Inflammatory bowel disease (IBD) is a chronic inflammatory bowel disease with unclear causes and limited treatment options. Sodium butyrate (NaB), a byproduct of dietary fiber in the intestine, has demonstrated efficacy in treating inflammation. However, the precise anti-inflammatory mechanisms of NaB in colon inflammation remain largely unexplored. This study aims to investigate the effects of NaB on dextran sulfate sodium (DSS)-induced colitis in rats. The findings indicate that oral administration of NaB effectively prevent colitis and reduce levels of serum or colon inflammatory factors. Additionally, NaB demonstrated in vitro inhibition of RAW264.7 inflammation cytokines induced by LPS, along with suppression of the ERK and NF-κB signaling pathway activation. Moreover, NaB mitigated LPS and Nigericin-induced RAW264.7 pyroptosis by reducing indicators of mitochondrial damage, including increased mitochondrial membrane potential (JC-1) levels and decreased Mito-ROS production. NaB increases ZO-1 and Occludin expression in CaCo2 cells by inhibiting RAW264.7 pyroptosis. These results suggest that NaB could be utilized as a therapeutic agent or dietary supplement to alleviate colitis.

The rapid approval of SARS-CoV-2 mRNA lipid nanoparticle (LNP) vaccines indicates the versatility of mRNA LNPs in an urgent vaccine need. However, the mRNA vaccines do not induce mucosal cellular responses or broad protection against recent variants. To improve cross-protection of mRNA vaccines, here we engineered a pioneered mRNA LNP encapsulating with mRNA constructs encoding cytokine adjuvant and influenza A hemagglutinin (HA) antigen for intradermal vaccination. The adjuvant mRNA encodes a novel fusion cytokine GIFT4 comprising GM-CSF and IL-4. We found that the adjuvanted mRNA LNP vaccine induced high levels of humoral antibodies and systemic T cell responses against heterologous influenza antigens and protected immunized mice against influenza A viral infections. Also, the adjuvanted mRNA LNP vaccine elicited early germinal center reactions in draining lymph nodes and promoted antibody-secreting B cell responses. In addition, we generated another adjuvant mRNA encoding CCL27, which enhanced systemic immune responses. We found the two adjuvant mRNAs both showed effective adjuvanticity in enhancing humoral and cellular responses in mice. Interestingly, intradermal immunizations of GIFT4 or CCL27 mRNA adjuvanted mRNA LNP vaccines induced significant lung tissue-resident T cells. Our findings demonstrate that the cytokine mRNA can be a promising adjuvant flexibly formulated into mRNA LNP vaccines to provoke strong immunity against viral variants.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been used for its immunomodulatory properties to enhance therapeutic outcomes and improve cure rates in fungal infections. However, the mechanisms of GM-CSF action in various fungal infections have not been systematically summarized in current literature, and the reliability and broad effectiveness of clinical data remain uncertain. This review provides a comprehensive analysis of how GM-CSF supports host defense against infections caused by specific fungal pathogens. These pathogens include yeasts (Candida spp., Cryptococcus spp.), filamentous fungi (Aspergillus spp., Mucorales, dematiaceous fungi), and thermally dimorphic fungi (Histoplasma capsulatum, Talaromyces marneffei, Paracoccidioides brasiliensis, and Blastomyces dermatitidis). These insights underscore the potential of GM-CSF as a promising adjunctive therapy in combating challenging fungal infections.

Immune cell infiltration in tumors has been reported to influence tumor progression and clinical outcomes. Considerable efforts have been made to understand interactions between tumors and the immune system. However, current models are either not comprehensive or limited to short-term studies. Recognizing thedynamic and long-term nature of tumor-immune interactions, an immune-infiltrated cancer spheroid model is developed by continuously perfusing and recirculating immune cells with gravity-driven flow through a tubular blood vessel adjacent to a cancer spheroid. Fibroblasts and pericytes are embedded in the gel matrix to support endothelial cells and enhance the vascular barrier. With continuous monocyte recirculation, monocyte adhesion, transendothelium migration, differentiation, and macrophage recruitment into breast carcinoma and hepatoma spheroids is successfully demonstrated over a week. The macrophage recruitment process is temporally dependent and tissue-specific, leading to the formation of cancer-macrophage heterospheroids. Elevated secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF), which regulates monocyte recruitment and macrophage activation, is observed in the breast carcinoma model. Increased levels of Interleukin 6 (IL-6) and Interleukin 8 (IL-8) are detected, indicating a pro-inflammatory environment associated with tumor progression and metastasis. This platform provides a valuable framework for investigating immune cell infiltration and differentiation within the tumor microenvironment, supporting the advancement of cancer immunotherapies.

The release of cytokines in the peritoneal fluid after stimulation with Bothrops atrox and Bothrops jararaca venoms is a crucial process in the inflammatory response triggered by these venoms. The toxins present in the venoms of snakes from the Bothrops genus induce a complex inflammatory response, which includes the production and release of pro-inflammatory cytokines such as TNF-α, IFN-γ, IL-6, IL-10, IL-1β, chemokines like GM-CSF, MCP-1, and the mast cell degranulation marker MCPT-1. These cytokines play a central role in amplifying inflammation, recruiting leukocytes, and increasing vascular permeability, resulting in edema, pain, and tissue damage at the inoculation site. Peritoneal fluid is commonly used in experimental studies to investigate local inflammatory responses, allowing for the evaluation of the dynamics of inflammatory molecule release. In this study, we used female C57BL/6 mice and observed that Bothrops atrox venom induced a significantly more intense inflammatory response compared to Bothrops jararaca venom. Specifically, Bothrops atrox venom led to a higher release of TNF-α and an increase in MCP-1 levels in peritoneal fluid when compared to Bothrops jararaca venom. These changes resulted in a more pronounced inflammatory condition, with increased leukocyte recruitment in the Bothrops atrox group. Understanding the cytokine profile released in response to these venoms can provide important insights into the pathophysiological mechanisms involved in snakebite accidents and contribute to the development of more effective treatments, such as antivenoms and inflammation modulators.

Background/Objectives: Liver inflammatory diseases are a major global health burden and are often exacerbated by inflammation driven by lipopolysaccharides (LPS) through toll-like receptor 4 signaling. This study evaluates the anti-inflammatory effects of psilocybin and eugenol in an LPS-induced liver inflammation model in C57BL/6J mice. Methods: Mice were treated with psilocybin (0.88 mg/kg) and/or eugenol (17.59 mg/kg) either before (pre-treatment) or after (post-treatment) LPS injection. Results: Psilocybin and eugenol, individually and in combination, significantly reduced the LPS-induced mRNA levels of pro-inflammatory cytokines, with post-treatment administration exhibiting stronger effects than pre-treatment. Psilocybin alone displayed the most pronounced anti-inflammatory response, especially for IL-1β, IL-6, and MCP-1, while its combination with eugenol in 1:50 ratio demonstrated similar results, with strongly reduced COX-2 and TNF-α. Histological analysis revealed improved nuclear circularity and reduced inflammatory infiltration in the treatment groups. Eugenol alone showed potential adverse effects, including increased MCP-1 and GM-CSF, but this was mitigated by the co-administration of psilocybin. Conclusions: These findings highlight psilocybin and its combination with eugenol as promising therapies for hepatic inflammation, suggesting their application in treating acute and chronic liver diseases. Future research should explore their long-term effects, the mechanisms underlying their anti-inflammatory actions, and their therapeutic efficacy in humans.

The present study aimed to evaluate the performance of plasma immune mediators in classifying leprosy patients [L(PB) and L(MB), paucibacillary and multibacillary leprosy, respectively], leprosy reaction patients (T1LR and T2LR, type 1 and type 2 leprosy reaction, respectively), household contacts (HHC), and non-infected (NI) controls. Quantitative measurements of these immune mediators were carried out using high-throughput multiplex microbead array. The results demonstrated that most of the plasma immune mediators were increased in all clinical groups compared with NI controls. Higher frequencies but lower maximum magnitudes of increase (fold change according to NI) were observed for T1LR (63%, 6.1×) and T2LR (63%, 9.7×) compared with HHC (48%, 68.5×), L(PB) (56%, 8.5×), and L(MB) (48%, 37.9×). The bi-dimensional scattering profiles (magnitude order vs. significance) identified a higher number of immune mediators in T2LR (12/27) compared with HHC (8/27), L(PB) (7/27), L(MB) (5/27), and T1LR (5/27). CXCL8 was selected as the parameter with the highest accuracy and significance [area under the receiver operating characteristic curve (AUC) = 0.98, p = 0.0002] in classifying NI vs. HHC. CCL3 (C-C motif chemokine ligand 3) was the single analyte with moderate accuracy and significance (AUC = 0.74, p = 0.0422) in classifying L(PB) vs. L(MB). IL-9 was selected as an attribute with moderate accuracy and significance (AUC = 0.77, p = 0.0041) in classifying T1LR vs. T2LR. Decision tree algorithms confirmed the high accuracy (96%) of CXCL8 in classifying NI vs. HHC. The use of CCL3 followed by IFN-γ classified L(MB) vs. L(PB) with high accuracy (93%). Moreover, the analysis of IL-9 followed by IL-6 and CXCL10 classified T1RL vs. T2RL with high accuracy (96%). In general, combined stepwise algorithms showed enhanced classification accuracy compared with single-attribute analysis. Together, our findings supported the potential use of plasma immune mediators as complementary laboratory biomarkers for the identification of HHC and the classification of distinct clinical forms of leprosy and leprosy reactions.

In the initial stage of the COVID-19 pandemic, high case fatality was noted. The case fatality during this was associated with the cytokine storm (CS) or cytokine storm syndrome (CSS). Sometimes, virus infections are due to the excessive secretion of pro-inflammatory cytokines, leading to cytokine storms, which might be directed to ARDS, multi-organ failure, and death. However, it was noted that several miRNAs are involved in regulating cytokines during SARS-CoV-2 and other viruses such as IFNs, ILs, GM-CSF, TNF, etc. The article spotlighted several miRNAs involved in regulating cytokines associated with the cytokine storm caused by SARS-CoV-2 and other viruses (influenza virus, MERS-CoV, SARS-CoV, dengue virus). Targeting those miRNAs might help in the discovery of novel therapeutics, considering CS or CSS associated with different virus infections.

Persistent infection of porcine reproductive and respiratory syndrome virus (PRRSV) significantly hampers both the quantity and quality of pork production in China. Although PRRSV is widely prevalent worldwide, the absence of effective vaccines has made it one of the major pathogens threatening the sustainable development of the global swine industry. Vaccination remains one of the most effective measures for controlling pathogen infections. However, the continuous genetic recombination and mutation of PRRSV demand more comprehensive strategies to address emerging threats, while ensuring the efficacy and safety of vaccines. This review provides an overview of the latest advances in PRRSV vaccine research, highlighting the importance of understanding the unique strengths and limitations of various vaccines in developing effective therapeutic approaches and vaccination strategies. Moreover, the development of adjuvants and antiviral drugs as adjuncts to combat PRRSV infection offers significant potential for enhancing disease control efforts. With the advancement of technologies such as proteolysis-targeting chimera (PROTAC) and mRNA, new avenues for controlling PRRSV and other pathogens are emerging, offering considerable hope. Ultimately, the goal of these vaccine developments is to alleviate the impact of PRRSV on animal health and the profitability of the swine industry.

Discrete subaortic stenosis (DSS) is a congenital heart disease characterized by a narrowing of the passage below the aortic valve in the left ventricular outflow tract (LVOT) [1]. While endocardial endothelial cells (EECs) are known to play a role in DSS, the response of these cells to shear stress is not known. In this study, we hypothesize that the response of EECs to shear stress in the LVOT is a mediator of DSS.

To test this hypothesis, we conditioned porcine EECs to controlled shear stress regimes using cone and plate bioreactors. Subsequently, we quantified the concentration of proinflammatory cytokine in the conditioned media using the Luminex assay. Bulk-RNA sequencing was used to quantify changes in the genotype of the shear stress conditioned EECs.

The expression of CD31 was knocked down and subsequently, the changes in release of shear stress induced proinflammatory cytokines released by EECs quantified using the Luminex assay. The results of these studies show that the inflammatory cytokines were highly selected in the conditioning medium, and under bioreactor treatment the cell activated the PI3K-AKT and TNF-a signaling, which also triggered the other immune cell responses though Th1, Th2 and Th17 cell differentiation pathways. Furthermore, CD31 was identified as a mediator of the pro-inflammatory response of shear stress conditioned EECs.

The studies provide a clear link between shear stress, and the subsequent proinflammatory response of EECs as a mediator of DSS.

Bacille Calmette-Guérin (BCG), the only tuberculosis vaccine currently in clinical use, provides inadequate long-term protection. Administered at birth, BCG induces broad immune responses against a large number of antigens shared with Mycobacterium tuberculosis (Mtb), but protection wanes over time. We have previously shown that unconventional B cell subsets play a role in tuberculosis control.

High-dimensional flow cytometry and multiplex cytokine analysis were employed to investigate the effects of immunotherapy on BCG-vaccinated mice in an Mtb challenge model.

In this study, we investigate the potential of recombinant cytokines targeting B cells - B-cell activating factor (BAFF) and A proliferation-inducing ligand (APRIL) - to modulate BCG immunity and improve protection in mice. Both cytokines play overlapping roles in B cell development and peripheral survival. Following subcutaneous BCG vaccination, immunotherapy with BAFF or APRIL resulted in an increased frequency of unconventional B cells potentially transitioning into antibody-producing plasma cells. Concurrently, we observed an increased frequency of central memory T cells, a subset critical for protective immunity. Changes in cellular immune responses were accompanied by reduced pro-inflammatory cytokine profiles and a contraction of the leukocyte population in lungs. Importantly, mice receiving BCG vaccination followed by BAFF or APRIL immunotherapy exhibited superior long-term protection against pulmonary tuberculosis relative to controls that received only BCG.

In summary, our findings demonstrate that combining BCG vaccination with B cell targeted immunomodulatory therapies can improve long-term protection against pulmonary tuberculosis, highlighting the continued relevance and underutilized potential of BCG as a vaccine platform.

Lymphedema is an intractable disease most commonly associated with lymph node dissection for cancer treatment and can lead to a decreased quality of life. Type 2 T helper (Th2) lymphocytes have been shown to be important in the progression of lymphedema. The activation of IL-33 and its receptor, the suppression of tumorigenicity 2 (ST2) signaling pathway, induces the differentiation of Th2 cells, but its involvement in lymphedema remains unclear. In the present study, we analyzed the dynamics of immune cell infiltration, including the IL-33/ST2 axis, in a mouse tail lymphedema model. Neutrophil infiltration was first detected in the lymphedema tissue on postoperative day (POD) 2. Macrophage infiltration increased from POD 2 to 5. The number of CD4+ T cells, including 50% Tregs, gradually increased from POD 14. The mRNA expression of ll13 and Ifng increased on POD 21. The expression of IL-33 was induced in fibroblast nuclei within dermal and subcutaneous tissues from POD 2, and the expression of the Il1rl1 gene encoding ST2 increased from POD 7. We demonstrated the infiltration process from innate to acquired immune cells through the development of a mouse tail lymphedema. The IL-33/ST2 axis was found to be induced during the transition from innate to acquired immunity.

Over the years, extensive research has been dedicated to performing in-depth analysis of cancer to uncover the intricate details of its nature - including the types of cancer, causative agents, stimulators of disease progression, factors contributing to poor prognosis, and efficient therapies to restrict the metastatic aggressiveness. This chapter highlights the mechanisms through which different arms of the host immune system - namely cytokines, lymphocytes, antigen-presenting cells (APCs) -can be mobilized to eradicate cancer. Most malignant tumors are either poorly immunogenic, or are harbored in a highly immuno-suppressive microenvironment. This is why reinforcing the host's anti-tumor defenses, through infusion of pro-inflammatory cytokines, tumor antigen-loaded APCs, and anti-tumor cytotoxic cells has emerged as a viable treatment option against cancer. The chapter also highlights the ongoing preclinical and clinical studies in different malignancies and the outcome of various therapies. Although these methods are not foolproof, and antigen escape variants can still evade or develop resistance to customized therapies, they achieve disease stabilization in several cases when conventional treatments fail. In many instances, combination therapies involving cytokines, T cells, and vaccinations prove more effective than monotherapies. The limitations of the current therapies are also discussed, along with ongoing modifications aimed at improving efficacy.

Melanoma is an aggressive tumor that is challenging to treat. Talimogene laherparepvec (T-VEC), the first oncolytic virus treatment approved by the US Food and Drug Administration to treat unresectable melanoma, was recently used in recurrent tumors after initial surgery. Our network meta-analysis aimed to compare T-VEC treatment of metastatic melanoma with treatment of granulocyte-macrophage colony-stimulating factor (GM-CSF) and control group. The protocol for this network meta-analysis was retrospectively registered with PROSPERO (CRD42022363321). Three databases, namely Embase, PubMed, and Cochrane Library, were searched until 10 June 2024. The search terms used were a combination of 'metastatic melanoma', 'melanoma', 'T-VEC', 'talimogene laherparepvec', and 'GM-CSF'. Seven studies, with 978 participants receiving T-VEC treatment, 649 participants receiving GM-CSF treatment, and 938 participants constituting the control group, were included in our meta-analysis. For 1-year overall survival (OS), the league table revealed significant differences between the control and T-VEC groups [0.90 (0.83, 0.99)]. The disease-free survival (DFS) over 2 years was also analyzed showing no difference between the groups in DFS in the league table. T-VEC may be a favorable treatment for metastatic melanoma owing to the notable increase in OS. Nevertheless, due to the side effects and limitations, the clinical benefits of T-VEC therapy in metastatic melanoma should be interpreted cautiously. This network meta-analysis demonstrates that T-VEC may be a favorable choice of treatment for metastatic melanoma.

Effective cancer therapies must address the tumor microenvironment (TME), a complex network of tumor cells and stromal components, including endothelial, immune, and mesenchymal cells. Durable outcomes require targeting both tumor cells and the TME while minimizing systemic toxicity. Interleukin-2 (IL-2)-based therapies have shown efficacy in cancers such as metastatic melanoma and renal cell carcinoma but are limited by severe side effects. Innovative IL-2-based immunotherapeutic approaches include immunotoxins, such as antibody-drug conjugates, immunocytokines, and antibody-cytokine fusion proteins that enhance tumor-specific delivery. These strategies activate cytotoxic CD8+ T lymphocytes and natural killer (NK) cells, eliciting a potent Th1-mediated anti-tumor response. Modified IL-2 variants with reduced Treg cell activity further improve specificity and reduce immunosuppression. Additionally, IL-2 conjugates with peptides or anti-angiogenic agents offer improved therapeutic profiles. Combining IL-2-based therapies with immune checkpoint inhibitors (ICIs), anti-angiogenic agents, or radiotherapy has demonstrated synergistic potential. Preclinical and clinical studies highlight reduced toxicity and enhanced anti-tumor efficacy, overcoming TME-driven immune suppression. These approaches mitigate the limitations of high-dose soluble IL-2 therapy, promoting immune activation and minimizing adverse effects. This review critically explores advances in IL-2-based therapies, focusing on immunotoxins, immunocytokines, and IL-2 derivatives. Emphasis is placed on their role in combination strategies, showcasing their potential to target the TME and improve clinical outcomes effectively. Also, the use of IL-2 immunocytokines in "in situ" vaccination to relieve the immunosuppression of the TME is discussed.

To explore the intricate interplay among cytokines, cognitive functioning, and conversion to psychosis in individuals at clinical high-risk (CHR) for psychosis.

We initially enrolled 385 individuals at CHR and 95 healthy controls (HCs). Subsequently, 102 participants at CHR completed the 1-year follow-up assessments, and 47 participants transitioned to psychosis. We assessed the levels of interleukins (IL-1β, IL-2, IL-6, IL-8, IL-10), tumor necrosis factor-α (TNF-α), granulocyte-macrophage colony-stimulating factor (GM-CSF), and vascular endothelial growth factor (VEGF). We comprehensively evaluated cognitive performance across six domains, including speed of processing (SP), attention/vigilance (AV), working memory (WM), verbal learning (VeL), visual learning (ViL), and reasoning and problem-solving (RPS).

Higher baseline cognitive domain scores were associated with elevated GM-CSF and reduced VEGF levels. In the follow-up analysis, significant time effects were observed for IL-1β and IL-2. We also observed significant interaction effects between specific cognitive domains (AV, WM, VeL, and OCS) and levels of cytokine (GM-CSF, IL-1β, IL-6, and TNF-α). Changes in WM were negatively correlated with changes in TNF-α levels and positively correlated with changes in VEGF levels. Variations in VeL were inversely correlated with changes in GM-CSF and IL-10 levels, whereas changes in RPS were positively associated with changes in GM-CSF and IL-8 levels.

Our results revealed intricate associations among cytokine levels, cognitive performance, and psychosis progression.

Sarcoidosis is a granulomatous multiorgan disease, thought to result from exposure to yet unidentified antigens in genetically susceptible individuals. The exaggerated inflammatory response that leads to granuloma formation is highly complex and involves the innate and adaptive immune system. Consecutive immunological studies using advanced technology have increased our understanding of aberrantly activated immune cells, mediators and pathways that influence the formation, maintenance and resolution of granulomas. Over the years, it has become increasingly clear that disease immunopathogenesis can only be understood if the clinical heterogeneity of sarcoidosis is taken into consideration, along with the distribution of immune cells in peripheral blood and involved organs. Most studies offer an immunological snapshot during disease course, while the cellular composition of both the circulation and tissue microenvironment may change over time. Despite these challenges, novel insights on the role of the immune system are continuously published, thus bringing the field forward. This review highlights current knowledge on the innate and adaptive immune responses involved in sarcoidosis pathogenesis, as well as the pathways involved in non-resolving disease and fibrosis development. Additionally, we describe proposed immunological mechanisms responsible for drug-induced sarcoid like reactions. Although many aspects of disease immunopathogenesis remain to be unraveled, the identification of crucial immune reactions in sarcoidosis may help identify new treatment targets. We therefore also discuss potential therapies and future strategies based on the latest immunological findings.

Bronchiectasis is one of the most common comorbidities in severe asthma. However, the mechanisms by which asthma promotes the development and progress of this condition are not well defined. This study aimed to analyze the inflammatory phenotypes and quantify the expression of proinflammatory and remodeling cytokines in asthma patients with and without bronchiectasis.

The study sample comprised individuals with severe asthma and bronchiectasis (group AB, n=55) and a control population of individuals with severe asthma without bronchiectasis (group AC, n=45). Induced sputum samples were obtained and cell types determined by differential cell count. Proinflammatory and bronchial remodeling cytokines (IL-8, neutrophilic elastase, TGFβ1, VEGF, IFN-γ, TNF-α, and GM-CSF) were analyzed by immunoassay in sputum supernatant.

Neutrophilic inflammation was the primary phenotype in both asthma groups. Higher levels of TGFβ1, VEGF and IFN-γ were observed in asthma patients with bronchiectasis (group AB) than in controls (group AC) (15 vs 24pg/ml, p=0.014; 183 vs 272pg/ml, p=0.048; 0.85 vs 19pg/ml, p<0.001, respectively). Granulocyte-macrophage colony-stimulating factor (GM-CSF) levels were significantly lower in the AB group than in the AC group (1.2 vs 4.4pg/ml, p<0.001). IL-8, neutrophil elastase and TNF-α did not present significant differences between the groups.

Raised levels of TGFβ1 and VEGF cytokines may indicate airway remodeling activation in asthma patients with bronchiectasis. The type of inflammation in asthma patients did not differ according to the presence or absence of bronchiectasis.

Nucleic acid vaccines play important roles in prevention and treatment of diseases. However, limited immunogenicity remains a major obstacle for DNA vaccine applications in the clinic. To address the issue, the present study investigates a cocktail approach to DNA vaccination. In this proof-of-the-concept study, the cocktail consists of two DNAs encoding viral hemagglutinin (HA) and granulocyte-macrophage colony stimulatory factor (GM-CSF), respectively. Data from the study demonstrate that recruitment and activation of antigen-presenting cells (APCs) can be substantially improved by spatiotemporal regulation of GM-CSF and HA expressions at the site of vaccination. The types of recruited APCs and their phenotypes are also controllable by adjusting the cocktail compositions. Compared to mono-ingredient vaccine, the optimized cocktail vaccine is able to enhance the anti-viral humoral and T cell immune responses. No significant systemic inflammation has been detected after either prime or boost immunization using the cocktail vaccine. Data in the study suggest that the DNA cocktail is a safe, effective, and controllable platform for improving vaccine efficacy.

To comprehensively identify and provide an overview of in vivo or clinical studies of nucleic acids (NA)-based vaccines against TB we included human or animal studies of NA vaccines for the prevention or treatment of TB and excluded in vitro or in silico research, studies of microorganisms other than M. tuberculosis, reviews, letters, and low-yield reports.

We searched PubMed, Scopus, Embase, selected Web of Science and ProQuest databases, Google Scholar, eLIBRARY.RU, PROSPERO, OSF Registries, Cochrane CENTRAL, EU Clinical Trials Register, clinicaltrials.gov, and others through WHO International Clinical Trials Registry Platform Search Portal, AVMA and CABI databases, bioRxiv, medRxiv, and others through OSF Preprint Archive Search. We searched the same sources and Google for vaccine names (GX-70) and scanned reviews for references. Data on antigenic composition, delivery systems, adjuvants, and vaccine efficacy were charted and summarized descriptively.

A total of 18,157 records were identified, of which 968 were assessed for eligibility. No clinical studies were identified. 365 reports of 345 animal studies were included in the review. 342 (99.1%) studies involved DNA vaccines, and the remaining three focused on mRNA vaccines. 285 (82.6%) studies used single-antigen vaccines, while 48 (13.9%) used multiple antigens or combinations with adjuvants. Only 12 (3.5%) studies involved multiepitope vaccines. The most frequently used antigens were immunodominant secretory antigens (Ag85A, Ag85B, ESAT6), heat shock proteins, and cell wall proteins. Most studies delivered naked plasmid DNA intramuscularly without additional adjuvants. Only 4 of 17 studies comparing NA vaccines to BCG after M. tuberculosis challenge demonstrated superior protection in terms of bacterial load reduction. Some vaccine variants showed better efficacy compared to BCG.

https://osf.io/, identifier F7P9G.

This study evaluates the potential of bioconverted garlic ferments (BGFs) to stimulate the intestinal immune system and modulate cecal microbiota composition.

In vitro, BGF significantly enhances Peyer's patch (PP)-mediated bone marrow cell proliferation and increases the production of interferon-gamma (IFN-γ), granulocyte macrophage-colony stimulating factor (GM-CSF), interleukin (IL)-6, and immunoglobulin A (IgA) but not IL-4, IL-5, and immunoglobulin E (IgE). Oral administration of BGF to C3H/HeN mice for 4 weeks significantly increases the GM-CSF (42.1-45.8 pg mL-1) and IFN-γ (6.5-12.1 pg mL-1) levels in PP cells. BGF also significantly elevates the levels of tumor necrosis factor-alpha (TNF-α, 165.0-236.3 pg mg-1), GM-CSF (2.4-3.0 ng mg-1), and IFN-γ (1.5-3.2 ng mg-1) in the small intestinal fluid, and TNF-α (2.2-3.1 pg mL-1) and IFN-γ (10.3-0.21.5 pg mL-1) in the mouse serum. Cecal microbial analysis reveals that BGF increases Bacteroidota and Verrucomicrobiota and decreases Actinobacteria and Bacillota at the phylum level in mice. At the genus level, BGF significantly increases the abundance of Fusimonas (250 mg kg-1 BW-1 day-1), Bacteroides (125 and 250 mg kg-1 BW-1 day-1), and Akkermansia (125 mg kg-1 BW-1 day-1) and decreases that of Bifidobacterium (62.5 and 250 mg kg-1 BW-1 day-1) and Limosilactobacillus (125 and 250 mg kg-1 BW-1 day-1).

This study provides the first evidence of BGF's ability to modulate the intestinal immune system and gut microbiota, supporting its potential as a novel functional material to enhance gut immunity.

Haematologic malignancies commonly arise from the bone marrow lesion, yet there are currently no effective targeted therapies against tumour cells in this location. Here we constructed a bone-marrow-targeting nanosystem, CSF@E-Hn, which is based on haematopoietic-stem-cell-derived nanovesicles adorned with gripper ligands (aPD-L1 and aNKG2D) and encapsulated with colony-stimulating factor (CSF) for the treatment of haematologic malignancies. CSF@E-Hn targets the bone marrow and, thanks to the gripper ligands, pulls together tumour cells and natural killer cells, activating the latter for specific tumour cell targeting and elimination. The therapeutic efficacy was validated in mice bearing acute myeloid leukaemia and multiple myeloma. The comprehensive assessment of the post-treatment bone marrow microenvironment revealed that the integration of CSF into a bone-marrow-targeted nanosystem promoted haematopoietic stem cell differentiation, boosted memory T cell generation and maintained bone homoeostasis, with long-term prevention of relapse. Our nanosystem represents a promising strategy for the treatment of haematologic malignancies.

Despite a high response rate in chimeric antigen receptor (CAR) T cell therapy for acute lymphocytic leukaemia (ALL)1-3, approximately 50% of patients relapse within the first year4-6, representing an urgent question to address in the next stage of cellular immunotherapy. Here, to investigate the molecular determinants of ultralong CAR T cell persistence, we obtained a single-cell multi-omics atlas from 695,819 pre-infusion CAR T cells at the basal level or after CAR-specific stimulation from 82 paediatric patients with ALL enrolled in the first two CAR T ALL clinical trials and 6 healthy donors. We identified that elevated type 2 functionality in CAR T infusion products is significantly associated with patients maintaining a median B cell aplasia duration of 8.4 years. Analysis of ligand-receptor interactions revealed that type 2 cells regulate a dysfunctional subset to maintain whole-population homeostasis, and the addition of IL-4 during antigen-specific activation alleviates CAR T cell dysfunction while enhancing fitness at both transcriptomic and epigenomic levels. Serial proteomic profiling of sera after treatment revealed a higher level of circulating type 2 cytokines in 5-year or 8-year relapse-free responders. In a leukaemic mouse model, type 2high CAR T cell products demonstrated superior expansion and antitumour activity, particularly after leukaemia rechallenge. Restoring antitumour efficacy in type 2low CAR T cells was attainable by enhancing their type 2 functionality, either through incorporating IL-4 into the manufacturing process or by priming manufactured CAR T products with IL-4 before infusion. Our findings provide insights into the mediators of durable CAR T therapy response and suggest potential therapeutic strategies to sustain long-term remission by boosting type 2 functionality in CAR T cells.

The polarization of macrophages with the resulting inflammatory response play a crucial part in tissue and organ damage due to inflammatory. Study has proved Lian Hua Qing Wen capsules (LHQW) can reduce activation of inflammatory response and damage of tissue derived from the inflammatory reactions. However, the mechanism of LHQW regulates the macrophage-induced inflammatory response is unclear. Therefore, we investigated the mechanism of LHQW regulated the inflammatory response of M1 macrophages by cellular experiments and computer simulations.

This study has analysed the targets and mechanisms of macrophage regulating inflammatory response at gene and protein levels through bioinformatics. The monomeric components of LHQW were analyzed by High Performance Liquid Chromatography (HPLC). We established the in vitro cell model by M1 macrophages (Induction of THP-1 cells into M1 macrophages). RT-qPCR and immunofluorescence were used to detect changes in gene and protein levels of key targets after LHQW treatment. Computer simulations were utilized to verify the binding stability of monomeric components and protein targets.

Macrophages had 140,690 gene targets, inflammatory response had 12,192 gene targets, intersection gene targets were 11,772. Key monomeric components (including: Pinocembrin, Fargesone-A, Nodakenin and Bowdichione) of LHQW were screened by HPLC. The results of cellular experiments indicated that LHQW could significantly reduce the mRNA expression of CCR5, CSF2, IFNG and TNF, thereby alleviating the inflammatory response caused by M1 macrophage. The computer simulations further validated the binding stability and conformation of key monomeric components and key protein targets, and IFNG/Nodakenin was able to form the most stable binding conformation for its action.

In this study, the mechanism of LHQW inhibits the polarization of macrophages and the resulting inflammatory response was investigated by computer simulations and cellular experiments. We found that LHQW may not only reduce cell damage and death by acting on TNF and CCR5, but also inhibit the immune recognition process and inflammatory response by regulating CSF2 and IFNG to prevent polarization of macrophages. Therefore, these results suggested that LHQW may act through multiple targets to inhibit the polarization of macrophages and the resulting inflammatory response.

This single-arm, multicenter, phase 2 trial (NCT04106180) investigated the triple combination of sintilimab (anti-PD1 antibody), stereotactic body radiotherapy (SBRT) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in metastatic non-small cell lung cancer (NSCLC). With a median follow-up of 32.1 months, 18 (36.7%, 90% CI 25.3%-49.5%) of the 49 evaluable patients had an objective response, meeting the primary endpoint. Secondary endpoints included out-of-field (abscopal) response rate (ASR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs). The ASR was 30.6% (95% CI 18.3%-45.4%). The median PFS and OS were 5.9 (95% CI 2.5-9.3) and 18.4 (95% CI 9.7-27.1) months, respectively. Any grade and grade 3 TRAEs occurred in 44 (86.3%) and 6 (11.8%) patients, without grade 4-5 TRAEs. Moreover, in pre-specified biomarker analyses, SBRT-induced increase of follicular helper T cells (Tfh) in unirradiated tumor lesions and patient's blood, as well as of circulating IL-21 levels, was found associated with improved prognosis. Taken together, the triple combination therapy was well tolerated with promising efficacy and Tfh may play a critical role in SBRT-triggered anti-tumor immunity in metastatic NSCLC.

Myeloid-derived suppressor cells (MDSCs), the negative immune regulators, have been demonstrated to be involved in immune responses to a variety of pathological conditions, such as tumors, chronic inflammation, and infectious diseases. However, the roles and mechanisms underlying the expansion of MDSCs in malaria remain unclear. In this study, the phenotypic and functional characteristics of splenic MDSCs during Plasmodium yoelii NSM infection are described. Furthermore, we provide compelling evidence that the sera from P. yoelii-infected C57BL/6 mice containing excess IL-6 and granulocyte-macrophage colony-stimulating factor promote the accumulation of MDSCs by inducing Bcl2 expression. Serum-induced MDSCs exert more potent suppressive effects on T cell responses than control MDSCs within both in vivo P. yoelii infection and in vitro serum-treated bone marrow cells experiments. Serum treatment increases the MDSC inhibitory effect, which is dependent on Arg1 expression. Moreover, mechanistic studies reveal that the serum effects are mediated by JAK/STAT3 signaling. By inhibiting STAT3 phosphorylation with the JAK inhibitor JSI-124, effects of serum on MDSCs are almost eliminated. In vivo depletion of MDSCs with anti-Gr-1 or 5-fluorouracil significantly reduces the parasitemia and promotes Th1 immune response in P. yoelii-infected C57BL/6 mice by upregulating IFN-γ expression. In summary, this study indicates that P. yoelii infection facilitates the accumulation and function of MDSCs by upregulating the expression of Bcl2 and Arg1 via JAK/STAT3 signaling pathway in vivo and in vitro. Manipulating the JAK/STAT3 signaling pathway or depleting MDSCs could be promising therapeutic interventions to treat malaria.

Inhibiting the functional role of negative regulators in immune cells is an effective approach for developing immunotherapies. The serine/threonine kinase hematopoietic progenitor kinase 1 (HPK1) involved in the T-cell receptor signaling pathway attenuates T-cell activation by inducing the degradation of SLP-76 through its phosphorylation at Ser-376, reducing the immune response. Interestingly, several studies have shown that the genetic ablation or pharmacological inhibition of HPK1 kinase activity improves the immune response to cancers by enhancing T-cell activation and cytokine production; therefore, HPK1 could be a promising druggable target for T-cell-based cancer immunotherapy. To increase the immune response against cancer cells, we designed and synthesized KHK-6 and evaluated its cellular activity to inhibit HPK1 and enhance T-cell activation. KHK-6 inhibited HPK1 kinase activity with an IC50 value of 20 nM and CD3/CD28-induced phosphorylation of SLP-76 at Ser-376 Moreover, KHK-6 significantly enhanced CD3/CD28-induced production of cytokines; proportion of CD4+ and CD8+ T cells that expressed CD69, CD25, and HLA-DR markers; and T-cell-mediated killing activity of SKOV3 and A549 cells. In conclusion, KHK-6 is a novel ATP-competitive HPK1 inhibitor that blocks the phosphorylation of HPK1 downstream of SLP-76, enhancing the functional activation of T cells. In summary, our study showed the usefulness of KHK-6 in the drug discovery for the HPK1-inhibiting immunotherapy.

Arginine methylation is a protein posttranslational modification important for the development of skeletal muscle mass and function. Despite this, our understanding of the regulation of arginine methylation under settings of health and disease remains largely undefined. Here, we investigated the regulation of arginine methylation in skeletal muscles in response to exercise and hypertrophic growth, and in diseases involving metabolic dysfunction and atrophy. We report a limited regulation of arginine methylation under physiological settings that promote muscle health, such as during growth and acute exercise, nor in disease models of insulin resistance. In contrast, we saw a significant remodeling of asymmetric dimethylation in models of atrophy characterized by the loss of innervation, including in muscle biopsies from patients with myotrophic lateral sclerosis (ALS). Mass spectrometry-based quantification of the proteome and asymmetric arginine dimethylome of skeletal muscle from individuals with ALS revealed the largest compendium of protein changes with the identification of 793 regulated proteins, and novel site-specific changes in asymmetric dimethyl arginine (aDMA) of key sarcomeric and cytoskeletal proteins. Finally, we show that in vivo overexpression of PRMT1 and aDMA resulted in increased fatigue resistance and functional recovery in mice. Our study provides evidence for asymmetric dimethylation as a regulator of muscle pathophysiology and presents a valuable proteomics resource and rationale for numerous methylated and nonmethylated proteins, including PRMT1, to be pursued for therapeutic development in ALS.

Rhinovirus is a widespread virus associated with several respiratory diseases, especially asthma exacerbation. Currently, there are no accurate therapies for rhinovirus. Encouragingly, it is found that during rhinovirus-induced immunoreactions the levels of certain cytokines in patients' serum will alter. These cytokines may have pivotal pro-inflammatory or anti-inflammatory effects via their specific mechanisms. Thus far, studies have shown that inhibitions of cytokines such as IL-1, IL-4, IL-5, IL-6, IL-13, IL-18, IL-25, and IL-33 may attenuate rhinovirus-induced immunoreactions, thereby relieving rhinovirus infection. Furthermore, such therapeutics for rhinovirus infection can be applied to viruses of other species, with certain practicability.

Helper T cells are traditionally classified into T helper 1 (TH1) and T helper 2 (TH2). The more recent discoveries of T helper 17 (TH17), follicular helper T cells (TFH) and regulatory T cells (Treg) enhanced our understanding on the mechanisms of immune function and hypersensitivity reactions, which shaped the modern perspective on the function and role of these different subsets of helper T cells in hypersensitivity reactions. Each subset of helper T cells has characteristic roles in different types of hypersensitivity reactions, hence giving rise to the respective characteristic clinical manifestations. The roles of helper T cells in allergic contact dermatitis (TH1-mediated), drug rash with eosinophilia and systemic symptoms (DRESS) syndrome (TH2-mediated), and acute generalised exanthematous pustulosis (AGEP) (TH17-mediated) are summarised in this article, demonstrating the correlation between the type of helper T cell involved and the clinical features. TFH plays crucial roles in antibody class-switch recombination; they may be implicated in antibody-mediated hypersensitivity reactions, but further research is warranted to delineate their exact pathogenic roles. The helper T cell subsets and their specific cytokine profiles implicated in different hypersensitivity reactions could be potential treatment targets by biologics, but more clinical trials are warranted to establish their clinical effectiveness.

Developing new adjuvants that can effectively induce humoral and cellular immune responses while broadening the immune response is of great value. In this study, we aimed to develop single-stranded RNA adjuvants expressing (1) granulocyte monocyte colony-stimulating factor or (2) interleukin 18 based on the encephalomyocarditis virus internal ribosome entry site; we also tested their efficacy in combination with ovalbumin or inactivated influenza vaccines. Notably, cytokine-expressing RNA adjuvants increased the expression of antigen-presenting cell activation markers in mice. Specifically, when combined with ovalbumin, RNA adjuvants expressing granulocyte monocyte colony-stimulating factor increased CD4+ T-cell responses, while those expressing interleukin 18 increased CD8+ T-cell responses. Cytokine-expressing RNA adjuvants further increased the frequency of polyclonal T cells with the influenza vaccine and reduced the clinical illness scores and weight loss of mice after viral challenge. Collectively, our results suggest that cytokine-expressing RNA adjuvants can be applied to protein-based or inactivated vaccines to increase their efficacy.

Autoimmune pulmonary alveolar proteinosis (APAP) is a diffuse lung disease that causes abnormal accumulation of lipoproteins in the alveoli; however, its pathogenesis remains unclear. Recently, APAP cases have been reported during the course of dermatomyositis. The combination of these two diseases may be coincidental; however, it may have been overlooked because differentiating APAP from a flare-up of interstitial pneumonia associated with dermatomyositis is challenging. This didactic case demonstrates the need for early APAP scrutiny.

A 50-year-old woman was diagnosed with anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody-positive dermatitis and interstitial pneumonia in April 2021. The patient was treated with corticosteroids, tacrolimus, and cyclophosphamide pulse therapy for interstitial pneumonia complicated by MDA5 antibody-positive dermatitis, which improved the symptoms and interstitial pneumonia. Eight months after the start of treatment, a new interstitial shadow appeared that worsened. Therefore, three additional courses of cyclophosphamide pulse therapy were administered; however, the respiratory symptoms and interstitial shadows did not improve. Respiratory failure progressed, and 14 months after treatment initiation, bronchoscopy revealed turbid alveolar lavage fluid, numerous foamy macrophages, and numerous periodic acid-Schiff-positive unstructured materials. Blood test results revealed high anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibody levels, leading to a diagnosis of APAP. The patient underwent whole-lung lavage, and the respiratory disturbance promptly improved. Anti-GM-CSF antibodies were measured from the cryopreserved serum samples collected at the time of diagnosis of anti-MDA5 antibody-positive dermatitis, and 10 months later, both values were significantly higher than normal.

This is the first report of anti-MDA5 antibody-positive dermatomyositis complicated by interstitial pneumonia with APAP, which may develop during immunosuppressive therapy and be misdiagnosed as a re-exacerbation of interstitial pneumonia. In anti-MDA5 antibody-positive dermatomyositis, APAP comorbidity may have been overlooked, and early evaluation with bronchoalveolar lavage fluid and anti-GM-CSF antibody measurements should be considered, keeping the development of APAP in mind.

Communications between immune cells are essential to ensure appropriate coordination of their activities. Here, we observed the infiltration of activated macrophages into the joint-footpads of chikungunya virus (CHIKV)-infected animals. Large numbers of CD64+MHCII+ and CD64+MHCII- macrophages were present in the joint-footpad, preceded by the recruitment of their CD11b+Ly6C+ inflammatory monocyte precursors. Recruitment and differentiation of these myeloid subsets were dependent on CD4+ T cells and GM-CSF. Transcriptomic and gene ontology analyses of CD64+MHCII+ and CD64+MHCII- macrophages revealed 89 differentially expressed genes, including genes involved in T cell proliferation and differentiation pathways. Depletion of phagocytes, including CD64+MHCII+ macrophages, from CHIKV-infected mice reduced disease pathology, demonstrating that these cells play a pro-inflammatory role in CHIKV infection. Together, these results highlight the synergistic dynamics of immune cell crosstalk in driving CHIKV immunopathogenesis. This study provides new insights in the disease mechanism and offers opportunities for development of novel anti-CHIKV therapeutics.

Inflammatory bowel disease (IBD), especially Crohn's disease (CD), characterized by a chronic inflammatory process and progressive intestinal tissue damage, leads to the unrestrained proliferation of mesenchymal cells and the development of bowel strictures. Complications induced by fibrosis are related to high rates of morbidity and mortality and lead to a substantial number of hospitalizations and surgical procedures, generating high healthcare costs. The development of easily obtained, reliable fibrogenesis biomarkers is essential to provide an important complementary tool to existing diagnostic and prognostic methods in IBD management, guiding decisions on the intensification of pharmacotherapy, proceeding to surgical methods of treatment and monitoring the efficacy of anti-fibrotic therapy in the future. The most promising potential markers of fibrosis include cartilage oligomeric matrix protein (COMP), hepatocyte growth factor activator (HGFA), and fibronectin isoform- extra domain A (ED-A), as well as antibodies against granulocyte macrophage colony-stimulating factor (GM-CSF Ab), cathelicidin (LL-37), or circulatory miRNAs: miR-19a-3p and miR-19b-3p. This review summarizes the role of genetic predisposition, and risk factors and serological markers potentially contributing to the pathophysiology of fibrotic strictures in the course of IBD.