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Genetically modified T cells expressing chimeric antigen receptors (CARs) so far have mostly failed in the treatment of solid tumors owing to a number of limitations, including an immunosuppressive tumor microenvironment and insufficient CAR T cell activation and persistence. Next-generation approaches using CAR T cells that secrete transgenic immunomodulatory cytokines upon CAR signaling, known as TRUCKs (“T cells redirected for universal cytokine-mediated killing”), are currently being explored. As TRUCKs were engineered by the transduction of T cells with two separate vectors, we developed a lentiviral modular “all-in-one” vector system that combines constitutive CAR expression and inducible nuclear factor of activated T cells (NFAT)-driven transgene expression for more efficient production of TRUCKs. Activation of the GD2-specific CAR via GD2+ target cells induced NFAT promoter-driven cytokine release in primary human T cells, and indicated a tight linkage of CAR-specific activation and transgene expression that was further improved by a modified NFATsyn promoter. As proof-of-concept, we showed that T cells containing the “all-in-one” vector system secrete the immunomodulatory cytokines interleukin (IL)12 or IL18 upon co-cultivation with primary human GD2+ tumor cells, resulting in enhanced effector cell properties and increased monocyte recruitment. This highlights the potential of our system to simplify application of TRUCK-modified T cells in solid tumor therapy.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune mediated neuropathy with incompletely defined triggers and no validated biomarkers. We investigated associations between bacterial and fungal communities, short chain fatty acids (SCFAs), and promoter variation with clinically/electrophysiologically relevant measures. We enrolled 32 treatment naive CIDP patients and 15 healthy controls. Stool, serum and cerebrospinal fluid (CSF) samples were collected. Disability was assessed using the clinical scale and related to nerve conduction study (NCS) parameters. promoter variants (rs187238, rs1946518, and rs1946519) were genotyped in haplotype based comparisons. SCFAs were quantified in stool, serum, and CSF. Faecal and CSF microbiota and mycobiota were profiled by amplicon sequencing of the 16S rRNA V3 V4 region and the ITS1 region, respectively. Bioinformatic processing and diversity analyses were performed in QIIME2. Alpha diversity and beta diversity metrics were computed across taxonomic levels. Differential abundance testing was conducted with ANCOM BC2. CIDP was characterised by increased faecal bacterial alpha diversity and significant shifts in beta diversity relative to controls. Diversity patterns differed across clinical subgroups, including diabetes status and disability severity. Higher faecal bacterial diversity metrics correlated with greater NCS abnormalities, whereas associations with beta diversity measures were weaker. Taxonomic analyses identified enrichment of and depletion of in CIDP. SCFAs concentrations correlated with bacterial diversity indices, and haplotypes were associated with distinct microbial signatures. Faecal mycobiota showed no robust case control differences in overall diversity. CSF sequencing revealed a low biomass bacterial signal and diversity metrics correlated with neurophysiological measures. We confirmed the increased gut microbiome alpha diversity in CIDP patients, as observed in previous research. Our findings suggest significant alterations in both gut microbiota and mycobiota during the course of CIDP, which correlate with clinical, electrophysiological, and laboratory parameters.

ObjectivesAllergic rhinitis (AR) is a chronic inflammatory disease of nasal mucosa. Loss of function of Th17 cells and regulatory T (Treg) cells plays a role in the pathogenesis of AR. IL18, FOXP3, and IL13 are key genes in the development of AR. However, the genetic associations between IL18, FOXP3 and IL13 genes polymorphisms and AR risk were inconclusive yet.MethodsA meta-analysis was performed by searching through Pubmed, EMBASE, web of science and CNKI databases. The ORs and 95%CIs were used to assess the genetic association between the allelic, dominant and recessive models of IL18, FOXP3 and IL13 genes polymorphisms and AR risk.ResultsA total of 15 articles (6 for FOXP3, 5 for IL18, and 5 for IL13) were enrolled in the present study. No association was detected between the IL18 rs187238, rs1946518, rs360721, FOXP3 rs2232365, rs3761548 and IL13 rs1800925 polymorphisms and AR risk (p > 0.05). Significant associations were observed between the allelic (p = 0.001, OR 1.32, 95% CI 1.12–1.56), dominant (p = 0.005, OR 1.43, 95% CI 1.11–1.83) and recessive models (p = 0.01, OR 1.64, 95% CI 1.13, 2.40) of IL13 rs20541 and AR risk. Subgroup analysis based on ethnicity revealed that the IL13 rs20541 was significantly associated with AR risk in Asian population (allelic model: p = 0.009, OR 1.36, 95% CI 1.13–1.63, dominant model: p = 0.005, OR 1.43, 95% CI 1.11–1.83; recessive model: p = 0.01, OR 1.64, 95% CI 1.13–2.40).ConclusionsIL13 rs20541 may contribute to the risk of AR in Asian population. To confirm these results, larger number of case–control study with more subjects is necessary in the future.

Multiple studies have investigated the role of blood circulating proteins in COVID-19 disease using the Olink affinity proteomics platform. However, study inclusion criteria and sample collection conditions varied between studies, leading to sometimes incongruent associations. To identify the most robust protein markers of the disease and the underlying pathways that are relevant under all conditions, it is essential to identify proteins that replicate most widely. Here we combined the Olink proteomics profiles of two newly recruited COVID-19 studies (N=68 and N=98) with those of three previously published COVID-19 studies (N=383, N=83, N=57). For these studies, three Olink panels (Inflammation and Cardiovascular II & III) with 253 unique proteins were compared. Case/control analysis revealed thirteen proteins (CCL16, CCL7, CXCL10, CCL8, LGALS9, CXCL11, IL1RN, CCL2, CD274, IL6, IL18, MERTK, IFNγ, and IL18R1) that were differentially expressed in COVID-19 patients in all five studies. Except CCL16, which was higher in controls, all proteins were overexpressed in COVID-19 patients. Pathway analysis revealed concordant trends across all studies with pathways related to cytokine-cytokine interaction, IL18 signaling, fluid shear stress and rheumatoid arthritis. Our results reaffirm previous findings related to a COVID-19 cytokine storm syndrome. Cross-study robustness of COVID-19 specific protein expression profiles support the utility of affinity proteomics as a tool and for the identification of potential therapeutic targets.

Alzheimer’s disease (AD) is characterized by the progressive destruction and dysfunction of central neurons. AD patients commonly have unprovoked seizures compared with age-matched controls. Amyloid peptide-related inflammation is thought to be an important aspect of AD pathogenesis. We previously reported that NLRP3 inflammasome KO mice, when bred into APPswe/PS1ΔE9 (APP/PS1) mice, are completely protected from amyloid-induced AD-like disease, presumably because they cannot produce mature IL1β or IL18. To test the role of IL18, we bred IL18KO mice with APP/PS1 mice. Surprisingly, IL18KO/APP/PS1 mice developed a lethal seizure disorder that was completely reversed by the anticonvulsant levetiracetam. IL18-deficient AD mice showed a lower threshold in chemically induced seizures and a selective increase in gene expression related to increased neuronal activity. IL18-deficient AD mice exhibited increased excitatory synaptic proteins, spine density, and basal excitatory synaptic transmission that contributed to seizure activity. This study identifies a role for IL18 in suppressing aberrant neuronal transmission in AD.

Acute pancreatitis is a common disease with limited supportive treatments. Finding effective biomarkers is of great significance for early diagnosis and therapy, as well as to achieve better prognosis. The core genes of AP were identified through bioinformatics and machine learning. The expression, clinical features, biological function and immunological effects of the characteristic gene were also evaluated. AP murine models were constructed to verify the results in vivo. Finally, Mendelian randomization studies were performed to determine the causal relationship between IL-18 and AP through genome-wide association studies. A total of 100 core genes were obtained, and IL18 was identified as the characteristic gene for AP. The expression of IL18 was increased in AP ( <0.001) with an AUC value of 0.917. And some immune responses were inhibited when IL18 is highly expressed. In addition, the OR for IL18 and AP was 0.908 (95% CI = 0.843-0.978, =0.011) via inverse variance weighting (IVW). Elevated IL18 can be used to predict the clinical prognosis and immune responses in AP. Meanwhile, MR suggests that an increase in IL18 indicates a low risk of AP, implying that the course of AP often presents a self-limiting feature in clinic.

Background Bladder cancer (BC) is the most common malignant disease of the urinary tract. Recurrent high grade non muscle invasive BC carries a serious risk for progression and subsequent metastases. The most common preclinical mouse model for bladder cancer relies on administration of N -butyl- N -(4-hydroxybutyl) nitrosamine (BBN) to mice. BBN-induced tumors in mice recapitulate the histology of human BC and were characterized with an overexpression of markers typical for basal-like cancer subtype in addition to a high mutational burden with frequent mutations in Trp53, similar to human muscle invasive BC. Methods Bladder cancer was induced in C57BL/6J male mice by administering the BBN in the drinking water. A thorough histopathological analysis of bladder specimen during and post BBN treatment was performed at 2, 4, 16, 20 and 25 weeks. RNA sequencing and qPCR was performed to assess the levels of expression of immunologically relevant genes at 2 weeks and 20 weeks during and post BBN treatment. Results We characterized the dynamics of the inflammatory response in the BBN-induced BC in mice. The treatment with BBN had gradually induced a robust inflammation in the first 2 weeks of administration, however, the inflammatory response was progressively silenced in the following weeks of the treatment, until the progression of the primary carcinoma. Tumors at 20 weeks were characterized with a marked upregulation of IL18 when compared to premalignant inflammatory response at 2 weeks. In accordance with this, we observed an increase in expression of IFNγ-responsive genes coupled to a pronounced lymphocytic infiltrate during the early stages of malignant transformation in bladder. Similar to human basal-like BC, BBN-induced murine tumors displayed an upregulated expression of immunoinhibitory molecules such as CTLA-4, PD-L1, and IDO1 which can lead to cytotoxic resistance and tumor escape. Conclusions Despite the recent advances in bladder cancer therapy which include the use of checkpoint inhibitors, the treatment options for patients with locally advanced and metastatic BC remain limited. BBN-induced BC in mice displays an immunological profile which shares similarities with human MIBC thus representing an optimal model for preclinical studies on immunomodulation in management of BC.

Oxaliplatin is widely used in cancer treatment, however, many patients will suffer from neuropathic pain (NP) induced by it at the same time. Therefore exploring the mechanism and founding novel target for this problem are needed. In this study, YTHDF1 showed upregulation in oxaliplatin treated mice. As m6A is known as conserved and it widely functions in numerous physiological and pathological processes. Therefore, we focused on exploring the molecular mechanism of whether and how YTHDF1 functions in NP induced by oxaliplatin. IHC and western blotting were conducted to measure proteins. Intrathecal injection for corresponding siRNAs in C57/BL6 mice or spinal microinjection for virus in YTHDF1 flox/flox mice were applied to specially knockdown the expression of molecular. Von Frey, acetone test and ethyl chloride (EC) test were applied to evaluate NP behavior. YTHDF1, Wnt3a, TNF-α and IL-18 were increased in oxaliplatin treated mice, restricted the molecular mentioned above respectively can significantly attenuate oxaliplatin-induced NP, including the mechanical allodynia and cold allodynia. Silencing YTHDF1 and inhibiting Wnt3a and Wnt signaling pathways can reduce the enhancement of TNF-α and IL-18, and the decreasing of the upregulation of YTHDF1 can be found when inhibiting Wnt3a and Wnts signaling pathways in oxaliplatin treated mice. Our study indicated a novel pathway that can contribute to oxaliplatin-induced NP, the Wnt3a/YTHDF1 to cytokine pathway, which upregulating YTHDF1 functioned as the downstream of Wnt3a signal and promoted the translation of TNF-α and IL-18 in oxaliplatin treated mice.

COVID-19 is characterized by a heterogeneous clinical presentation and prognosis. Risk factors contributing to the development of severe disease include old age and the presence of comorbidities. However, the genetic background of the host has also been recognized as an important determinant of disease prognosis. Considering the pivotal role of innate immunity in the control of SARS-CoV-2 infection, we analyzed the possible contribution of several innate immune gene polymorphisms (including TLR2-rs5743708, TLR4-rs4986790, TLR4-rs4986791, CD14-rs2569190, CARD8-rs1834481, IL18-rs2043211, and CD40-rs1883832) in disease severity and prognosis. A total of 249 individuals were enrolled and further divided into five (5) groups, according to the clinical progression scale provided by the World Health Organization (WHO) (asymptomatic, mild, moderate, severe, and critical). We identified that elderly patients with obesity and/or diabetes mellitus were more susceptible to developing pneumonia and respiratory distress syndrome after SARS-CoV-2 infection, while the IL18-rs1834481 polymorphism was an independent risk factor for developing pneumonia. Moreover, individuals carrying either the TLR2-rs5743708 or the TLR4-rs4986791 polymorphisms exhibited a 3.6- and 2.5-fold increased probability for developing pneumonia and a more severe disease, respectively. Our data support the notion that the host’s genetic background can significantly affect COVID-19 clinical phenotype, also suggesting that the IL18-rs1834481, TLR2-rs5743708, and TLR4-rs4986791 polymorphisms may be used as molecular predictors of COVID-19 clinical phenotype.

Currently, cardiovascular risk associated with COVID-19 has been brought to people's attention, but the mechanism is not clear. The aim of this study is to elucidate the mechanisms based on multiple omics data. Weighted gene co-expression network analysis (WGCNA) was used to identify key pathways. Combination analysis with aneurysm and atherosclerosis related pathways, hypoxia induced factor-1 (HIF-1) signaling were identified as key pathways of the increased cardiovascular risk associated with COVID-19. ScMLnet algorithm based on scRNA-seq was used to explore the regulation of HIF-1 pathway by intercellular communication. Proteomic analysis was used to detect the regulatory mechanisms between IL18 and HIF-1 signaling pathway. Pseudo time locus analysis was used to study the regulation of HIF1 signaling pathway in macrophages and vascular smooth muscle cells (VSMC) phenotypic transformation. The Virtual Inference of protein-activity by Enriched Regulon (VIPER) analysis was used to study the activity of regulatory proteins. Epigenetic analysis based on methylation revealed epigenetic changes in PBMC after SARS-CoV-2 infection. Potential therapeutic compounds were explored by using Cmap algorithm. HIF-1 signaling pathway is a common key pathway for aneurysms, atherosclerosis and SARS-CoV-2 infection. Intercellular communication analysis showed that macrophage-derived interleukin-18 (IL-18) activates the HIF-1 signaling pathway through IL18R1. Proteomic analysis showed that IL18/IL18R1 promote NF-κB entry into the nucleus, and activated the HIF-1 signaling pathway. Macrophage-derived IL18 promoted the M1 polarization of macrophages and the syntactic phenotype transformation of VSMCs. MAP2K1 mediates the functional regulation of HIF-1 signaling pathway in various cell types. Epigenetic changes in PBMC after COVID-19 infection are characterized by activation of the type I interferon pathway. MEK inhibitors are the promising compounds for the treatment of HIF-1 overactivation. The IL18/IL18R1/HIF1A axis is expected to be an therapeutic target for cardiovascular protection after SARS-CoV-2 infection. MEK inhibitors may be an choice for cardiovascular protection after SARS-COV-2 infection.