydrogel (MMP-gel). Results: The in situ gelation of hydrogels enables local retention of OXA and model antibody IgG, as well as MMP-triggered sustained release. Meanwhile, the OXA-loaded MMP-gel caused the immunogenic cell death (ICD) of tumor cells. When administered intratumorally in mice carrying B16F10 melanoma, the MMP-gel co-loaded with OXA and anti-PD-L1 (OXA&anti-PD-L1@MMP-gel) demonstrated superior tumor suppression efficacy and prolonged the survival time of the animals with low systemic toxicity. Meanwhile, the OXA&anti-PD-L1@MMP-gel induced an increase in CD8⁺ T cells and M1 macrophages within tumors, and a decrease in Treg cells and M2 macrophages, demonstrating that the drug-loaded system enhanced the antitumor immune response. Moreover, the OXA&anti-PD-L1@MMP-gel effectively inhibited the growth of distal tumors in a bilateral-tumor experiment. Conclusions: Consequently, the responsive hydrogel-based chemo-immunotherapy holds potential in tumor treatment. Full article

Background: Hepatocellular carcinoma remains a global health challenge with high mortality rates. The tumor immune microenvironment significantly impacts disease progression and survival. However, traditional analyses predominantly focus on single immune genes, overlooking the critical interplay among multiple immune gene signatures. Our study explores the prognostic significance of chemokine (C-C motif) ligand 5 (CCL5) expression and associated immune genes through an innovative combination of Autoregressive Integrated Moving Average (ARIMA) and Convolutional Neural Network (CNN) models. Methods: A time series dataset of CCL5 expression, comprising 230 liver cancer patients, was analyzed using an ARIMA model to capture its temporal dynamics. The residuals from the ARIMA model, combined with immune gene expression data, were utilized as input features for a CNN to predict survival outcomes. Survival analyses were conducted using the Cox proportional hazards model and Kaplan–Meier curves. Furthermore, the ARIMA-CNN framework’s results were systematically compared with traditional median-based stratification methods, establishing a benchmark for evaluating model efficacy and highlighting the enhanced predictive power of the proposed integrative approach. Results: CNN-extracted features demonstrated superior prognostic capability compared to traditional median-split analyses of single-gene datasets. Features derived from CD8⁺ T cells and effector T cells achieved a hazard ratio (HR) of 0.7324 (p = 0.0008) with a statistically significant log-rank p-value (0.0131), highlighting their critical role in anti-tumor immunity. Hierarchical clustering of immune genes further identified distinct survival associations. Notably, a cluster comprising B cells, Th2 cells, T cells, and NK cells demonstrated a moderate protective effect (HR: 0.8714, p = 0.1093) with a significant log-rank p-value (0.0233). Conversely, granulocytes, Tregs, macrophages, and myeloid-derived suppressor cells showed no significant survival association, emphasizing the complex regulatory landscape within the tumor immune microenvironment. Conclusions: Our study provides the first ARIMA-CNN framework for modeling gene expression and survival analysis, marking a significant innovation in integrating temporal dynamics and machine learning for biological data interpretation. This model offers deeper insights into the tumor immune microenvironment and underscores the potential for advancing precision immunotherapy strategies and identifying novel biomarkers, contributing significantly to innovative cancer management solutions. Full article

Kidney diseases in patients with SLE include glomerulonephritis (GN), tubulointerstitial nephritis (TIN) and vasculitis alone or in combination. Immune complex (IC) deposition with complement activation in renal glomeruli causes lupus GN. However, IC deposition can also occur in the tubular basement membrane, renal interstitium, peritubular capillaries and arteries/arterioles to elicit inflammatory responses. TIN is usually associated with more severe GN with inflammation induced by IC. Immunopathologically, the aberrant presentation of T cell subpopulations, T_h1, T_h2, T_h9, T_h17, Treg and follicular T helper cells (T_fh), is closely implicated in TIN in SLE. In addition, M₁/M₂ macrophages and more specific dendritic cells (DCs) contribute to the inflammatory reactions of SLE-TIN. TIN may also present alone (isolated TIN) in apparently normal glomeruli or class I GN. It is intriguing that lupus nephritis constitutes two different pathological predilections, i.e., GN and tubulointerstitial inflammation. Alternatively, these two types may represent a continuous spectrum of inflammatory renal damages. In the present review, we will discuss in detail the pathology/immunopathogenesis, likely specific biomarkers/predictors and novel therapeutic designs for SLE-tubulointerstitial inflammation. In addition, we also raise several plausible investigation methods in SLE-tubulointerstitial inflammation that may help further elucidate this setting of perplexing renal diseases with rheumatic characteristics. Full article

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by T-cell-mediated destruction of pancreatic beta cells, resulting in insulin deficiency. Both genetic predisposition and environmental factors contribute to T1D development, with growing evidence implicating the gut microbiome as a critical environmental modulator in disease pathogenesis. Gut microbial composition and derived metabolites influence immune homeostasis and autoimmunity. This review summarizes recent advances elucidating immune dysregulations in T1D and novel therapeutic strategies to preserve beta cell function. We discuss approaches such as immune cell engineering, including CAR-Treg therapy, and targeted modulation of immune signaling pathways like JAK-STAT. Furthermore, we explore the role of the gut microbiota and its metabolites in modulating host immunity and describe emerging microbiome-targeting interventions, including fecal microbiota transplantation and metabolite supplementation. These interventions show promise in modulating disease progression in preclinical and early clinical studies. An integrated understanding of immune and microbiome-related mechanisms is critical for developing next-generation therapies. Further research and clinical trials are needed to optimize these approaches and translate them into durable, personalized treatments for individuals with T1D. Full article

Canine atopic dermatitis (AD) is a chronic allergic skin disease in which various immunological markers have been investigated. While peripheral eosinophil counts, serum allergen-specific immunoglobulin E (IgE), and cytokines have each been evaluated in allergic disorders, their simultaneous assessment in dogs with AD has rarely been reported in Korea. This study aimed to evaluate the diagnostic and clinical utility of these parameters in affected dogs. A total of 93 dogs were included between August 2019 and February 2020, comprising 65 dogs diagnosed with AD and 28 healthy controls. Clinical information, peripheral blood eosinophil counts and ratios, serum allergen-specific IgE using a multiple allergen panel (60 allergens), and cytokines related to T helper 2 (Th2) and T regulatory (Treg) cells (IL-4, IL-13, IL-31, TGF-β1) were analyzed. The mean age of AD dogs was 6.34 ± 3.99 years, with a predominance of small breeds and males. Eosinophil counts and ratios showed no significant difference between groups. In contrast, allergen-specific IgE levels were significantly elevated for several allergens, including Dermatophagoides pteronyssinus, Acarus siro, Tyrophagus putrescentiae, alder/birch, hazel, oak, cladosporium, and selected dietary antigens (pea, soybean, pumpkin, apple) (p < 0.05). Sensitization rates were also higher for Acarus siro, Tyrophagus putrescentiae, oak, and sheep sorrel (p < 0.05). Th2-related cytokines tended to increase and TGF-β1 tended to decrease in AD dogs, though without statistical significance. These findings indicate that peripheral eosinophil counts have limited diagnostic value, whereas allergen-specific IgE testing provides clinically useful information for the diagnosis and management of canine AD. Further research stratifying disease stages and assessing local tissue cytokine expression is warranted. Full article

Der p 23 induces a high-frequency sensitization in allergic individuals. However, its allergenic activity and clinical impact are scarce. We aimed to evaluate the ability of rDer p 23 to induce allergic inflammation in a mouse model and to test IgE reactivity in humans. Female Balb/c mice were sensitized and challenged with rDer p 23 and Dermatophagoides pteronyssinus extract. Specific antibodies were determined by ELISA, inflammatory cell infiltration and goblet cells hyperplasia were evaluated by lung histology, and bronchial hyperreactivity (BHR) was assessed by the FinePoint RC System^TM and whole-body plethysmography (WBP). IgE reactivity was evaluated by ELISA, the basophils activation test (BAT) and the skin pick test (SPT) in humans. rDer p 23, produced in Escherichia coli, adopts a random coil structure, predominantly exists in a monomeric state, and exhibits high stability. rDer p 23-treated mice showed a significant increase in lung resistance and bronchial hyperreactivity, as well as in eosinophils, neutrophils, and T cell count in bronchoalveolar lavage fluid (BALF). Cytokine and antibodies profiles were biased to a Type-2 response. No significant difference was observed in group 2 Innate Lymphoid Cells (ILC-2s) in lung and regulatory T cells (Treg) in the spleen. In asthmatic individuals sensitized to D. pteronyssinus, serum IgE reactivity to rDer p 23 was 67.5%. BAT and SPT results were significantly higher in allergic patients. Our findings support the pro-allergenic role of rDer p 23 in the development of the pathological features of asthma. Full article

The oral cavity harbors one of the most diverse microbial ecosystems in the human body, second only to the gut. Periodontitis, a chronic inflammatory disease arising from oral microbiota dysbiosis, has been increasingly associated with systemic disorders such as diabetes mellitus, atherosclerosis, rheumatoid arthritis, inflammatory bowel disease, and neurodegenerative conditions. Although hematogenous dissemination of oral pathogens and inflammatory mediators has long been proposed as a mechanistic link, emerging evidence identifies the oral–gut axis as a novel bidirectional pathway. Swallowed oral pathobionts, such as Porphyromonas gingivalis and Fusobacterium nucleatum, can colonize the gut, disrupt the intestinal barrier, and induce dysbiosis, immune imbalance, and metabolic alterations that aggravate systemic inflammation and disease progression. In contrast, gut dysbiosis, especially in obesity or high-fat-diet models, can exacerbate periodontal tissue destruction through hyperuricemia, altered bone metabolism, and Th17/Treg immune imbalance. Experimental and clinical studies further support this reciprocal relationship, implicating microbial, metabolic, and immune crosstalk in both oral and systemic pathology. Understanding this oral–gut–systemic axis offers a paradigm shift in diagnostics and therapeutics, focusing on precision interventions such as microbiome modulation, probiotics, and integrated oral care to mitigate systemic inflammatory burden and improve overall health outcomes. Full article

Background: Methotrexate (MTX) is the most used anti-rheumatic drug for the treatment of early rheumatoid arthritis (ERA) patients, with an adequate response rate of only 30–40%. Thus, early detection of response failure is very crucial to prevent permanent disability. Objectives: We aimed to provide an update on the current evidence of potential predictive biomarkers of MTX treatment response (MTX-TR) in patients with ERA. Materials and Methods: PubMed/MEDLINE, Scopus, EBSCO, and Cochrane Library were searched for studies that investigated a multitude of predictive metabolites of MTX-TR in ERA patients during the 2000–2024 period. This study was registered in PROSPERO (ID: CRD42024547651). Results: We determined that 31 out of 102 metabolites studied were the best predictive of MTX-TR in ERA, using clinical response (DAS28-ESR score). Our results on serum protein profiles revealed that higher pre-treatment levels of myeloid-related proteins, MTX–polyglutamates, choline, inosine, hypoxanthine, guanosine, nicotinamide, and diglyceride, and lower pre-treatment levels of N-methyl isoleucine, 2,3-dihydroxy butanoic acid, nor-nicotine, glucosylceramide, and itaconic acid, were associated with a good MTX-TR. However, lower baseline plasma itaconate and its derivatives and haptoglobin, but a higher baseline level of galactosylated glycans (FA2G) of IgG1, were associated with a good response to MTX. The results on immune cell biology indicated that higher pre-treatment of regulatory B cells, lower pre-treatment of Treg, and RDW were correlated with a good MTX-TR. The results on inflammatory biomarkers showed that a lower IL-1ra/IL1B ratio and IL-6 levels after MTX indicated a good response. Conclusions: This study provides an update on the current evidence of the potential predictive metabolites for the best MTX-TR in ERA patients. We revealed that few biomarkers resulted in a remission state of patients with ERA. These biomarkers are promising but not yet ready for routine clinical use; they warrant validation in larger prospective trials. We recommend that, for the implementation of personalized medicine, these biomarkers should be the first-line biomarkers for use in routine clinical practice after validation. Full article

Background: Chimeric Antigen Receptor T-cell (CAR-T) cell therapy has revolutionized cancer treatment and is now being explored as a novel approach to treat refractory autoimmune diseases by targeting autoreactive immune components, especially B cells. Objective: Our aim was to provide a narrative review of the current evidence, mechanisms, efficacy, safety, and future directions of CAR-T cell therapy in autoimmune diseases. Methods: A structured literature search was conducted in MEDLINE via PubMed using keywords such as “CAR-T”, “chimeric antigen receptor T-cell”, “autoimmune diseases”, “lupus”, “rheumatoid arthritis”, “multiple sclerosis”, and “vasculitis”. Studies on CAR-T mechanisms, efficacy, safety, and clinical outcomes were included. Results: CAR-T cell therapies, especially CD19-directed constructs, demonstrated sustained drug-free remission in all patients across early SLE case series (n = 5–7), with normalization of serological markers and improved renal outcomes. Emerging preclinical and early clinical data in rheumatoid arthritis, multiple sclerosis, ANCA-associated vasculitis, juvenile autoimmune diseases, and idiopathic inflammatory myopathies also report clinical improvement and biomarker normalization. Reported adverse events in autoimmune cohorts were limited to mild cytokine release syndrome in a minority of cases, with no severe neurotoxicity or life-threatening infections, suggesting a more favorable safety profile compared to oncology settings. In parallel, next-generation innovations—including dual-target CARs, CAR-Tregs, and molecular safety switches—are advancing toward clinical translation. Conclusions: CAR-T cell therapy is emerging as a transformative strategy for autoimmune disease management, especially in refractory cases. Although initial outcomes are promising, long-term safety, cost-effectiveness, and broader accessibility remain key challenges. Future research should focus on optimizing cell targets, minimizing off-target effects, and improving affordability. Full article

Since forkhead box P3 (FOXP3) is a hallmark of regulatory T (Treg) cells, the expansion of FOXP3⁺ adult T-cell leukemia/lymphoma (ATL) cells is believed to contribute to immune suppression and the pathogenesis of ATL. However, the mechanisms underlying the expansion of FOXP3⁺ ATL cells remain unclear. OX40, a co-stimulatory molecule, is expressed in ATL cells, and OX40 signaling has been shown to promote the differentiation and proliferation of Treg cells in mouse models. To investigate the mechanisms driving the expansion of FOXP3⁺ ATL cells, we examined the expression of OX40 and its ligand, OX40L. Our findings revealed that OX40 expression was elevated in patients with ATL and with a high frequency of FOXP3⁺ ATL cells. Flow cytometric analysis of peripheral blood mononuclear cells (PBMCs) from patients with acute ATL cultured for 18 h demonstrated that FOXP3⁻ and FOXP3⁺ cells predominantly expressed OX40L and OX40, respectively. Furthermore, small interfering RNA-mediated FOXP3 knockdown in HTLV-1-infected cell lines increased OX40L expression. These results suggest that interactions between FOXP3⁻ OX40L⁺ cells and FOXP3⁺ OX40⁺ cells may promote the proliferation of FOXP3⁺ ATL cells. Full article

Multiple Sclerosis (MS) is an autoimmune and neurodegenerative disorder of the central nervous system (CNS), characterized by demyelination, neuronal loss and physical disability. To date, the exact causes of MS remain unknown. Lifestyle factors, in particular diet, have received growing attention due to their impact on human health, their role in modulating disease pathogenesis, and their influence on gut microbiota composition and activity. As a result, numerous studies have been conducted to examine how specific nutrients, and thereby distinct dietary patterns, may affect the onset and progression of MS. In this narrative review, we aim to explore the most recent and updated evidence concerning the role of fatty acids, carbohydrates, proteins and fibers macronutrients in MS development and progression by evaluating the most relevant literature findings from preclinical models, and clinical trials on people with MS. Dietary macronutrients influence MS pathology through immune and gut–brain axis modulation. Diets rich in saturated fats and refined carbohydrates exacerbate neuroinflammation, promote Th1/Th17 polarization, and worsen disease severity. Conversely, monounsaturated and omega-3 polyunsaturated fatty acids, dietary fibers, and adequate tryptophan metabolism exert anti-inflammatory effects, enhance regulatory T cell (Treg) activity, and improve clinical outcomes. Fiber-derived short-chain fatty acids (SCFAs) and omega-3 metabolites also support gut barrier integrity and suppress astrocyte activation. Evidence on dairy, meat and gluten remains inconclusive, though certain milk proteins and certain components of red/processed meat and of wheat may promote inflammation. Overall, anti-inflammatory and fiber-rich diets, such as those emphasizing unsaturated fats and low sugar intake, appear to confer protective effects in MS. The clarification of the role of dietary components in relation to the disease could help to guide patients toward a healthy and balanced diet, with positive effects on their overall health. Full article

Background: Current disease-modifying therapies (DMTs) for multiple sclerosis (MS) attenuate pathogenic immune responses but are limited by safety and tolerability concerns. Antigen-specific tolerance approaches provide targeted immunomodulation yet remain constrained by their dependence on known autoantigens. LPX-TI641, an orally bioavailable, clinical-stage small-molecule agonist of Tim-3/4, represents an antigen-independent strategy to restore immune tolerance by expanding regulatory T cells (Tregs). Methods: LPX-TI641 was evaluated in vitro for its ability to induce Treg populations in murine splenocytes. Therapeutic efficacy was assessed in vivo using MOG_35–55- and PLP_139–151-induced experimental autoimmune encephalomyelitis (EAE) mouse models. Ex vivo, peripheral blood mononuclear cells (PBMCs) from people with MS (PwMS) were analyzed for Treg phenotype and function in response to LPX-TI641. Results: LPX-TI641 induced dose-dependent expansion of CD4⁺Foxp3⁺ and CD4⁺Foxp3⁺Tim-3⁺ Tregs in vitro. In EAE models, treatment significantly reduced disease severity, prevented relapses, and maintained clinical benefit after discontinuation. In PBMCs from patients with MS, LPX-TI641 restored diminished Tim-3⁺ Treg populations and reversed Treg dysfunction in recall assays. Efficacy in animal models was comparable to or exceeded that of high-efficacy DMTs, including natalizumab. Conclusions: LPX-TI641 promotes antigen-independent immune tolerance through Tim receptor agonism and Treg expansion. These findings support its potential as a novel therapeutic candidate for MS, addressing the limitations of current DMTs. Full article