Changes In Cytokine Profile Research Articles

Change in cytokine profiles released by mast cells mediated by lung cancer-derived exosome activation may contribute to cancer-associated coagulation disorders

BackgroundCoagulation disorders are a significant cause of lung cancer mortality. Although mast cells are known to play a role in coagulation abnormalities, their specific role in this process has not yet been elucidated.MethodWe detected mast cells in the tumor microenvironment using single-cell sequencing data and examined their correlation with thrombosis-related genes, neutrophil-related genes, neutrophil extracellular trap-related signature genes, and immune infiltration levels in lung cancer patients through bioinformatics analysis. Bone marrow mast cell uptake of exosomes isolated from the lung adenocarcinoma cell line A549, which were labeled using PKH67, was observed using confocal microscopy. Mast cell degranulation was detected by measuring the β-hexosaminidase release rate. Additionally, cytokine array analysis was performed to identify altered mediators released by bone marrow mast cells after uptake of the exosomes.ResultsIn our study, we found a close correlation between the proportion of mast cells in lung cancer patients and the expression levels of thrombosis-related genes and neutrophil extracellular trap signature genes, both of which play a key role in thrombophilic disorder. Moreover, we discovered that lung cancer cell-derived exosomes can be taken up by mast cells, which in turn become activated to release procoagulant mediators.ConclusionOur study shows that exosomes derived from lung cancer cells can activate mast cells to release procoagulants that may contribute to abnormal blood clotting in lung cancer patients.1oJ_R92kgJ4YF4EGRWZHdzVideo

Abstract 4898: Imipridones and EZH2 inhibitors induce similar changes in cytokines and regulated genes in GBM and DMG while vorinostat potentiates anti-tumor efficacy despite variability in cytokine profiles

Abstract TIC10/ONC201 and ONC206 are small molecule imipridones with anti-cancer activity. ONC201, EZH2i and HDACi can modulate tumor microenvironment (TME) and antitumor immunity. We studied the impact of these drugs or their combinations on the TME or tumor immunity by investigating cytokine profiles. We treated U251 GBM and HCT116 CRC cells with vorinostat and found upregulation of CXCL11, CXCL14, INF-γ and TRAIL, and downregulation of prolactin, CXCL9, VEGF and CCL2 in U251. CXCL11 promotes anti-tumor immunity by increasing activated CD8+ T cells in tumors but was associated with metastasis of GBM. CXCL13 induces tertiary lymphoid structures and enhances infiltration of CD8+ T cells in tumors. INF-γ enhances antigen presentation and promotes activation of NK cells. Vorinostat upregulated the secretion of pro-immune cytokines and TRAIL which induces tumor apoptosis. Downregulated cytokines in U251 were prolactin, CXCL9 involved in tumor growth and metastasis, VEGF, and CCL2 involved in immunosuppression in GBM. Cytokines upregulated in HCT116 included IL-8 contributing to CRC progression, and CXCL13, and CXCL11 which correlates with anti-tumor immunity in colon cancer. Downregulated cytokines in HCT116 were soluble TRAIL R2 functioning as a decoy receptor for TRAIL, VEGF, and prolactin. We treated DMG, GBM and HCC cells with imipridones, EHZ2i tazemetostat or HDACi panobinostat alone or combination of imipridones plus tazemetostat or panobinostat or the triple combination of imipridone plus tazemetostat and panobinostat. We observed that cytokines impairing immunity were downregulated and cytokines promoting immunity were upregulated by individual drugs or combinations. Hep3B HCC cells showed the most robust changes among the mentioned tumors with respect to the changes of cytokine profile following the treatments. Imipridone or EZH2i treated cells showed similar cytokine profile changes in tumor cells. Imipridones downregulated EZH1 and EZH2 proteins in tumor cells. We RNA-seq to investigate gene expression profiles following treatment with ONC201 or tazemetostat. In GBM and DMG, ONC201 and tazemetostat shared similar top regulated genes. GO enrichment analysis showed overlap of top regulated pathways between ONC201 and EZH2i treated cells. Shared regulated pathways in U251 included cell cycle arrest, cell adhesion, nervous system development, cell proliferation, negative regulation of proliferation, PERK-mediated unfolded protein response, extracellular matrix organization, regulation of transcription from RNA polymerase II promoter, and cellular response to hypoxia pathways. We conclude that imipridones ONC201, ONC206, and ONC212 which reduce EZH1 and EZH2 proteins share similar cytokine alterations, gene expression targets and actions with EZH2 inhibitors. Citation Format: Yiqun Zhang, Kelsey Huntington, Wafik S. El-Deiry. Imipridones and EZH2 inhibitors induce similar changes in cytokines and regulated genes in GBM and DMG while vorinostat potentiates anti-tumor efficacy despite variability in cytokine profiles. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4898.

Changes in cervical cytokine profiles following focused ultrasound treatment for high-risk human papillomavirus infection-related low-grade cervical lesions.

To evaluate the changes of cervical soluble immune markers after focused ultrasound (FU) treatment to explore the underlying local immune effects of FU in the treatment of high-risk human papillomavirus (HR-HPV) infection-related low-grade squamous intraepithelial lesion (LSIL). A total of 35 patients diagnosed with HR-HPV infection-related histological LSIL who met the inclusion criteria were enrolled in this prospective study and treated with FU. The authors used cytometric bead array to measure T-helper type 1 (Th1) cytokine (interleukin [IL] 2, tumor necrosis factor, and interferon γ) and Th2 cytokine (IL-4, IL-5, IL-6, and IL-10) levels in the cervicovaginal lavage of patients before and 3 months after FU treatment. After FU treatment, the concentrations of Th2 cytokines IL-5 and IL-6 were significantly lower than those before FU treatment (P = 0.044 and P = 0.028, respectively). HR-HPV infection was cleared in 27 patients, with a clearance rate of 77.1% (27 of 35). The concentration of IL-4 in patients with HR-HPV clearance after FU treatment was significantly lower than that in patients without HR-HPV clearance (P = 0.045). FU can inhibit the production of certain Th2 cytokines and may improve the local immune status of the cervix, thereby eliminating HR-HPV infection.

Serum miRNA profiles are altered in patients with primary sclerosing cholangitis receiving high-dose ursodeoxycholic acid

Background & AimsPrimary sclerosing cholangitis (PSC) is a chronic, progressive cholestatic liver disease that can lead to end-stage liver disease and cholangiocarcinoma. High-dose ursodeoxycholic acid (hd-UDCA, 28–30 mg/kg/day) was evaluated in a previous multicentre, randomised placebo-controlled trial; however, the study was discontinued early because of increased liver-related serious adverse events (SAEs), despite improvement in serum liver biochemical tests. We investigated longitudinal changes in serum miRNA and cytokine profiles over time among patients treated with either hd-UDCA or placebo in this trial as potential biomarkers for PSC and response to hd-UDCA, as well as to understand the toxicity associated with hd-UDCA treatment. MethodsThirty-eight patients with PSC were enrolled in a multicentred, randomised, double-blinded trial of hd-UDCA vs. placebo. ResultsSignificant alterations in serum miRNA profiles were found over time in both patients treated with hd-UDCA or placebo. Additionally, there were striking differences between miRNA profiles in patients treated with hd-UDCA compared with placebo. In patients treated with placebo, the changes in concentration of serum miRNAs miR-26a, miR-199b-5p, miR-373, and miR-663 suggest alterations of inflammatory and cell proliferative processes consistent with disease progression. However, patients treated with hd-UDCA exhibited a more pronounced differential expression of serum miRNAs, suggesting that hd-UDCA induces significant cellular miRNA changes and tissue injury. Pathway enrichment analysis for UDCA-associated miRNAs suggested unique dysregulation of cell cycle and inflammatory response pathways. ConclusionsPatients with PSC have distinct miRNAs in the serum and bile, although the implications of these unique patterns have not been studied longitudinally or in relation to adverse events related to hd-UDCA. Our study demonstrates marked changes in miRNA serum profiles with hd-UDCA treatment and suggests mechanisms for the increased liver toxicity with therapy. Impact and implicationsUsing serum samples from patients with PSC enrolled in a clinical trial comparing hd-UDCA with placebo, our study found distinct miRNA changes in patients with PSC who are treated with hd-UDCA over a period of time. Our study also noted distinct miRNA patterns in patients who developed SAEs during the study period.

Review article: Mechanisms underlying the effectiveness of exclusive enteral nutrition in Crohn's disease.

Exclusive enteral nutrition (EEN) induces remission and mucosal healing in patients with Crohn's disease, but the mechanism of action remains unknown. To outline current understanding of the mechanisms of action of EEN. From a comprehensive literature search, published data were critically examined in a narrative review. Multiple potential mechanisms of action have been identified. EEN optimises nutritional status. Differences in gut microbiota in terms of overall diversity and taxonomic community structure are observed between responders and non-responders to EEN. Therapy with EEN alters microbial metabolites (including faecal short-chain fatty acids, amino acids, branched-chain amino acids and sulphide) and faecal pH. Epithelial effects and restoration of barrier function, as well as changes in mucosal cytokine profiles and T-cell subsets are observed in responders to EEN. The impact of inclusion or exclusion of specific dietary components may be of importance, but putative detrimental components are found in many formulas. A major challenge in interpreting these findings is that they often contradict or change in opposite directions to what is considered 'beneficial'. It is difficult to differentiate between the observations following EEN being driven by EEN per se and those associated with resolving inflammation. The mechanisms of action of EEN are likely to involve a complex interplay between host mucosal immune response and luminal environment, but the identity of key factors remains poorly understood. A better definition of pathogenic factors may aid in developing more targeted dietary treatment and provide insights into the pathogenesis of Crohn's disease.

Cytokine profiles of plasma extracellular vesicles as progression biomarkers in Parkinson’s disease

Inflammation contributes substantially to the pathogenesis of Parkinson's disease (PD). Plasma extracellular vesicle (EV)-derived cytokines are emerging biomarkers of inflammation. We conducted a longitudinal study of the plasma EV-derived cytokine profiles of people with PD (PwP). A total of 101 people with mild to moderate PD and 45 healthy controls (HCs) were recruited, and they completed motor assessments (Unified Parkinson Disease Rating Scale [UPDRS]) and cognitive tests at baseline and 1-year follow-up. We isolated the participants' plasma EVs and analyzed their levels of cytokines, including interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-β. We noted no significant changes in the plasma EV-derived cytokine profiles of the PwPs and HCs between baseline and the 1-year follow-up. Among the PwP, changes in plasma EV-derived IL-1β, TNF-α and IL-6 levels were significantly associated with changes in the severity of postural instability and gait disturbance (PIGD) and cognition. Baseline plasma EV-derived IL-1β, TNF-α, IL-6, and IL-10 levels were significantly associated with the severity of PIGD and cognitive symptoms at follow-up, and PwP with elevated IL-1β and IL-6 levels exhibited significant progression of PIGD over the study period. These results suggested the role of inflammation in PD progression. In addition, baseline levels of plasma EV-derived proinflammatory cytokines can be used to predict the progression of PIGD, the most severe motor symptom of PD. Additional studies with longer follow-up periods are necessary, and plasma EV-derived cytokines may serve as effective biomarkers of PD progression.

Dynamic Changes in Serum Cytokine Profile in Rats with Severe Acute Pancreatitis

Background and Objectives: Most published research has only investigated a single timepoint after the onset of severe acute pancreatitis (SAP), meaning that they have been unable to observe the relationship between the dynamic changes in cytokines and SAP progression. In this study, we attempted to reveal the relationship between dynamic changes in cytokine expression levels and SAP disease progression and the relationship between cytokines, using continuous large-scale cytokine detection. Materials and Methods: Seventy rats were randomly assigned to control (Con), sham operation (SO) and SAP groups. The SAP group was randomly allocated to five subgroups at 3, 6, 9, 12 and 15 h after the operation. In the SAP group, 5% sodium taurocholate was injected retrograde into the pancreatic bile duct. Animals in the SO group received a similar incision, a turning over of the pancreas. Control animals did not receive any treatment. We observed the survival, ascites fluid amount, pancreatic histopathological scores and serum amylase activity of SAP rats. We used the cytokine microarray to simultaneously detect 90 cytokines and the dynamic changes in one experiment and to analyze the correlation between cytokine expression and disease progression. Results: The mortality of SAP rats increased with an increase in time. Serum amylase activity, pancreatic histopathological scores and ascites fluid amount were time-dependent. Compared with normal rats, 69 cytokines in SAP rats were significantly changed for at least one timepoint, and 49 cytokines were significantly changed at different timepoints after SAP induction. The changes in inflammatory cytokines were significantly upregulated at 6 and 9 h and 12 h and then significantly decreased. Conclusions: The trend of cytokine expression in SAP rats was not consistent with the disease progression. The cytokine-cytokine receptor interaction and MAPK signal's dominant cytokines were always highly expressed at various time points over the course of SAP.

Dynamic Changes of Cytokine Profiles and Their Correlation With Tumor Recurrence Following Thermal Ablation in Hepatocellular Carcinoma.

The 5-year recurrence rate of thermal ablation for hepatocellular carcinoma (HCC) is high, and whether this treatment strategy induces systemic immune response remains elusive. This study aimed to investigate the effects of thermal ablation on HCC patients' cytokine profiles and to explore the correlation of cytokine profiles with tumor recurrence after ablation. A total of 22 HCC patients were included in this prospective study. The levels of 27 cytokines in the peripheral blood of HCC patients were measured before ablation (baseline), week 1, and week 4 after ablation using a Bio-Plex Pro Human Cytokine 27-plex Assay kit. Cytokines showed different dynamic changing trends after ablation treatment. It was found that the level of IL-6 was significantly elevated at week 1 and returned to the baseline level at week 4 after ablation. The level of IL-10 was slightly reduced at week 1 and significantly decreased at week 4. The levels of MCP-1, macrophage inflammatory protein-1β (MIP-1β), and TNF-α were similarly reduced at week 1 and increased at week 4. The levels of IL-17, platelet-derived growth factor-BB (PDGF-BB), and regulated upon activation, normal T cell expressed and secreted (RANTES) showed little to no change at week 1 while an observable increase at week 4. Patients with a high IL-10 level (2.99 pg/ml) at baseline and low levels of TNF-α (20.4 pg/ml), PDGF-BB (107.78 pg/ml), and RANTES (2303.94 pg/ml) at week 4 were at risk of tumor recurrence during 1-year follow-up. The results suggested that thermal ablation activated systemic immune responses by changing the levels of cytokines. The results also demonstrated that measurement of IL-10 at baseline, TNF-α, PDGF-BB, and RANTES at week 4 after ablation might predict the risk of tumor recurrence.

Dynamic Changes of Serum Cytokine Profile in Rats with Severe Acute Pancreatitis

Dynamic Changes of Serum Cytokine Profile in Rats with Severe Acute Pancreatitis

Evaluation of asthma–chronic obstructive pulmonary disease overlap using a mouse model of pulmonary disease

BackgroundFeatures of asthma and chronic obstructive pulmonary disease (COPD) can coexist in the same patient, in a condition termed asthma– chronic obstructive pulmonary disease overlap (ACO). ACO is heterogeneous condition exhibiting various combinations of asthma and COPD features. No clinically acceptable experimental model of ACO has been established. We aimed to establish an animal model of ACO.MethodsWe generated two phenotypes of ACO by administering ovalbumin and porcine pancreatic elastase in combination, and papain. The proinflammatory cytokines and cell types in bronchoalveolar lavage fluid (BALF) were investigated, and lung function parameters were measured using the FlexiVent system.ResultsGreater airway inflammation was observed in the asthma and both ACO models, and emphysema was found in the COPD and both ACO models. The proportion of eosinophils in BALF was elevated in the asthma and ACO-a model. Type 2 inflammatory cytokine levels were highest in the ACO-a model, and the neutrophil gelatinase–associated lipocalin level was elevated in the asthma and ACO-a model. Of lung function parameters, compliance was greater in the COPD and ACO-b model, in which elastance was lower than in the asthma model. Airway resistance increased with the methacholine concentration in the asthma and both ACO models, but not in the control or COPD model.ConclusionWe established two murine models of ACO that exhibit features of asthma and COPD. We validated the clinical relevance of the ACO models based on changes in cytokine profiles and lung function. These models will be useful in further studies of the pathogenesis of, and therapeutic targets for ACO.

Increased Cellular Expression of Interleukin-6 in Patients With Ossification of the Posterior Longitudinal Ligament.

We performed histologic, immunohistochemical, immunoblot examination and suspension array analyses of cytokine expression in cultured cells derived from human cervical ossification of the posterior longitudinal ligament (OPLL). To determine the roles of interleukin-6 (IL-6) during the maturation of osteoblasts and chondrocytes associated with the development of OPLL. Ectopic OPLL affects ~3% of the general population, with a higher incidence in Asian ethnic groups. Alterations in cytokine profiles may influence osteoblast differentiation, but the mechanisms and signaling pathways associated with the ossification process remain unclear. Samples were collected from 14 patients with OPLL who had undergone spinal surgery and seven with cervical spondylotic myelopathy without OPLL. Tissue sections were used for histologic and immunohistochemical studies, and primary cells from ligamentum samples were used for cytokine array and immunoblotting. A suspension array was used to measure the concentrations of 27 inflammatory cytokines or growth factors. Suspension array and immunoblot analyses revealed significantly elevated levels of IL-6 in OPLL patients. Alterations in IL-6 concentrations were found to alter the expression of the genes Sox9 , Runx2 , and SIRT1 . In addition, immunohistochemical analysis revealed that these factors are present in mesenchymal cells within the degenerative portion of the ligament matrix that is adjacent to the ossification front. IL-6 plays a profound role in the osteoblast differentiation process along with the induction of chondrocyte hypertrophy and cell apoptosis in the early stages of ossification in OPLL. These changes in cytokine profiles are essential factors for regulation of the ectopic ossified plaque in OPLL.

Efficacy and Safety of Ropeginterferon Alfa-2b for Pre-Fibrotic Primary Myelofibrosis and DIPSS Low/Intermediate-1 Risk Myelofibrosis

Most patients with early/pre-fibrotic primary myelofibrosis (pre-PMF) and dynamic international prognostic scoring system (DIPSS) low or intermediate-1 risk myelofibrosis (MF) progress to overt PMF or higher risk MF. There is currently no consensus on the optimal treatment strategies in these patients. Ropeginterferon alfa 2b (P1101) is a next generation monopegylated interferon alfa-2b developed specifically to treat myeloproliferative neoplasms (MPN). The P1101MF study is a multicenter phase 2 study of P1101 for patients with pre-PMF and DIPSS low/intermediate-1 risk MF (NCT04988815). Key eligibility included the need for cytoreduction, morphologically confirmed pre-PMF, overt PMF, post-polycythemia vera MF (PPV-MF) or post-essential thrombocythemia MF (PET-MF), and DIPSS low/intermediate-1 risk category. The primary outcome was the clinicohematologic complete response (CHCR) rate at 24 and 48 weeks. Secondary outcomes included adverse events (AEs), changes in allele burden of driver genes and other non-driver mutations, changes in quality-of-life (QOL), changes in cytokine profiles and changes in bone marrow morphology. Patients received P1101 at a starting dose of 250mcg followed by 350mcg at week 2 and 500mcg every 2 weeks from week 4 onwards. At the data cut-off of 28 July 2022, 56 patients (33 men, 23 women) with a median age of 58 (range: 30-87) were enrolled. Thirty eight patients (68%) had pre-PMF, 5 (9%) had overt PMF, 3 (5%) had PPV-MF and 10 (18%) had PET-MF. Next-generation sequencing (NGS) in 53 patients showed JAK2V617F in 39 patients (74%), CALR mutations in 13 patients (25%) and MPL mutation in 1 patient (2%). On day 1, the mean white blood cell (WBC) count, hemoglobin concentration, platelet count, and lactate dehydrogenase (LDH) level were 9.4 x 109/L (range: 3.3-33.95), 12.5 g/dL (range: 7.1-15.9), 520 x 109/L (range: 113-1038) and 359 IU/L (range: 136-1146) respectively. The median duration of follow-up was 24 (2-28) weeks. Forty-six and 30 patients completed 12 and 24 weeks of treatment respectively. At 12 and 24 weeks the CHCR rate was 74% and 67%, respectively. At 24 weeks, 36 (92%) of 39 JAK2V617F mutated patients had stable or improved JAK2V617F allele burden by droplet digital polymerase reaction (ddPCR). Three patients (8%) had >50% reduction in the JAK2V617F allele burden with one patient achieving undetectable JAK2V617F from week 16 onwards. Disease progression or blastic transformation were not observed during the study. The most common AEs were malaise (N=22, 39%; Grade 1-2, N=21; Grade 3-4, N=1), anemia (N=12, 21%; Grade 1-2, N=8; Grade 3-4, N=4), muscle pain (N=11, 20%; Grade 1-2, N=11; Grade 3-4, N=0) and hair loss (N=10, 18%; Grade 1-2, N=10; Grade 3-4; N=0) . There were no treatment discontinuations, safety signals or deaths related to treatment. In summary, P1101 was well-tolerated, effective in cytoreduction and induced molecular responses. The recruitment of patients is ongoing.

Multiplex Analysis of Serum Cytokine Profiles in Systemic Lupus Erythematosus and Multiple Sclerosis.

Changes in cytokine profiles and cytokine networks are known to be a hallmark of autoimmune diseases, including systemic lupus erythematosus (SLE) and multiple sclerosis (MS). However, cytokine profiles research studies are usually based on the analysis of a small number of cytokines and give conflicting results. In this work, we analyzed cytokine profiles of 41 analytes in patients with SLE and MS compared with healthy donors using multiplex immunoassay. The SLE group included treated patients, while the MS patients were drug-free. Levels of 11 cytokines, IL-1b, IL-1RA, IL-6, IL-9, IL-10, IL-15, MCP-1/CCL2, Fractalkine/CX3CL1, MIP-1a/CCL3, MIP-1b/CCL4, and TNFa, were increased, but sCD40L, PDGF-AA, and MDC/CCL22 levels were decreased in SLE patients. Thus, changes in the cytokine profile in SLE have been associated with the dysregulation of interleukins, TNF superfamily members, and chemokines. In the case of MS, levels of 10 cytokines, sCD40L, CCL2, CCL3, CCL22, PDGF-AA, PDGF-AB/BB, EGF, IL-8, TGF-a, and VEGF, decreased significantly compared to the control group. Therefore, cytokine network dysregulation in MS is characterized by abnormal levels of growth factors and chemokines. Cross-disorder analysis of cytokine levels in MS and SLE showed significant differences between 22 cytokines. Protein interaction network analysis showed that all significantly altered cytokines in both SLE and MS are functionally interconnected. Thus, MS and SLE may be associated with impaired functional relationships in the cytokine network. A cytokine correlation networks analysis revealed changes in correlation clusters in SLE and MS. These data expand the understanding of abnormal regulatory interactions in cytokine profiles associated with autoimmune diseases.

Treatment-dependent changes in cytokine profile of capillary and venous blood in patients with psoriasis

Psoriasis is a chronic autoimmune skin disease with affected T-cell immunity. The interleukin IL-23/IL-17/IL-22 cytokine axis is a key to immunopathogenesis of psoriasis. Certain role of the IL-36 subfamily is shown in regulation of skin inflammation. Topically applied preparations are used to treat psoriasis. Our aim was to evaluate the treatment-related changes in the cytokine profile of venous and capillary blood collected close to the foci of psoriatic inflammation. Forty patients with psoriasis (mean age, 43.7 years), were examined. Group 1a (20 people) received local treatment with Mometasone, Group 1b (20 people) received topical gel containing an IL-36 receptor antagonist. Twenty healthy people (mean age, 46.6 years) comprised the control group 2. 200-μL aliquots of capillary blood were collected in a microvette with EDTA from the patients’ finger near to the lesion area. Venous blood (3 mL) was taken from the cubital vein to a vacuum tube with EDTA. The concentration of 15 cytokines in blood plasma was tested by the multiplex method (MagPix, BioRad, USA). Clinical effectiveness of therapy was assessed using the PASI and DLQI indexes. Upon completion of treatment (day 14), the PASI and DLQI indices were significantly decreased in both groups. On the 28th day, the PASI index in Group 1a returned to its original level, in group 1b it remained permanently reduced. Before treatment, the levels of all cytokines, except of IL-10, were significantly increased in capillary blood samples of patients with psoriasis compared to Group 2, and the levels of five cytokines were increased in the venous blood. In group 1a, the levels of IL-1, IL-4, IL-6, IL-21, IL-22, IL-23, IL-25, IL-33 were significantly decreased in capillary blood after 14 days, and only IL-17F, IL-21, IL-33 and TNF showed a decrease in the venous blood specimens. On the day +28, the concentrations of almost all cytokines returned to their original level. In Group 1b, on the 14th day, the levels of IFNγ, IL-1, IL-4, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-33 were significantly decreased in capillary blood compared to altered IFNγ, IL-21, IL-22, IL-23, IL-33 in venous blood. On the 28th day, their concentration continued to decrease, or the level of these cytokines remained reduced, along with significant decrease of IL-6 in venous samples. Thus, the method for determining cytokine profile in capillary blood from the area of psoriatic lesions may be used for tracing the effects of therapy in psoriatic patients.

Changes of blood serum cytokine profile in the patients with papillomavirus infection before and after therapeutic pregravid preparation

Human papillomavirus is one of the most common sexually transmitted viruses. The state of the immune system is fundamental to the outcome of infectious processes of viral and bacterial genesis, thus determining the quality of pre-gravidar preparation. The purpose of present study was to perform a comprehensive analysis of pro- and anti-inflammatory cytokines in papillomavirus infection and to provide immunological assessment of therapeutic efficiency in women. Materials and methods: 137 patients with papillomavirus infection were observed, at the average age of 312.5 years old. The study consisted of 2 stages: stage 1 included analysis of humoral innate immunity in women of the main group, distributed according to etiological factor, i.e., G-I was with papillomavirus infection (PVI); G-II presented with papillomavirus and herpetic infection (PVI + HVI 1/2 type); G-III included the patients with papillomavirus and Chlamydia infection (PVI + Trash.). At Stage 2, we performed immunological analysis of the therapeutic efficiency for PVI: in G-IA group with papillomavirus infection (PVI) we used Inosine pranobex (n = 11); in the IB group, Solanum tuberosum was applied (n = 10); in G-II A group with papillomavirus and herpes infection (PVI+HVI 1/2 type), we used Valacyclovir + Inosine pranobex (n = 24); in G-IIB patients Valacyclovir + Solanum tuberosum were administered (n = 23); for G-IIIA group with papillomavirus and chlamydia infection (PVI + Trash.) Doxycycline + Inosine pranobex were used (n = 20); the patients from IIIB group were treated with Doxycycline + Solanum tuberosum (n = 19). Determination of levels of IL-17A, IL-12 p70, IL-12 p40, IL- 13 in blood serum was carried out using specific reagents from RD Diagnostics Inc. (USA). Results: Before therapy, an increase in IL-17 and IL-13 (p 0.05), and a pronounced deficiency of IL-12 p40 and IL-12 p70 (p 0.001) were observed in blood serum of the patients. After the course of therapy, a decrease in IL-13 and an increase in IL-12 p40 and IL-12 p 70 were found. The IL-17 level remained without dynamic changes. The applied therapeutic approaches had a positive effect in all studied groups of patients, regardless of the drug administered.

Online, low-volume meditation does not alter immune-related biomarkers

ObjectivesPrior studies of mindfulness meditation have demonstrated anti-inflammatory and immunoregulatory effects but whether meditation courses delivered online can exert similar effects is poorly understood. Barriers to large scale implementation of traditional mindfulness meditation programs has created an increased interest in the effect of less time- and resource-intensive online meditation courses. The purpose of this study was to determine whether a 6-week online mindfulness program with low time demands on nurses would lead to changes in gene expression, cytokine profiles, telomerase activity, and cortisol profiles. MethodsThis was a randomized, parallel pilot study comparing an online mindfulness-based stress management program to an active control group from December 2018 to May 2019. Healthy nurses with above average levels of perceived stress were randomized to receive a 6-week online mindfulness-based stress management program including ≥5 min daily meditation practice or listen to relaxing music for ≥5 min daily as the control arm. Blood samples were collected at baseline and after 6 weeks, and various self-reported measures of stress, physical and emotional health were collected at baseline, after 6 weeks, and after 12 weeks. Whole transcriptome mRNA sequencing of whole blood at baseline and after 6 weeks was performed along with measurement of plasma IL-6, IL-8, IL-10, TNF-α, and IFN-γ. Peripheral blood mononuclear cells were isolated, and telomerase activity was measured. Diurnal salivary cortisol profiles were assessed at baseline and after 6 weeks. The primary outcome was change over time in a pre-determined set of 53 genes representative of the immune-related changes seen with stress, which was analyzed using a mixed linear model. Secondary outcomes included all other self-reported measures and biomarkers mentioned above. ResultsA total of 61 nurses were randomized, with 52 having sufficient data to include in the final analysis. After 6 weeks, nurses in the control group reported significant reductions in stress as measured by the Perceived Stress Scale while those in the mindfulness group did not. However, after 12 weeks, the mindfulness group also showed a significant reduction in stress. When compared to the control group, no significant changes in RNA gene expression or any other biomarkers were observed in the nurses who participated in the mindfulness program. ConclusionsOur study found that this brief online mindfulness-based intervention was effective in reducing stress in nurses, albeit with a delayed effect compared to listening to relaxing music. Regarding immunoregulatory effects, there were no significant differences between treatment and control groups in transcriptomic or other tested biomarkers of immune function. This study provides evidence for a floor effect of mindfulness on transcriptional and circulating biomarkers of immune function.

Dynamic changes of cytokine profiles and virological markers during 48 weeks of entecavir treatment for HBeAg-positive chronic hepatitis B.

ObjectiveThe aims of this study were to investigate the kinetic changes of serum, virological, and immunological markers during entecavir (ETV) antiviral therapy and to explore whether these indicators can predict the antiviral efficacy of ETV in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients.MethodsHBeAg-positive CHB patients were enrolled and treated with ETV 0.5 mg/day. Clinical biochemical, virological, and serological tests were performed at baseline and every 12 weeks during the 48-week treatment. Plasma levels of cytokines (Flt-3L, IFN-α2, IFN-γ, IL-10, IL-17A, IL-6, TGF-β1, TGF-β2, TGF-β3, and TNF-α) were measured at baseline and at 12 and 24 weeks after treatment. Analysis of the trends of these clinical indicators in ETV antiviral therapy was performed.ResultsA total of 105 HBeAg-positive CHB patients were enrolled, and 100 of them completed 48 weeks of ETV treatment and follow-up. After 48 weeks of treatment, hepatitis B s antigen (HBsAg) decline ≥ 1 log10 was found in seven patients, but no patient achieved HBsAg disappearance. serological HBeAg disappeared in 13 patients, and serological HBeAg transformed in 3 patients. The baseline HBsAg and HBeAg levels, HBV DNA load, IL-10, and TGF-β1 levels in the complete virological response group were lower than those in the incomplete virological response group, while the ALT level in the complete virological response group was higher than that in the incomplete virological response group. Both univariate analysis and multivariate analysis showed that baseline biochemical indexes, virological indexes, and cytokine levels had no correlation with the complete virological response at 48 weeks. In multivariate analysis, low baseline HBV DNA load, and HBeAg and IL-10 levels were significantly associated with ALT normalization after 48 weeks of ETV treatment (HBeAg OR = 1.003, 95% CI 1.001–1.006, p = 0.007; HBV DNA OR = 0.184, 95% CI 0.046–0.739, p = 0.017; IL-10 OR = 0.040, 95% CI 0.972–0.999, p = 0.040).ConclusionCytokine levels changed dynamically during ETV antiviral therapy. Low baseline HBV DNA load, and HBeAg and IL-10 levels were significantly associated with ALT normalization after 48 weeks of ETV treatment.

Hepatic Stellate Cell Modulates the Immune Microenvironment in the Progression of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a major cause of increases in the mortality rate due to cancer that usually develops in patients with liver fibrosis and impaired hepatic immunity. Hepatic stellate cells (HSCs) may directly or indirectly crosstalk with various hepatic cells and subsequently modulate extracellular remodeling, cell invasion, macrophage conversion, and cancer deterioration. In this regard, the tumor microenvironment created by activated HSC plays a critical role in mediating pathogenesis and immune escape during HCC progression. Herein, intermediately differentiated human liver cancer cell line (J5) cells were co-cultured with HSC-conditioned medium (HSC-CM); changes in cell phenotype and cytokine profiles were analyzed to assess the impact of HSCs on the development of hepatoma. The stage of liver fibrosis correlated significantly with tumor grade, and the administration of conditioned medium secreted by activated HSC (aHSC-CM) could induce the expression of N-cadherin, cell migration, and invasive potential, as well as the activity of matrix metalloproteinases in J5 cells, implying that aHSC-CM could trigger the epithelial-mesenchymal transition (EMT). Next, the HSC-CM was further investigated and network analysis indicated that specific cytokines and soluble proteins, such as activin A, released from activated HSCs could remarkably affect the tumor-associated immune microenvironment involved in macrophage polarization, which would, in turn, diminish a host’s immune surveillance and drive hepatoma cells into a more malignant phenotype. Together, our findings provide a novel insight into the integral roles of HSCs to enhance hepatocarcinogenesis through their immune-modulatory properties and suggest that HSC may serve as a potent target for the treatment of advanced HCC.

Relationship between circadian rhythm disordersand course of inflammatory bowel diseases

Crohns disease (CD) and ulcerative colitis (UC) belong to the group ofinflammatory bowel diseases (IBD), chronic immunological diseases ofthe digestive tract (1). The pathogenesis of IBD is not fully understood;probably under the influence of various environmental and infectiousfactors as well as genetic predisposition in patients suffering from IBD,the cytokine profile changes (2). The main goal of the research currentlybeing carried out around the world is to identify risk factors for the developmentof IBD. It is suggested that disturbances of the circadian rhythmas well as quantitative and qualitative sleep disturbances may cause theimmune inbalance towards the pro-inflammatory profile and lead to thedevelopment of IBD.The aim of the study was to confirm the hypothesis about the relationshipof immune imbalance disorders with the circadian rhythm and to try toexplain its clinical significance in the course of IBD. In the longer term,the research was about to answer the question of whether the treatmentof sleep disorders, both psychological and pharmacological, should becomea new target in the treatment of IBD.Based on the literature review and own research, the following conclusionswere drawn: 1. sleep disturbances occurring 30 days before the examinationmay be a risk factor for the exacerbation of the underlying diseasein patients with IBD, regardless of the diagnosis (CD or UC). Sleepdisturbances are more common in people with moderate to severe exacerbationscompared to patients in clinical remission and compared tothe control group, 2. patients with IBD with sleep disorders have significantlyhigher levels of IL-6, IL-17 and IL-23 compared to group of patientswithout these disturbances, 3. patients with IBD with sleep disordershave increased levels of resistin and decreased levels of adiponectinand leptin compared to group of patients without these disturbances.The conducted studies will allow to consider disturbances in the circadiancycle as a risk factor for exacerbation in IBD. We also suggest thatthe treatment of sleep disorders, both pharmacological and behavioral,may become an additional treatment target among patients.

O-224 Novel bio-markers of Immunological response to the implanting embryo

Abstract Embryos, as allograft, will fail to implant unless they can escape rejection by maternal immune response. It is postulated that embryos escape Immune surveillance using a mechanism similar to that of cancer cells via Immune check point pathways: (a) via producing a surface protein called PD-L1, which binds to PD-1 receptor in T-cells; and (b) via producing a surface protein called Galectin-9 which binds to T-cell immunoglobulin and mucin domain 3 (TIM-3). The binding of these ligands to the corresponding receptors in the T-cells would prevent the latter from recognizing them as foreign, hence escape destruction. In a prospective, longitudinal, observational cohort study involving subjects undergoing blastocyst transfer, it was found that among women who conceived, there was an instant, transient and significant reduction of Tim-3 expression on the surface of peripheral NK cells, T cells and NK-like T cells on days 3 and 6 after ET, which returned to baseline level by day 9 after ET. The change in women who did not conceive appeared in an opposite direction. Furthermore, reduction in Tim-3 expression in pNK cells predates the occurrence of miscarriage by 3 weeks in women with miscarriage when compared with those with live birth. These observations are accompanied by significant changes in peripheral blood cytokine profiles which may be used as clinically useful biomarkers to monitor the maternal immunological response to successful implantation.