Cytokine Network Research Articles

Effects of chronic stress on cytokine networks in ovarian cancer ascites (268)

Objectives: A cancer diagnosis increases stress hormones and leads to altered psychological states, such as chronic stress. Work from our team suggests that chronic stress promotes an increased inflammatory response. Preliminary data show an altered CD4+/CD8+ T cell ratio and a heterogeneous expression of exhaustion markers in patients with high-grade serous ovarian cancer (HGSOC). Therefore, we hypothesized that chronic stress increases inflammation and an exhausted tumor microenvironment (TME). We sought to characterize the relationship between stress hormones and adrenergic signaling on cytokine networks in ascites from patients with HGSOC. Methods: We obtained ascites samples from 66 patients with HGSOC and 18 ID8 tumor-bearing mice (8 to 12 - week-old C57BL6/7 female mice) subjected to restraint stress. Then, we measured cytokine levels using a comprehensive Cytokine/Chemokine magnetic bead panel. Cortisol, metanephrine, normetanephrine, and corticosterone levels from ascites were measured by ELISA. Results: Results showed a significant increase in inflammatory cytokines in patients with recurrent tumors, including sCD40L (p=0.0319), IL-6 (p=0.0035), VEGF (p=0.0231), Eotaxin (p=0.0005), IL-15 (p=0.0399) and IL-7 (p=0.01). When assessing cytokines and cortisol levels, we found that elevated cortisol was associated with a downregulation of antitumor cytokines: IP-10 (p=0.0162) and IFN-gamma (p=0.0227). Moreover, metanephrine levels were positively correlated with pro-tumoral and inflammatory cytokines: SCD40L (p=0.032, r=0.3234), FGF-2 (p=0.033, r=0.3217) and MIP1a (p=0.03, r=0.3296). Normetanephrine was also moderately correlated with pro-inflammatory cytokines: IL-6 (p<0.0001, r=0.5241), MCP-1 (p=0.0268, r=0.2790), VEGF (p=0.0042, r=0.3560), MCP-3 (p=0.0130, r=0.3114), GRO (p=0.0129, r=0.3116) and IL-7 (p<0.0001, r=0.5287), while FGF-2 (p=0.0080, r=0.3315) was negatively correlated. In addition, corticosterone levels obtained from ascites derived from our animal model were positively correlated with pro-inflammatory cytokines: VEGF (p<0.0001, r=0.88), TNF-alpha (p=0.036, r=0.498) and Eotaxin (p=0.02, r=0.50). These results suggest a role for stress hormones in increased inflammation and immune exhaustion. Conclusions: Ascites from patients with recurrent HGSOC were associated with increased pro-inflammatory cytokines, while elevated cortisol was associated with a downregulation of antitumor cytokines. Similarly, high metanephrine, normetanephrine, and corticosterone levels correlated with increased expression of pro-inflammatory cytokines. These data suggest a role for stress in immunosuppression and may impact the efficacy of therapies that aim to restore T cell function. Objectives: A cancer diagnosis increases stress hormones and leads to altered psychological states, such as chronic stress. Work from our team suggests that chronic stress promotes an increased inflammatory response. Preliminary data show an altered CD4+/CD8+ T cell ratio and a heterogeneous expression of exhaustion markers in patients with high-grade serous ovarian cancer (HGSOC). Therefore, we hypothesized that chronic stress increases inflammation and an exhausted tumor microenvironment (TME). We sought to characterize the relationship between stress hormones and adrenergic signaling on cytokine networks in ascites from patients with HGSOC. Methods: We obtained ascites samples from 66 patients with HGSOC and 18 ID8 tumor-bearing mice (8 to 12 - week-old C57BL6/7 female mice) subjected to restraint stress. Then, we measured cytokine levels using a comprehensive Cytokine/Chemokine magnetic bead panel. Cortisol, metanephrine, normetanephrine, and corticosterone levels from ascites were measured by ELISA. Results: Results showed a significant increase in inflammatory cytokines in patients with recurrent tumors, including sCD40L (p=0.0319), IL-6 (p=0.0035), VEGF (p=0.0231), Eotaxin (p=0.0005), IL-15 (p=0.0399) and IL-7 (p=0.01). When assessing cytokines and cortisol levels, we found that elevated cortisol was associated with a downregulation of antitumor cytokines: IP-10 (p=0.0162) and IFN-gamma (p=0.0227). Moreover, metanephrine levels were positively correlated with pro-tumoral and inflammatory cytokines: SCD40L (p=0.032, r=0.3234), FGF-2 (p=0.033, r=0.3217) and MIP1a (p=0.03, r=0.3296). Normetanephrine was also moderately correlated with pro-inflammatory cytokines: IL-6 (p<0.0001, r=0.5241), MCP-1 (p=0.0268, r=0.2790), VEGF (p=0.0042, r=0.3560), MCP-3 (p=0.0130, r=0.3114), GRO (p=0.0129, r=0.3116) and IL-7 (p<0.0001, r=0.5287), while FGF-2 (p=0.0080, r=0.3315) was negatively correlated. In addition, corticosterone levels obtained from ascites derived from our animal model were positively correlated with pro-inflammatory cytokines: VEGF (p<0.0001, r=0.88), TNF-alpha (p=0.036, r=0.498) and Eotaxin (p=0.02, r=0.50). These results suggest a role for stress hormones in increased inflammation and immune exhaustion. Conclusions: Ascites from patients with recurrent HGSOC were associated with increased pro-inflammatory cytokines, while elevated cortisol was associated with a downregulation of antitumor cytokines. Similarly, high metanephrine, normetanephrine, and corticosterone levels correlated with increased expression of pro-inflammatory cytokines. These data suggest a role for stress in immunosuppression and may impact the efficacy of therapies that aim to restore T cell function.

Cytokine chemokine network in tumor microenvironment: Impact on CSC properties and therapeutic applications

A subpopulation of cells in many cancers has stem cell traits, mediates metastasis, and contributes to treatment resistance. These cells are considered as cancer stem cells (CSCs). CSC properties of tumor cells are immensely regulated by close interactions with tumor microenvironment components such as mesenchymal stem cells, tumor related fibroblasts, adipocytes, endothelial cells, and immune cells via the intricate network of cytokines, chemokines, and growth factors. Inflammatory cytokines including interleukin (IL)-1, IL-6, and IL-8 play a major role in these interactions via the activation of signal transduction pathways like Stat3/NF-κB etc. in stromal and tumor cells. The activation of these pathways increases the release of more cytokines, resulting in positive feedback loops which help in CSC self-renewal. The pathways controlled by these cytokine loops are similar to those that are active during chronic inflammation and wound healing, suggesting that they might have critical role in establishing relationship between inflammation and cancer. Anti-inflammatory drugs have been identified to inhibit these cytokines and their receptor mediated pathways. These agents have the potential to target CSCs by inhibiting signals from the tumor microenvironment and considered to be a potential candidate for future therapeutics. The significance of cytokines released from the tumor microenvironment in different phases of cancer, as well as their potential application in cancer therapeutics is discussed in this article.

Jak Inhibitors for Treatment of Autoimmune Diseases: Lessons from Systemic Sclerosis and Systemic Lupus Erythematosus.

Systemic sclerosis and systemic lupus erythematosus represent two distinct autoimmune diseases belonging to the group of connective tissue disorders. Despite the great progress in the basic science, this progress has not been translated to the development of novel therapeutic approaches that can radically change the face of these diseases. The discovery of JAK kinases, which are tyrosine kinases coupled with cytokine receptors, may open a new chapter in the treatment of so far untreatable diseases. Small synthetic compounds that can block Janus kinases and interact directly with cytokine signalling may provide therapeutic potential in these diseases. In this review, we discuss the therapeutic potential of Jak kinases in light of the cytokine network that JAK kinases are able to interact with. We also provide the theoretical background for the rationale of blocking cytokines with specific JAK inhibitors.

Simultaneous Effect of Aerobic Training and Resveratrol Supplementation on Interleukin-6 Serum Levels in Women With Type 2 Diabetes

Background and Aims Diabetes pathogenesis is driven by a complex network of pro-inflammatory cells and cytokines, of which interleukin-6 (IL-6) plays a key role in the chronic inflammation associated with type 2 diabetes. The use of supplements and plant extracts and exercise to treat type 2 diabetes is common today. The aim of this study was to evaluate the simultaneous effect of aerobic training and resveratrol supplementation on IL-6serum levels in women with type 2 diabetes. Methods This study was a quasi-experimental study with a pre-test-post-test design and a control group, in which 24 women with type 2 diabetes were randomly assigned to three equal groups of supplement (age 55.25±5.11 years), training+supplement (400 mg resveratrol) (age 54.62±7.22 years), and control (age 52.25±8.60 years). The subjects practiced for six weeks and every week for three days for 40-60 min and at a heart rate of 45-65. Data analysis was performed using analysis of covariance and correlated t-test at the significant level of &lt;0.05. Results The results showed that after the intervention, IL-6 serum levels in the aerobic training + supplement group (P=0.01) had a significant decrease compared to the supplement and control groups. Examination of intergroup changes shows that there was a significant difference in IL-6 levels between the training + supplement group and the supplement group (P=0.002, f=1.56). Also, the results of the Tukey post hoc test showed that there was a significant difference between the control group and the training + supplement group (P=0.003) and between the supplement group and the training+supplement group in IL-6 levels (P=0.031). Conclusion Based on the findings of the present study, it seems that concomitant use of resveratrol supplementation and aerobic training can reduce the levels of IL-6 and the supplement have anti-inflammatory and protective effects in women with type 2 diabetes.

Single-Cell Transcriptomics of Proliferative Phase Endometrium: Systems Analysis of Cell-Cell Communication Network Using CellChat.

The endometrium thickness increases by which endometrial angiogenesis occurs in parallel with the rapid growth of endometrium during the proliferative phase, which is orchestrated by complex cell–cell interactions and cytokine networks. However, the intercellular communication has not been fully delineated. In the present work, we studied the cell–cell interactome among cells of human proliferative phase endometrium using single-cell transcriptomics. The transcriptomes of 33,240 primary endometrial cells were profiled at single-cell resolution. CellChat was used to infer the cell–cell interactome by assessing the gene expression of receptor–ligand pairs across cell types. In total, nine cell types and 88 functionally related signaling pathways were found. Among them, growth factors and angiogenic factor signaling pathways, including EGF, FGF, IGF, PDGF, TGFb, VEGF, ANGPT, and ANGPTL that are highly associated with endometrial growth, were further analyzed and verified. The results showed that stromal cells and proliferating stromal cells represented cell–cell interaction hubs with a large number of EGF, PDGF incoming signals, and FGF outgoing signals. Endothelial cells exhibited cell–cell interaction hubs with a plenty of VEGF, TGFb incoming signals, and ANGPT outgoing signals. Unciliated epithelial cells, ciliated epithelial cells, and macrophages exhibited cell–cell interaction hubs with substantial EGF outgoing signals. Ciliated epithelial cells represented cell–cell interaction hubs with a large number of IGF and TGFb incoming signals. Smooth muscle cells represented lots of PDGF incoming signals and ANGPT and ANGPTL outgoing signals. This study deconvoluted complex intercellular communications at the single-cell level and predicted meaningful biological discoveries, which deepened the understanding of communications among endometrial cells.

NR4A1-3 nuclear receptor activity and immune cell dysregulation in rheumatic diseases.

The development and progression of immune-mediated rheumatic disease (IMRD) involves dysfunction of innate and adaptive immune cell populations leading to altered responses including inflammasome activation, dysregulated cytokine networks, increased immune cell numbers and multifaceted cell-cell communication. Several rheumatic diseases are further characterized by the presence of autoantibodies, immune complex mediated complement activation and the deficit of peripheral immune tolerance due to reduced regulatory T-lymphocyte cell function. Ultimately, in rheumatic disease the loss in cellular and tissue homeostasis culminates in the advancement of chronic inflammation. The three members of the NR4A subfamily of nuclear receptors are immediate early genes, and act as potent transcriptional responders to changes in the cellular and tissue microenvironment. Subfamily members are rapidly expressed in diseases characterized by inflammation and function to control the differentiation and activity of innate and adaptive immune cells in a cell-type and cell-context specific manner. Rheumatic disease including rheumatoid-, psoriatic-, osteo-arthritis and systemic sclerosis display altered NR4A1-3 activity in controlling immune cell migration and function, production of paracrine signaling molecules, synovial tissue hyperplasia, and regulating cartilage turn-over in vivo. Additionally, NR4A1-3 activities mediate cytokine, prostanoid and growth factor signaling to control angiogenesis, modulate the regulatory functions of mesenchymal stromal cells, alter the activation status of dendritic cells, influence the generation of peripheral myeloid and T-lymphocyte lineages and promote the maintenance of functional regulatory T-cells. Further reports uncover the potential of moderating NR4A 1-3 receptors as therapeutic targets in altering immune tolerance, pathological angiogenesis and controlling inflammation in several models of disease.

LPAR2-mediated action promotes human renal cell carcinoma via MAPK/NF-κB signaling to regulate cytokine network.

Lysophosphatidic acid (LPA) exerts various physiological and pathological effects by activating its distinct G-protein-coupled LPA receptors. We demonstrated that LPA can increase the migration and proliferation of renal carcinoma cells. Meanwhile, LPAR1 and LPAR2 were preferentially expressed in renal cancer (RC) cell lines. So, the study aimed to determine the LPA receptor subtypes involved in LPA-induced actions and whether they could be used as a precision therapeutic target for renal cancer. Biological approaches combined with big data analysiswere usedto demonstrate the role of LPAR2 in the progression of renal cancer. We found that the proliferation, clone formation, and migration in response to LPA were enhanced in LPAR2-overexpressing renal cancer cells, whereas, the actions were suppressed by LPAR2 antagonist in the cells. LPAR2 has also shown clinical diagnostic and prognostic value in renal carcinoma based on bioinformatics analysis and clinical tissue microarray analysis. In vivo study shown that tumor growth and metastasis were significantly increased in the LPAR2-overexpressing cells-derived solid tumors. LPA stimulated MAPK and NF-κB activation, and LPA-induced actions were inhibited by MAPKs and NF-κB inhibitors, respectively. Subsequently, the transcriptomic results revealed that LPAR2 strongly affected the cytokines production, and the increased IL6, CXCL8, and TNF were confirmed again using Kit assay. We have identified that LPAR2 is critical for LPA-promoted renal cancer progression, and the actions mainly dependent the MAPK and NF-κB activation mechanism. Then, the expression of inflammatory factors activated by NF-κB is also suspected to be involved in LPAR2-mediated carcinogenesis. Thus, LPAR2 may be a promising therapeutic target for renal cancer.

In Prostate Cancer Cells Cytokines Are Early Responders to Gravitational Changes Occurring in Parabolic Flights

The high mortality in men with metastatic prostate cancer (PC) establishes the need for diagnostic optimization by new biomarkers. Mindful of the effect of real microgravity on metabolic pathways of carcinogenesis, we attended a parabolic flight (PF) mission to perform an experiment with the PC cell line PC-3, and submitted the resulting RNA to next generation sequencing (NGS) and quantitative real-time PCR (qPCR). After the first parabola, alterations of the F-actin cytoskeleton-like stress fibers and pseudopodia are visible. Moreover, numerous significant transcriptional changes are evident. We were able to identify a network of relevant PC cytokines and chemokines showing differential expression due to gravitational changes, particularly during the early flight phases. Together with differentially expressed regulatory lncRNAs and micro RNAs, we present a portfolio of 298 potential biomarkers. Via qPCR we identified IL6 and PIK3CB to be sensitive to vibration effects and hypergravity, respectively. Per NGS we detected five upregulated cytokines (CCL2, CXCL1, IL6, CXCL2, CCL20), one zink finger protein (TNFAIP3) and one glycoprotein (ICAM1) related to c-REL signaling and thus relevant for carcinogenesis as well as inflammatory aspects. We found regulated miR-221 and the co-localized lncRNA MIR222HG induced by PF maneuvers. miR-221 is related to the PC-3 growth rate and MIR222HG is a known risk factor for glioma susceptibility. These findings in real microgravity may further improve our understanding of PC and contribute to the development of new diagnostic tools.

The Role of Inflammatory Cytokines in the Pathogenesis of Colorectal Carcinoma-Recent Findings and Review.

The inflammatory process plays a significant role in the development of colon cancer (CRC). Intestinal cytokine networks are critical mediators of tissue homeostasis and inflammation but also impact carcinogenesis at all stages of the disease. Recent studies suggest that inflammation is of greater importance in the serrated pathway than in the adenoma-carcinoma pathway. Interleukins have gained the most attention due to their potential role in CRC pathogenesis and promising results of clinical trials. Malignant transformation is associated with the pro-tumorigenic and anti-tumorigenic cytokines. The harmony between proinflammatory and anti-inflammatory factors is crucial to maintaining homeostasis. Immune cells in the tumor microenvironment modulate immune sensitivity and facilitate cancer escape from immune surveillance. Therefore, clarifying the role of underlying cytokine pathways and the effects of their modulation may be an important step to improve the effectiveness of cancer immunotherapy.

Compound Ipratropium Bromide plus Budesonide Inhalation in the Treatment of Acute Exacerbation of Chronic Obstructive Pulmonary Disease and Its Effect on Heparin-Binding Protein.

Objective To analyze the clinical effect of compound ipratropium bromide combined with budesonide atomization inhalation on acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and its effect on the heparin-binding protein. Methods A total of 110 patients with AECOPD who were admitted to our hospital between January 2020 and January 2021 were enrolled and assigned into control group (conventional treatment + compound ipratropium bromide) and combined group (conventional treatment + compound ipratropium bromide + budesonide) in a 1 : 1 ratio according to different treatment methods. The clinical effects, pulmonary function indexes, and heparin-binding protein levels before and after treatment were compared between the two groups. Results The treatment with oxygen-driven nebulization of ipratropium bromide combined with budesonide led to a significantly higher total effective rate versus the treatment with ipratropium bromide alone (P < 0.001). After treatment, remarkably higher arterial oxygen partial pressure (PaO2), arterial oxygen saturation (SaO2), forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and FEV1/FVC in the combined group vs. the control group were observed (P < 0.001). The carbon dioxide partial pressure (PaCO2) levels in the two groups were significantly lower than those before treatment, and the decrease in the combined group was greater (P < 0.001). A significantl reduction was observed in heparin-binding protein in both groups after treatment, and the decrease in the combined group was greater versus the control group (P < 0.001). Conclusion Compound ipratropium bromide plus budesonide via aerosol inhalation therapy might be a preferable approach for AECOPD patients. It exhibits a synergistic effect on inhibiting inflammatory mediators and cytokine networks, significantly reduces airway hyperresponsiveness, and improves blood gas indicators and lung function.

Recent Update on Immunopathogenesis of Psoriasis.

Psoriasis is a chronic disabling complex inflammatory disorder prevalent worldwide with environmental and genetic components that involve predominantly skin in addition to nails and joints associated with various systemic comorbidities having periods of exacerbations and remissions. Psoriasis is characterized by hyper-proliferation as well as abnormal differentiation of epidermal keratinocytes and lymphocyte infiltration (mainly T cells) with resultant inflammatory cytokines and chemokines. Immunological and genetic studies over the last decade have identified genetic susceptibility risk alleles, molecular, cellular and immunological mechanisms involved in immunopathogenesis of psoriasis. The current disease model emphasizes the role of aberrant Th1 and Th17 responses regulated by a complex network of different cytokines, including TNF-α, IL-17 and IL-23; signal transduction pathways downstream to the cytokine receptors; and various activated transcription factors, including NF-κB, interferon regulatory factors and signal transducer and activator of transcriptions. Cytokines targeting biologics (IL-17, IL-23 and TNFα) therapies have revolutionized the management of severe skin disease having beneficial effects on joints and systemic inflammation of psoriasis as well. Further better understanding of immunopathogenesis of psoriasis will pave way for precision medicine based on specific immunopathogenic targets in a given phenotype of disease. Complex interplay of psoriasis with associated comorbidities is also a future area of research for overall better patient management and to improve their quality of life.

TOWARDS A NETWORK APPROACH IN THE CHARACTERIZATION OF THE IMMUNE RESPONSE IN COLORECTAL CANCER

Objectives: Colorectal cancer (CRC) is one of the tumors with a dominant inflammatory component. An impressive volume of research has focused on the potential diagnostic or therapeutic application of the molecules (cytokines, adhesion molecules, others) that alter their expression during inflammation in tumors. However, recently these molecules have been shown to establish complicated relations (cytokine networks) in tumor biology. The present study aims to characterize the cytokine network in colorectal cancer, to highlight the quantitative development of immune modules, the ways in which they are organized and to determine whether there is a superior level coordination in the immune response in colorectal cancer. Methods: The serum levels of nine interleukins (IL-1β, IL-6, IL-8, IL-33, IL-17A, IL-22, IFN (interferon)-γ, IL-4 and IL-10) two cell adhesion molecules-ICAM-1 and P-sel (P-selectin)- and a matrix-metalloproteinase (MMP-7) were measured by ELISA (Enzyme-linked immunosorbent assay) in thirty-three CRC patients and thirty-five healthy controls. Cytokines were selected to represent the main immune networks in CRC. Data were processed in order to find molecules with correlated or group behavior. Results: Three groups or ensembles and a number of independent modules were determined by the present study. Conclusions: The study highlights a heterogenous immune response, with an overall reduced level, with both pro-and antitumoral elements, which tend to be organized into functional groups. This may serve as starting point for strategic approaches in therapy. Keywords: Colorectal, cancer, cytokine, adhesion, network

Social environment improves the cytokine profile and lymphoproliferative response in chronologically old and prematurely aging mice

Among the age-associated changes in the immune system, the most evident is the decrease in proliferative responses of lymphocytes to mitogenic stimuli, which is accompanied by the loss of cytokine network homeostasis. Chronic low-grade inflammatory stress, termed as sterile inflammation, is also observed during aging. In chronologically and prematurely aging mice, cohabitation with adult animals for two months favored improvements in several immune functions. This study aimed to determine whether cohabitation could restore several cytokine networks, improve lymphoproliferative responses to mitogens, and diminish sterile inflammation. Chronologically old mice (76 ± 4 weeks) and prematurely aging mice (33 ± 4 weeks) (PAM and TH-HZ) were cohabited with adults (without premature aging) for two months. Subsequently, lymphoproliferation in both basal (unstimulated) conditions and in the presence of mitogenic stimuli lipopolysaccharide A (LPS) or concanavalin A (ConA) was analyzed in cultures of peritoneal leukocytes for 48 h. Cytokine secretions (IL-1β, TNF-α, IL-6, IL-10, and IL-17) in these cultures were also evaluated. The results showed that cohabitation restored the levels of these cytokines in old and prematurely aging mice and improved the subsequent lymphoproliferative responses. In addition, this social strategy diminished sterile inflammation and decreased inflammatory stress in unstimulated conditions. Therefore, this strategy seems to be capable of restoring the relevant immune function of lymphocytes and reducing the inflammatory stress, which are the improvements required for an adequate immune response.

The alterations of cerebrospinal fluid TNF-alpha and TGF-beta2 levels in early relapsing-remitting multiple sclerosis.

This study aimed to analyze serum and cerebrospinal fluid (CSF) concentrations of proinflammatory and anti-inflammatory cytokines produced by T regulatory (Treg) cells in early RRMS according to the 2017 McDonald criteria. Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS) with the cytokine network playing an important role. However, there is a continual lack of data regarding the immunopathogenesis of early RRMS, especially according to the 2017 McDonald criteria. The study groups included early RRMS patients during relapse (n = 18), remission (n = 14), and the control group. The MS diagnosis was established according to the 2017 McDonald criteria. Patients were studied up to 1year after diagnosis was made. A quantitative test kit based on ELISA was used for cytokine measurement in the serum and CSF. Comparative and correlation analyses between the levels of TNF-α, TGF-β2, IgG index, and relapse duration were performed. Significantly higher CSF concentrations of TNF-α in both RRMS-relapse and RRMS-remission groups were found compared to the controls (p &lt; 0.01). The CSF levels of TGF-β2 in the RRMS-relapse group were significantly lower in comparison to the control group (p = 0.01). An inappropriate inflammatory response seems to occur in early RRMS and includes the production of TNF-α and a decrease in TGF-β2 release suggesting a significant Treg cells role. Further studies on the topic may contribute to developing new disease-modifying drugs and biochemical markers of the disorder.

From Unknown Unknowns to Known Unknowns: Intestinal Microbiota As a Previously Unappreciated Contributor to Cytokine Networks

From Unknown Unknowns to Known Unknowns: Intestinal Microbiota As a Previously Unappreciated Contributor to Cytokine Networks

Resistin Associated With Cytokines and Endothelial Cell Adhesion Molecules Is Related to Worse Outcome in COVID-19.

IntroductionResistin is reported to form a cytokine network and cause endothelial damage. The pathogenesis of coronavirus disease 2019 (COVID-19) remains unknown, but the association between cytokine storm and endothelial damage is crucial. This study aimed to evaluate resistin in COVID-19 pathogenesis compared with sepsis.Materials and MethodsFirst, we evaluated the association of plasma resistin levels and disease severity and clinical outcome in two large cohorts: a publicly available cohort including 306 COVID-19 patients in the United States (MGH cohort) and our original cohort including only intubated 113 patients in Japan (Osaka cohort 1). Second, to understand pathogenesis, we evaluate resistin, cytokines and endothelial cell adhesion molecules in COVID-19 compared with sepsis. Blood samples were collected from 62 ICU-treated COVID-19 patients and 38 sepsis patients on day 1 (day of ICU admission), days 2-3, days 6-8, and from 18 healthy controls (Osaka cohort 2). The plasma resistin, inflammatory cytokines (IL-6, IL-8, MCP-1 and IL-10) and endothelial cell adhesion molecules (ICAM-1 and VCAM-1) were compared between patients and control. Correlations among resistin, inflammatory cytokines and endothelial cell adhesion molecules were evaluated in COVID-19 and sepsis.ResultsIn the MGH cohort, the day 1 resistin levels were associated with disease severity score. The non-survivors showed significantly greater resistin levels than survivors on days 1, 4 and 8. In the Osaka cohort 1, 28-day non-survivors showed significantly higher resistin levels than 28-day survivors on days 6-8. Patients with late recovery (defined as the day of weaning off mechanical ventilation >12 or death) had significantly higher resistin levels than those with early recovery on day 1 and days 6-8. In the Osaka cohort 2, plasma resistin levels were elevated in COVID-19 and sepsis patients compared to controls at all measurement points and were associated with inflammatory cytokines and endothelial cell adhesion molecules.ConclusionResistin was elevated in COVID-19 patients and was associated with cytokines and endothelial cell adhesion molecules. Higher resistin levels were related to worse outcome.

Abstract 4214: LIGHT (TNFSF14) costimulation with TIGIT blockade broadens the activity of checkpoint inhibitors (CPIs) into CPI refractory and resistant tumors through targeted myeloid cell and effector lymphocyte activation

Abstract Although increased TIGIT expression on TILs is associated with poor survival in patients with cancer, monotherapy TIGIT antibody blockade has not yet demonstrated significant clinical activity. PD-1 is commonly co-expressed on TILs, and PD-1 mediated SHP-2 signaling inhibits DNAM-1 (CD226), preventing PVR co-stimulation in the setting of TIGIT blockade. The interaction between PD-1 and CD226 explains why TIGIT blockade only translates to clinical benefit in the setting of co-blockade of PD-1/L1, however does not explain why co-blockade of TIGIT and PD-1/L1 does not provide benefit in advanced and PD-1/L1 resistant tumors. In advanced and PD-1/L1 resistant tumors, progressive downregulation of CD226 has been reported. Thus, we hypothesized that the lack of CD226 may underlie the lack of clinical responses to combined TIGIT/PD-1/L1 blockade in PD-1/L1 experienced tumors and we sought to identify alternative costimulatory receptors with high-expression. Analysis of TCGA, as well as single-cell RNASeq from TILs, identified HVEM and LTβR as two costimulatory receptors with higher expression in advanced cancers as compared to CD226. HVEM and LTβR directly activate CD8+ T, natural killer (NK), and myeloid cells when bound by their TNF superfamily ligand, known as LIGHT. LIGHT potentiates effector lymphocyte function through signaling that obviates the co-stimulatory role of DNAM-1. We demonstrated that when the extracellular domain (ECD) of LIGHT is combined with the ECD of TIGIT on a TIGIT-Fc-LIGHT bi-functional fusion protein, the simultaneous blockade of PVR, PVRL2, PVRL3, and Nectin-4 and immune co-stimulation by LIGHT increased CD8+ T and NK infiltration into tumors. This translated into tumor cell killing, regression of established tumors, and improved survival in preclinical models of checkpoint primary and acquired resistance. The translation of TIGIT-Fc-LIGHT activity was evaluated in cynomolgus macaques and was well tolerated at doses up to 40 mg/kg. A series of adaptive immune and proinflammatory cytokines, including IL-2, CCL2, CCL4, IL-10, CXCL10, and CCL17, were induced within two hours of TIGIT-Fc-LIGHT infusion. Additionally, receptor engagement led to the rapid margination of HVEM+CD8+ T cells from the periphery into secondary immune tissues. This network of cytokines and post-dose immune cell margination identified in the monkey, was identical to findings in murine models that ultimately translated into significant anti-tumor responses. Lastly, the combination of TIGIT-Fc-LIGHT with anti-PD(L)1 broadened anti-tumor activity of the checkpoint antibodies in aggressive CPI-resistant tumors. These results suggest that LIGHT could be the differentiator that extends the clinical activity of conventional CPIs into PD-L1 low or CPI acquired resistance tumors. Citation Format: Kyung Jin Yoo, Louis Gonzalez, Kellsey Johannes, Jayalakshmi Miriyala, Karen Lenz, Kristen Campbell, Suresh de Silva, Taylor H. Schreiber, George J. Fromm. LIGHT (TNFSF14) costimulation with TIGIT blockade broadens the activity of checkpoint inhibitors (CPIs) into CPI refractory and resistant tumors through targeted myeloid cell and effector lymphocyte activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4214.

COVID- 19 Following Acute Psychosis: Case series report

IntroductionCoronavirus disease (COVID-19) could result in various medical consequences. Clinical manifestations are diverse and range from asymptomatic or mild, fever-like symptoms, to more severe and life-threatening complications. Although the clinical presentation was initially dominated by respiratory symptoms, psychiatric symptoms and sequelae have been reported in COVID- 19 patients and convalescents.ObjectivesTo describe four clinical case reports of patients admitted to the inpatient unit of Psychiatric Hospital Sarajevo (PHS) with acute onset of psychosis in the recovery stage of COVID-19.Methods In this case series we report cases of 4 patients, all female, mean age 53.25 years, hospitalized in PHS during the third wave of the COVID-19 pandemic. All developed psychotic symptoms in the recovery phase of COVID-19. None had a previous history of psychiatric disturbances of any kind. All patients were diagnosed with brief psychotic disorder (BPD), according to DSM 5 criteria for BPD.ResultsCOVID-19 affects various organ systems, including the brain, with variable symptoms based on disease severity. Psychotic features have been observed as well. The pathophysiology and direct biological effects of the disease are not fully understood. COVID-19 patients and convalescents can develop psychotic symptoms as a consequence of multiple concurrent factors. Several proposed mechanisms include direct central nervous system infiltration, cytokine network dysregulation, peripheral immune cell transmigration, and post-infectious autoimmunity [1], treatments used to manage the infection, and psychosocial stress.ConclusionsClinicians need to be aware of possible psychotic manifestations in COVID-19 patients and survivors. Long-term follow-up is warranted to provide efficient patient care.DisclosureNo significant relationships.

Cytokine network analysis in a community-based pediatric sample of patients with myalgic encephalomyelitis/chronic fatigue syndrome.

Studies have demonstrated immune dysfunction in adolescents with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS); however, evidence is varied. The current study used network analysis to examine relationships between cytokines among a sample of pediatric participants with ME/CFS. 10,119 youth aged 5-17 in the Chicagoland area were screened for ME/CFS; 111 subjects and controls were brought in for a physician examination and completed a blood draw. Youth were classified as controls (Cs, N = 43), ME/CFS (N = 23) or severe (S-ME/CFS, N = 45). Patterns of plasma cytokine networks were analyzed. All participant groups displayed a primary network of interconnected cytokines. In the ME/CFS group, inflammatory cytokines IL-12p70, IL-17A, and IFN-γ were connected and included in the primary membership, suggesting activation of inflammatory mechanisms. The S-ME/CFS group demonstrated a strong relationship between IL-17A and IL-23, a connection associated with chronic inflammation. The relationships of IL-6 and IL-8 in ME/CFS and S-ME/CFS participants also differed from Cs. Together, these results indicate pro-inflammatory responses in our illness populations. Our data imply biological differences between our three participant groups, with ME/CFS and S-ME/CFS participants demonstrating an inflammatory profile. Examining co-expression of cytokines may aid in the identification of a biomarker for pediatric ME/CFS.

Cytokine markers of clinical variants of infective endocarditis

Introduction. Infective endocarditis is a bacterial disease. Pathogen is localized mainly on heart valves and endocardium. This condition is accompanied by immunopathological manifestations and potential generation of septic process being unfavorable prognosis for disease outcome. Currently, the causes of death of patients with endocarditis have been increasingly presented as thromboembolic complications, which severity depends on variant of the disease course. An important role in imbalanced immune system in the infectious process is assigned to altered intercellular interaction mediated via cytokine network. Activated immune cells produce cytokines, which investigating is important in terms of interpreting changes in immune system functionality, assessing the severity of diseases and controlling therapeutic effectiveness. Infective endocarditis remains a severe disease associated with high mortality despite current advances in diagnostics and treatment. A timely diagnostic process and early initiation of treatment are major factors for successful patient management necessitating to improve diagnostics of various clinical variants of endocarditis course, taking into account pathogenetically relevant cytokines. Objective was to comparatively evaluate the importance of serum cytokine concentrations in patients with uncomplicated course of infective endocarditis and its thromboembolic complications and determine cytokine markers of various variants of endocarditis course. Materials and methods. An immunological examination of 119 blood serum samples from patients with confirmed diagnosis of infectious endocarditis and 20 samples from apparently healthy persons was carried out. Depending on the clinical disease form, the patients were divided into 4 groups: group 1 primary infective endocarditis (PIE) with thromboembolic complications (n = 24), 2 PIE without thromboembolic complications (n = 34), 3 secondary IE with thromboembolic complications (n = 27), 4 secondary IE without thromboembolic complications (n = 34). The control group consisted of 20 apparently healthy subjects. Immunological studies of serum cytokine concentrations were conducted in all groups. Results. Statistically significant increase in serum concentration of IL-10, IL-6, VEGF-A, IL-18, IL-1Ra and IL-8 was revealed in all clinical groups of patients compared to those in control group (p 0,05). By correlation analysis, we found a significant positive relationship between IL-10 and IL-18 or IL-6. An increase in the concentration of IL-10 leads to increased level of pro-inflammatory IL-18 and IL-6. The marker of secondary endocarditis was observed as increased level of serum concentrations of IFN. A characteristic feature of primary infective endocarditis with thromboembolic complications was revealed as significantly increased serum concentration of IL-8, IL-1Ra and IL-6. Markers of secondary complicated endocarditis were identified as increased level of IL-6, VEGF-A and IL-18.