Peripheral Cytokine Research Articles

Clinical Significance of the Levels of Peripheral Blood Tregs and Cytokines IL-35, TGF-β and IL-10 in Hemophilia A Patients with FⅧ Inhibitor

To explore the levels of regulatory T cells (Tregs) and cytokines IL-35, TGF-β and IL-10 in peripheral blood of hemophilia A(HA) patients with FⅧ inhibitor and their clinical significance. 43 HA patients admitted to the Hematology Department of the Affiliated Hospital of North China University of Science and Technology from October 2019 to December 2020 were selected, including 6 cases with FⅧ inhibitor and 37 cases without FⅧ inhibitor. In addition, 20 healthy males who underwent physical examinations were selected as healthy controls. Flow cytometry was used to detect the levels of CD4 + CD25 + CD127 - Tregs in peripheral blood of the HA patients and healthy controls, and ELISA assay was used to detect the expression levels of IL-35, TGF-β and IL-10 in serum, and their differences between different groups were compared. Compared with the healthy control group, the level of Tregs in HA patients was decreased, and the level of Tregs in the FⅧ inhibitor positive group was the lowest, the difference was statistically significant (P <0.05). There was no significant difference in the expression level of Tregs in HA patients of different severity levels. The serum IL-35, TGF-β, and IL-10 levels in both FⅧ inhibitor negative and positive groups were significantly lower than those in healthy control group, and those in FⅧ inhibitor positive group were significantly lower than those in FⅧ inhibitor negative group (all P <0.05). The decrease of Tregs, IL-35, TGF-β, and IL-10 levels in HA patients may be related to the formation of FⅧ inhibitors.

Extended analysis on peripheral blood cytokines correlated with hepatitis B virus viral load in chronically infected patients - a systematic review and meta-analysis.

Hepatitis B Virus (HBV) can affect life quality. Monitoring and understanding the fluctuations of the HBV level of viremia related to the intricate immune activity of the host helps in the development of new treatment strategies and evaluation patterns. This meta-analysis presents the correlations between cytokines and the level of viremia in chronic HBV patients for a better comprehension of the immune mechanisms behind this infection. We used PRISMA guidelines for this meta-analysis. The databases assessed were PUBMED, WEB OF SCIENCE, SCOPUS, and Cochrane Library. ZOTERO and PlotDigitizer helped the systematic research process. We extracted information related to the correlations between cytokines and the HBV-DNA level. Effect measures included comparisons between standardized mean differences and correlation coefficients. We evaluated retrieved articles with the Newcastle-Ottawa Quality Assessment Scale (NOS). The R 4.2.2 software displayed the statistical calculation and graphical representations. From 58,169 records, we extracted 16 articles with 32 different cytokine determinations. The main interleukins included in detection panels were IL-10 and IL-21. The meta-correlation analysis comprised 1,199 chronic HBV patients. The standardized mean difference between cytokine levels in HBV patients and healthy controls was 0.82 (95% CI = [-0.19, 1.84], p = 0.11). We observed a significant, fair, pooled correlation coefficient between IL-10, IL-9, and the viral load (r = 0.52, 95% CI = [0.19, 0.85]). This meta-analysis brings novelty because it gives a first rigorous systematic look at multiple studies with many cytokines. Our research approaches a debatable issue and gives a possible solution for settling controversies. Future studies can arise towards understanding the immune disruption in HBV and the development of new, improved assays for prognosis.

Application of blood parameters for the early diagnosis of natural ascending placentitis in pregnant mares

Placental infection is an important cause of late-term pregnancy loss and neonatal diseases in horses. Detection of changes in blood parameters especially during early placentitis could improve the diagnostic accuracy, treatment decision, and potential outcomes. The objectives of this 2-part study were to identify differences in circulating immunological, inflammatory, and hormonal parameters between mares with natural ascending placentitis and control mares; evaluate each and combination of parameters as predictors of placentitis; and determine how these parameters indicate severity of placentitis. Reproductive examination and blood sampling were prospectively performed on pregnant mares in a natural setting. Study 1 enrolled mares diagnosed with early stage of ascending placentitis based on ultrasonographic findings (n = 12), and gestationally age-matched mares with healthy pregnancies as controls (n = 12). Blood samples were classified as pre-onset (before) and early onset (at the time of ultrasonographic changes) of placentitis. There were no detected statistically significant differences between groups and timepoints in immunological and inflammatory parameters, including peripheral lymphocyte subpopulations, cytokine, and serum amyloid A concentrations. The placentitis group showed a reduced (P = 0.01) DHP/20α-DHP ratio when compared to the control group at the early onset timepoint. Plasma estradiol-17β concentration <359 pg/mL predicted ascending placentitis with acceptable accuracy (area under the curve, AUC = 0.71). Combined albumin <3.7 g/dL, estradiol-17β < 499 ng/mL, and DHP <33 ng/mL predicted 100 % of cases of ascending placentitis. In study 2, samples were classified according to the presence and severity of the abnormal ultrasonographic findings as mild (n = 11) and moderate-severe (n = 23), and gestationally age-matched with samples from control mares (n = 34). Mares with moderate-severe ascending placentitis had increased (P = 0.03) plasma 20α-DHP concentration and reduced (P = 0.03) DHP/20α-DHP ratio when compared to control mares. Our results suggest that the early events of ascending placentitis detected by ultrasonographic findings include hormonal alterations of feto-placental metabolism measurable in the mare's circulation, yet without obvious systemic immunological and inflammatory changes. Additional studies are warranted to further assess how hormonal markers and cutoff values could guide decisions for timely therapeutic intervention.

Peripheral Blood Mononuclear Cells and Serum Cytokines in Patients with Lupus Nephritis after COVID-19.

Systemic lupus erythematosus (SLE) patients have an increased risk of infections and infection-related mortality. Therefore, during the global SARS-CoV-2 pandemic, SLE patients were particularly vulnerable to SARS-CoV-2 infections. Also, compared to other patients, SLE patients seem to develop more severe manifestations of coronavirus disease 2019 (COVID-19), with higher rates of hospitalization, invasive ventilation requirements, or death. This study evaluated the immune parameters after SARS-CoV-2 infection in SLE patients. We analyzed subpopulations of peripheral blood cells collected from patients with renal manifestation of SLE (lupus nephritis, LN). LN patients were divided into two subgroups: those unexposed to SARS-CoV-2 (LN CoV-2(-)) and those who had confirmed COVID-19 (LN-CoV-2(+)) six months earlier. We analyzed basic subpopulations of T cells, B cells, monocytes, dendritic cells (DCs), and serum cytokines using flow cytometry. All collected data were compared to a healthy control group without SARS-CoV-2 infection in medical history. LN patients were characterized by a decreased percentage of helper T (Th) cells and an increased percentage of cytotoxic T (Tc) cells regardless of SARS-CoV-2 infection. LN CoV-2(+) patients had a higher percentage of regulatory T cells (Tregs) and plasmablasts (PBs) and a lower percentage of non-switched memory (NSM) B cells compared to LN CoV-2(-) patients or healthy controls (HC CoV-2(-)). LN patients had a higher percentage of total monocytes compared with HC CoV-2(-). LN CoV-2(+) patients had a higher percentage of classical and intermediate monocytes than LN CoV-2(-) patients and HC CoV-2(-). LN CoV-2(+) patients had higher serum IL-6 levels than HC CoV-2(-), while LN CoV-2(-) patients had higher levels of serum IL-10. LN patients are characterized by disturbances in the blood's basic immunological parameters. However, SARS-CoV-2 infection influences B-cell and monocyte compartments.

The Characterization of the Th1/Th2 Ratio in Multiple Sclerosis Patients and its Response to a Dietary Supplement Regimen

Introduction Multiple sclerosis (MS) is a debilitating neurodegenerative disease affecting the central nervous system, causing disability and life-threatening complications. The interplay between immune cells and signaling pathways is a topic for investigating novel therapies. Past research has shown how the Th1/Th2 ratio plays a key role in the pathogenesis of MS lesions. Modulating the Th1/Th2 ratios with an efficacious dietary supplement may improve some of the consequences of MS. Methods Participants (n = 15) diagnosed with MS for an average of 12.4 years (standard deviation = 7.4; range = 2, 25) were enrolled in a clinical trial in which they consumed a dietary supplement regimen daily for 12 months. Venous blood was drawn at baseline and 12-month follow-up and peripheral blood mononuclear cells, cytokines, and growth factors were quantified. Infections, physical functioning, and quality of life were also assessed at baseline and 12 months. Results The IL-2/IL-10 and IFN-γ/IL-10 ratios were significantly higher than those of the healthy adults, and while only IFN-γ/IL-10 increased significantly at 12 months, all ratios other than IFN-γ/TNF-α increased over the course of the intervention. The decrease in yeast infections was inversely correlated with IL-2/TNF-α and IFN-γ/TNF-α. Significant improvements in physical functioning and quality of life correlated with changes in the Th1/Th2 ratios in response to the dietary supplement regimen. Conclusions The results show that dietary supplementation somewhat impacted the Th1/Th2 ratios over the course of the intervention (toward more Th1 dominance), and those changes were related to various clinical improvements of the participants’ symptoms in cognitive, motor, and psychosocial dimensions.

Inflammatory Markers Predict Blood Neurofilament Light Chain Levels in Acute COVID-19 Patients.

Acute coronavirus disease 2019 (COVID-19) is paralleled by a rise in the peripheral levels of neurofilament light chain (NfL), suggesting early nervous system damage. In a cohort of 103 COVID-19 patients, we studied the relationship between the NfL and peripheral inflammatory markers. We found that the NfL levels are significantly predicted by a panel of circulating cytokines/chemokines, including CRP, IL-4, IL-8, IL-9, Eotaxin, and MIP-1ß, which are highly up-regulated during COVID-19 and are associated with clinical outcomes. Our findings show that peripheral cytokines influence the plasma levels of the NfL, suggesting a potential role of the NfL as a marker of neuronal damage associated with COVID-19 inflammation.

Peripheral blood immune parameters, response, and adverse events after neoadjuvant chemotherapy plus durvalumab in early-stage triple-negative breast cancer.

We evaluated T- and B-cell receptor (TCR and BCR) repertoire diversity and 38 serum cytokines in pre- and post-treatment peripheral blood of 66 patients with triple-negative breast cancer (TNBC) who received neoadjuvant chemotherapy plus durvalumab and assessed associations with pathologic response and immune-related adverse events (irAEs) during treatment. Genomic DNA was isolated from buffy coat for TCR and BCR clonotype profiling using the Immunoseq platform and diversity was quantified with Pielou's evenness index. MILLIPLEX MAP Human Cytokine/Chemokine Magnetic Bead Panel was used to measure serum cytokine levels, which were compared between groups using moderated t-statistic with Benjamini-Hochberg correction for multiple testing. TCR and BCR diversity was high (Pielou's index > 0.75) in all samples. Baseline receptor diversities and change in diversity pre- and post-treatment were not associated with pathologic response or irAE status, except for BCR diversity that was significantly lower post-treatment in patients who developed irAE (unadjusted p = 0.0321). Five cytokines increased after treatment in patients with pathologic complete response (pCR) but decreased in patients with RD, most prominently IL-8. IFNγ, IL-7, and GM-CSF levels were higher in pre-treatment than in post-treatment samples of patients who developed irAEs but were lower in those without irAEs. Baseline peripheral blood cytokine levels may predict irAEs in patients treated with immune checkpoint inhibitors and chemotherapy, and increased post-treatment B-cell clonal expansion might mediate irAEs.

Application of peripheral blood cytokine and immunoglobulin detection in ACTH therapy for the treatment of infantile spasms.

This research aims to investigate the levels of lymphocytes, immunoglobulins, and cytokines in children with infantile spasms (IS) before and after adrenocorticotropic hormone (ACTH) therapy and to explore the application of these markers in evaluating the therapeutic effects of ACTH on infantile spasms. From May to November 2022, 35 children initially diagnosed with IS and treated at our hospital were regarded as the observation group, and 35 healthy children who underwent physical examination at our hospital during the same period were regarded as the control group. Children in the observation group received intramuscular injections of ACTH for 2 weeks. Fasting venous blood was collected from the control group and the observation group before and after ACTH therapy. Serum levels of immunoglobulins IgG, IgA, and IgM in serum were detected by immunoturbidimetry. T-cell subsets (CD3+, CD3+CD4+, and CD3+CD8+) and B-cell subsets [CD3-CD19+ and CD3-CD16+CD56+ natural killer (NK) cells] were detected by flow cytometry, and the ratio of CD3+CD4+/CD3+CD8+ was calculated. Serum levels of interleukin-1β (IL-1β), interleukin-2R (IL-2R), and interleukin-6 (IL-6) cytokines were detected by the enzyme-linked immunosorbent assay, and changes in serum cytokine and immunoglobulin levels in the two groups were compared before therapy, whereas in observation group one, these comparisons were made both before and after ACTH therapy. Compared to the control group, the observation group showed significantly increased serum levels of immunoglobulins IgG and IgM before therapy, while the level of IgA was significantly decreased (p < 0.05). Also, the percentage of CD3-CD19+ B cells was significantly increased, while the percentages of CD3+ T cells and CD3+CD4+ T cells were significantly decreased (p < 0.05). The percentages of CD3+CD8+ T cells, CD3-CD16+CD56+ NK cells, and CD3+CD4+/CD3+CD8+ cells did not change significantly (p > 0.05); the levels of cytokines IL-1 β, IL-2R, and IL-6 were significantly increased (p < 0.05). Compared to levels before treatment, the serum level of immunoglobulin IgG in the observation group after ACTH therapy was significantly reduced (p < 0.05), while the IgA and IgM levels did not change significantly (p > 0.05). The percentages of CD3+ T cells and CD3+CD4+ T cells were significantly increased, while the percentages of CD3-CD16+CD56+ NK cells and CD3-CD19+ B cells were significantly decreased (p < 0.05); however, the percentages of CD3+CD8+ T cells and the CD3+CD4+/CD3+CD8+ ratio did not change significantly (p > 0.05). Furthermore, the levels of cytokines IL-1 β, IL-2R, and IL-6 were significantly reduced (p < 0.05). Children with IS exhibit immune dysfunction, and the changes in serological immune indices after ACTH treatment indicate that ACTH may control seizures in IS children by regulating and improving immune dysfunction. Therefore, the therapeutic effects of ACTH on IS can be evaluated by detecting the levels of cytokines and immunoglobulins.

The associations of peripheral interleukin alterations and hippocampal subfield volume deficits in schizophrenia.

The hippocampus is one of the brain regions most vulnerable to inflammatory insults, and the relationships between peripheral inflammation and hippocampal subfields in patients with schizophrenia remain unclear. In this study, forty-six stably medicated patients with schizophrenia and 48 demographically matched healthy controls (HCs) were recruited. The serum levels of IL - 1β, IL-6, IL-10, and IL-12p70 were measured, and 3D high-resolution T1-weighted magnetic resonance imaging was performed. The IL levels and hippocampal subfield volumes were both compared between patients and HCs. The associations of altered IL levels with hippocampal subfield volumes were assessed in patients. Patients with schizophrenia demonstrated higher serum levels of IL-6 and IL-10 but lower levels of IL-12p70 than HCs. In patients, the levels of IL-6 were positively correlated with the volumes of the left granule cell layer of the dentate gyrus (GCL) and cornu Ammonis (CA) 4, while the levels of IL-10 were negatively correlated with the volumes of those subfields. IL-6 and IL-10 might have antagonistic roles in atrophy of the left GCL and CA4. This suggests a complexity of peripheral cytokine dysregulation and the potential for its selective effects on hippocampal substructures, which might be related to the pathophysiology of schizophrenia.

Preoperative Immune Cell Dysregulation Accompanies Ovarian Cancer Patients into the Postoperative Period.

Ovarian cancer (OC) poses a significant global health challenge with high mortality rates, emphasizing the need for improved treatment strategies. The immune system's role in OC progression and treatment response is increasingly recognized, particularly regarding peripheral blood mononuclear cells (PBMCs) and cytokine production. This study aimed to investigate PBMC subpopulations (T and B lymphocytes, natural killer cells, monocytes) and cytokine production, specifically interleukin-1 beta (IL-1β), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-10 (IL-10), interleukin-12 (IL-12), and tumor necrosis factor alpha (TNFα), in monocytes of OC patients both preoperatively and during the early postoperative period. Thirteen OC patients and 23 controls were enrolled. Preoperatively, OC patients exhibited changes in PBMC subpopulations, including decreased cytotoxic T cells, increased M2 monocytes, and the disbalance of monocyte cytokine production. These alterations persisted after surgery with subtle additional changes observed in PBMC subpopulations and cytokine expression in monocytes. Considering the pivotal role of these altered cells and cytokines in OC progression, our findings suggest that OC patients experience an enhanced pro-tumorigenic environment, which persists into the early postoperative period. These findings highlight the impact of surgery on the complex interaction between the immune system and OC progression. Further investigation is needed to clarify the underlying mechanisms during this early postoperative period, which may hold potential for interventions aimed at improving OC management.

Exploring the Gut Microbiome - Autism Spectrum Disorder Connection: Implications for Therapeutic Interventions and Future Directions

The gut microbiome, a diverse community of microorganisms in the gastrointestinal tract, is vital for human health and has a symbiotic relationship with the host. Autism spectrum disorder (ASD), a complex condition affecting social interaction, speech, and behavior, manifests early in life and affects 1 in 36 children globally. Research shows a significant link between the gut microbiome and ASD symptoms, with dysbiosis observed in individuals with ASD compared to neurotypical populations. Pathogenic gut microbiota can produce toxins that increase gut permeability, impair the intestinal barrier, and activate the immune system. The vagal nerve, influencing central nervous system (CNS) activity, can release peripheral cytokines inducing depression-like behaviors. Thus, dietary changes and treatments targeting the gut microbiota, such as Microbiota Transfer Therapy (MTT), offer promising methods for treating ASD symptoms. Current research focuses on dietary therapies like gluten-free and casein-free diets, ketogenic diets, and probiotics/prebiotics supplementation to modify the gut microbiota and enhance ASD treatment outcomes. However, more research is needed to fully understand the gut microbiota-ASD connection and establish evidence-based interventions. Individualized approaches are crucial for the safety and effectiveness of therapeutic strategies for ASD. Exploring the gut microbiome's role in ASD offers promising avenues for novel treatments and improved understanding of the disorder.

Evidence of the Immunomodulatory Effects of Selective Serotonin Reuptake Inhibitors in Patients With Depression Through a Systematic Review.

Depression is a common illness, affecting >264 million people worldwide. According to the literature, depression patients have baseline subclinical inflammation. The immunomodulatory effects of antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), are largely unclear and poorly understood. Using evidence-based medicine, this study aimed to determine the immunomodulatory effects of SSRIs by assessing changes in immunomodulatory markers following SSRI treatment. Using the PubMed website, a literature search was conducted with various terminologies related to the treatment of depression and various markers of inflammation. Out of 387 retrieved articles, after critical appraisal and screening based on inclusion and exclusion criteria, 17 were selected. Qualitative synthesis and quantitative analysis were carried out. RevMan 5 software was used to synthesize and evaluate the data. Microsoft Word and Excel (Microsoft Corporation, Redmond, Washington, United States) were used for generating tables and figures. We extracted data from a total of 839 patients in 17 studies. A highly significant reduction in interleukins-6 (IL-6) (standardised mean difference (SMD) = 1.32 (95% confidence interval (CI): 0.58, 2.06), Z = 3.48, P = 0.0005), a significant reduction in tumor necrosis factor-alpha (TNF-α) (SMD = 1.29 (95% CI: 0.19, 2.39), Z = 2.30, P = 0.02) but no change in overall C-reactive protein (CRP) (SMD = 0.40 (95% CI: -0.26, 1.07), Z = 1.19, P = 0.23) levels were observed by using the random-effects model. There was substantial heterogeneity found between the studies. SSRIs have an immunomodulatory effect in patients with depression by significantly reducing the peripheral pro-inflammatory cytokine markers of IL-6 and TNF-α, which may contribute to ameliorating the response to antidepressant drug treatment. In contrast, no effects of SSRIs on acute-phase protein CRP were found.

Unsupervised clustering analysis based on multidimensional features reveals distinct clinical characteristics and associated factors of different phenotypes in patients with chronic rhinosinusitis with nasal polyp

Objective: To utilize routinely available clinical parameters to uncover the clinical features of different clusters in patients with chronic rhinosinusitis with nasal polyp (CRSwNP) through unsupervised clustering analysis. Methods: The clinical data from 155 CRSwNP patients undergoing nasal endoscopic surgery at Renmin Hospital of Wuhan University from 2021 to 2023 were prospectively collected, including 112 males and 43 females, aged from 7 to 87 years. Unsupervised clustering analysis was conducted using various clinical parameters, including age, gender, smoking and drinking history, local eosinophil (EOS) and neutrophil (NEU) counts, comorbid allergic rhinitis (AR), comorbid asthma, recurrence status, serum-specific IgE, total IgE, cytokine levels, peripheral blood EOS count and percentage, Lund-Mackay CT score, the ratio of CT scores for the maxillary sinus and ethmoid sinus (E/M ratio), visual analogue scale (VAS) score, Lund-Kennedy endoscopic score, and other common clinical indicators to elucidate the clinical characteristics of each cluster. Statistical analysis was conducted using GraphPad Prism 9.5 software. Results: Hierarchical clustering analysis identified four main clusters (Cluster A1-A4), showcasing distinct characteristics such as mild nasal polyps with higher peripheral blood cytokines levels, nasal polyps accompanied by allergies and asthma, a subtype of nasal polyps with high recurrence rates dominated by neutrophils, and nasal polyps with high eosinophil levels. Further subset clustering revealed two clusters of mild polyps (Cluster B1-B2) featuring high cytokine expression and comorbid AR; and two clusters of severe polyps (Cluster B3-B4) presented with severe symptoms, high Lund-Mackay CT score, and high Lund-Kennedy endoscopic score. Variations between Cluster B3 and B4 included symptom complexity, the degree of eosinophil infiltration, and the probability of comorbid asthma. Further clustering analysis for eosinophilic nasal polyps revealed a cluster characterized by highly neutrophilic infiltration and recurrent nasal polyps. The comprehensive analysis of multi-index correlations demonstrated valuable insights into the relationships between common clinical parameters of nasal polyps, providing valuable information for a deeper understanding of the pathogenesis of CRSwNP. Conclusion: The clustering analysis in this study categorizes CRSwNP patients into different clusters based on clinical features and disease outcomes, providing a new perspective for more precise clinical treatment strategies.

The effects of postoperative targeted immunotherapy on peripheral blood cytokines and immune cell profile in lung cancer patients.

Cytokines and cell subsets are important components of the tumor microenvironment. Previous research has revealed that there are differences in cytokines and cell subsets in the peripheral blood of lung cancer (LCA) patients before and after eradication. The purpose of this study is to explore the monitoring value of cytokines and cellular subpopulations as biomarkers in post-immunotherapy monitoring of patients with LCA after surgery. We conducted a case-control study using double-antibody sandwich magnetic microsphere flow cytometry with immunofluorescence technology and fluorescent monoclonal antibody multiparameter flow cytometry to detect differences in peripheral blood cytokines and cell subsets between LCA patients after immunotherapy and healthy controls. Our research results show that there are differences in the levels of IL-4, IL-6, IL-10, IL-17, IFN-γ, TNF-α in the peripheral blood of LCA patients (n=70) after immunotherapy compared to the healthy controls (n=55) (P<0.05), and there are differences in 10 cell subgroups including DP T Cells, AT cells, and NLR in the peripheral blood compared to the healthy controls (n=35) (P<0.05). Further analysis revealed significant differences in the detection data of IL-6, IL-10, IFN-γ, CD56dim NK cells, Total B cells, Total NE cells, CD15+M cells, and NLR between LCA deceased patients (n=25) and LCA surviving patients (n=27) during the same period (P<0.05). The continuous monitoring of cytokines and cell subsets is far more valuable than a single-time test, as abnormal fluctuations in the data of cytokines and cell subsets are often associated with poor prognosis. In addition, IL-6 and NLR showed the strongest discriminative ability between postoperative immunotherapy-treated LCA patients and healthy controls, with AUC values of 0.840 and 0.822, respectively. There was a significant association between IFN-γ and distant metastasis in LCA (P<0.05), as well as between CD56dim NK cells and lymph node infiltration (P<0.05). This research results support peripheral blood cytokines and cell subsets as biomarkers for monitoring the postoperative immune status and predicting the prognosis of LCA patients after immunotherapy. The continuous monitoring of cytokines and cell subsets is far more valuable than a single-time detection.

Evaluation of the clinical application value of cytokine expression profiles in the differential diagnosis of prostate cancer

BackgroundThe significance of tumor-secreted cytokines in tumor development has gained substantial attention. Nevertheless, the precise role of tumor-related inflammatory cytokines in prostate cancer (PCa) remains ambiguous.ObjectivesTo gain deeper insights into the inflammatory response in the process of PCa.MethodsA total of 233 cases were collected, including 80 cases of prostate hyperplasia as disease control, 65 cases of postoperative prostate cancer and 36 cases of prostate cancer as PCa group. Additionally, 52 patients undergoing physical examinations during the same period were collected as the healthy control. The levels of 12 inflammatory cytokines in peripheral blood samples were analyzed using flow cytometric bead array technology. The levels of total prostate-specific antigen (TPSA) and free prostate-specific antigen (FPSA) in peripheral blood samples were analyzed using electrochemiluminescence technology.ResultsOur findings revealed significant increases in serum IL-8 levels in PCa group compared to the healthy control group. Additionally, IL-6, IL-10, IFN-γ and IL-12p70 levels were markedly elevated in the PCa group compared to the disease control group (all p < 0.05). Conversely, the level of IL-4, TNF-α, IL-1β, IL-17A and IFN-α were lower in the PCa group compared to those in control group. Following surgery, the concentration of IL-6 decreased; whereas, the concentrations of IL-4, TNF-α, IL-17A, IL-1β, IL-12p70, and IFN-α increased, demonstrating significant differences (p < 0.05). The differential upregulation of IL-6 or downregulation of IL-17A in peripheral blood exhibited diagnostic efficacy in PCa patients. Moreover, we observed a significant increase in IL-17A levels, accompanied by decreased of IL-2, IL-4, IL-10, TNF-a, IFN-γ, IL-1β, and IL-12P70 in patients with distant metastasis.ConclusionThe peripheral blood cytokines are closely associated with the occurrence and development of prostate cancer, especially the serum levels of IL-6 and IL-17A may be useful as potential predictors of PCa diagnosis.

SMART: A phase II study of sacituzumab govitecan (SG) with or without atezolizumab immunotherapy in rare genitourinary (GU) tumors such as small cell, adenocarcinoma, and squamous cell bladder/urinary tract cancer, renal medullary carcinoma (RMC) and penile cancer.

TPS4627 Background: Rare tumors of the GU tract often exhibit aggressive clinical behavior, yet lack effective standard of care treatment options. SG is an antibody-drug conjugate (ADC) targeting trophoblastic cell surface antigen 2 (Trop2) with a payload of SN-38, a topoisomerase inhibitor. SG monotherapy gained accelerated approval in pts with metastatic urothelial carcinoma (mUC) post platinum and immune-checkpoint inhibitor (ICI) therapy based on the TROPHY-U-01 trial (Tagawa S et al., JCO 2021). Atezolizumab is an anti-PD-L1 ICI approved for use in multiple solid tumors. SMART will evaluate the efficacy and safety of SG monotherapy or SG plus atezolizumab in select rare GU tumors. Methods: SMART is an open-label, non-randomized, Phase 2 trial. Pts must have locally advanced (unresectable) or metastatic GU tumors of the following histologies: small cell carcinoma, squamous cell carcinoma, or primary adenocarcinoma of the bladder or urinary tract, RMC, or squamous cell carcinoma of the penis. Pts may be treatment-naïve or have received any number of prior therapies; pts with small cell carcinoma must have received a platinum-based regimen. Pts treated with a PD-1/PD-L1 ICI will be assigned to Cohort A/Treatment Arm 1 and will receive SG monotherapy (10mg/kg IV, D1 and D8 of 21 day cycles). Pts without prior ICI treatment will be assigned to Cohort B/Treatment Arm 2 and will receive SG (10mg/kg IV, D1 and D8 of 21 day cycles) with concomitant atezolizumab (1200mg IV, D1 of 21 day cycles). Treatment will continue until disease progression (max duration of treatment 5 years) or intolerable side effects. The primary endpoint is objective response rate (ORR) (RECIST v1.1) for each Cohort, with restaging every 3 cycles. Secondary endpoints include safety, clinical benefit rate (CR+PR+SD), median PFS/OS for each Cohort, and ORR for each histology. Exploratory analyses include determination of baseline tumor mutation and transcriptional profile, Trop2 expression, ctDNA/CTCs, peripheral blood immune subsets and cytokine profile correlation with response, and correlation of UGT1A1 allele genotype with response and safety. This study utilizes a Simon minimax two-stage design, with enrollment of up to 43 evaluable pts (accrual ceiling of 60 pts). Cohort A will enroll 11 pts in Stage 1; if 1 or more of the first 11 pts has a response (unacceptably low rate of 5%, p0=0.05; alpha 0.10, beta=0.20), accrual will continue into Stage 2 up to 18 evaluable pts. Cohort B will enroll 16 evaluable pts in Stage 1; if 2 or more pts have a response (unacceptably low rate of 10%, p0=0.10; alpha 0.10, beta=0.10), accrual will continue in Stage 2 up to a total of 25 evaluable pts. This study is open at the NIH Clinical Center (CC); enrollment may open at 1-2 additional centers. Clinical trial information: NCT06161532 .

A first-in-human phase 1 trial of T cell membrane-anchored tumor targeted IL12 (ATTIL12) -T cell therapy in advanced/metastatic soft tissue and bone sarcoma.

TPS11586 Background: Interleukin-12 (IL12) is a cytokine that induces antitumor immune response and immune memory by activation of NK cells, induction of IFNg, and maturation of DC cells in the tumor microenvironment (TME). However, prior clinical experience with IL12 has been limited by toxicities including cytokine release syndrome (CRS) and hepatotoxicity. We developed a novel tumor-targeted IL12 gene (ttIL12) that encodes the p35 and p40 VNTANST fusion subunits that targets cell surface vimentin (CSV). Vimentin is expressed intracellularly in many normal and neoplastic mesenchymal cells but our group discovered that intracellular vimentin is often flipped to the cell surface (referred to as CSV) across multiple tumor types.2 Preclinical studies demonstrated efficacy and induction of long-term memory of ttIL12 against metastatic osteosarcoma with reduced toxicity in immune competent models.3 However, ttIL12 had limited efficacy in treating large volume tumors and did not completely eliminate toxic peripheral cytokines. To address this, our team generated a membrane anchored ttIL12 to arm T cells known as attIL12-T cell therapy. We hypothesize attIL12 will minimize toxic cytokines in peripheral tissues but promote induction of INFg/TNFa in the TME to decrease the toxicity and boost efficacy. Methods: This is a phase 1 trial of attIL12-T cells in patients (pts) with locally advanced or metastatic soft tissue or bone sarcomas to assess safety, maximal tolerated dose (MTD) and recommended phase 2 dose (RP2D). Pts in part A (dose finding) will be enrolled using a Bayesian optimal interval (BOIN) design in up to 6 dose levels. Part B (dose expansion) will evaluate preliminary efficacy in 10 additional pts with osteosarcoma treated at the RP2D. Treatment:Pts will undergo leukapheresis to collect peripheral blood mononuclear cells (PBMCs) for generation of attIl12-T cells. Bridging therapy is permitted but not required. Pts will receive cyclophosphamide (Cy) IV prior to planned T cell administration. attIL12 T cells will be administered at the specified dose level IV in a single infusion (dose level 1 and 2) or 2 serial doses (dose level 3-6) on day 0 and day 14. Pts will be monitored for toxicity and response evaluation. Pts will also undergo pre-treatment/on-treatment tumor biopsies for translational and correlative analysis. Eligibility:Pts must be ≥ 12 years of age, have a confirmed diagnosis of locally advanced or metastatic sarcoma, evaluable disease, received at least 1 prior line of standard systemic therapy, ECOG PS 0-1, and adequate organ function to tolerate immune-effector cell therapy. Pts with known sensitivity to Cy, active/prior autoimmune disease, uncontrolled CNS disease, or other uncontrolled comorbidities that pose potential safety risk will be excluded. Enrollment to cohort 1 began in Dec 2023. Clinical trial information: NCT05621668 .

Peripheral cytokine interleukin-10 alleviates perihematomal edema after intracerebral hemorrhage via interleukin-10 receptor/JAK1/STAT3 signaling.

The extent of perihematomal edema following intracerebral hemorrhage (ICH) significantly impacts patient prognosis, and disruption of the blood-brain barrier (BBB) exacerbates perihematomal edema. However, the role of peripheral IL-10 in mitigating BBB disruption through pathways that link peripheral and central nervous system signals remains poorly understood. Recombinant IL-10 was administered to ICH model mice via caudal vein injection, an IL-10-inhibiting adeno-associated virus and an IL-10 receptor knockout plasmid were delivered intraventricularly, and neurobehavioral deficits, perihematomal edema, BBB disruption, and the expression of JAK1 and STAT3 were evaluated. Our study demonstrated that the peripheral cytokine IL-10 mitigated BBB breakdown, perihematomal edema, and neurobehavioral deficits after ICH and that IL-10 deficiency reversed these effects, likely through the IL-10R/JAK1/STAT3 signaling pathway. Peripheral IL-10 has the potential to reduce BBB damage and perihematomal edema following ICH and improve patient prognosis.

Search in the Periphery for Potential Inflammatory Biomarkers of Dementia with Lewy Bodies and Alzheimer's Disease.

Neuroinflammation, with altered peripheral proinflammatory cytokine production, plays a major role in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD), while the role of inflammation in dementia with Lewy bodies (DLB) is less known and the results of different studies are often in disagreement. The present study aimed to investigate the levels of TNFα and IL-6 in serum and supernatants, and the related DNA methylation in patients affected by DLB and AD compared to healthy controls (HCs), to clarify the role of epigenetic mechanisms of DNA promoter methylation on of pro-inflammatory cytokines overproduction. Twenty-one patients with DLB and fourteen with AD were frequency-matched for age and sex with eleven HCs. Clinical evaluation, TNFα and IL-6 gene methylation status, cytokine gene expression levels and production in serum and peripheral blood mononuclear cell (PBMC) supernatants were performed. In AD and DLB patients, higher serum levels of IL-6 and TNFα were detected than in HCs. Differences in LPS-stimulated versus spontaneous PBMCs were observed between DLB, AD, and HC in the levels of TNFα (p = 0.027) and IL-6 (p < 0.001). Higher levels were also revealed for sIL-6R in DLB (p < 0.001) and AD (p < 0.001) in comparison with HC.DNA hypomethylation in IL-6 and TNFα CpG promoter sites was detected for DLB and AD patients compared to the corresponding site in HCs. Our preliminary study documented increased levels of IL-6 and TNFα in DLB and AD patients to HCs. This overproduction can be due to epigenetic mechanisms regarding the hypomethylation of DNA promoters.

Elevated IL-6 and Tumor Necrosis Factor-α in Immune Checkpoint Inhibitor Myocarditis.

The impact of peripheral cytokine levels on the prognosis and treatment of immune checkpoint inhibitor (ICI) myocarditis has not been well studied. This study aimed to identify cytokines that can prognosticate and direct the treatment of ICI myocarditis. This was a single-center, retrospective cohort study of patients with ICI myocarditis who had available peripheral cytokine levels between January 2011 and May 2022. Major adverse cardiovascular events (MACEs) were defined as a composite of heart failure with/without cardiogenic shock, arterial thrombosis, life-threatening arrhythmias, pulmonary embolism, and sudden cardiac death. In total, 65 patients with ICI myocarditis had cytokine data available. Patients were mostly males (70%), with a mean age of 67.8 ± 12.7 years. Interleukin (IL)-6 and tumor necrosis factor-α (TNF-α) were the most common cytokines to be elevated with 48/65 (74%) of patients having a peak IL-6 above normal limits (>5 pg/mL) and 44/65 (68%) of patients with peak TNF-α above normal limits (>22 pg/mL). Patients with elevated peak IL-6 had similar 90-day mortality and MACE outcomes compared to those without (10.4% vs. 11.8%, p = 0.878 and 8.8% vs. 17.7%, p = 0.366, respectively). Similarly, those with elevated peak TNF-α had similar 90-day mortality and MACEs compared to those without (29.6% vs. 14.3%, p = 0.182 and 13.6% vs. 4.8%, p = 0.413, respectively). Kaplan-Meier survival analysis also showed that there was not a significant difference between MACE-free survival when comparing elevated and normal IL-6 and TNF-α levels (p = 0.182 and p = 0.118, respectively). MACEs and overall survival outcomes were similar between those who received infliximab and those who did not among all patients and those with elevated TNF-α (p-value 0.70 and 0.83, respectively). Peripheral blood levels of IL-6 and TNF-α are the most commonly elevated cytokines in patients with ICI myocarditis. However, their role in the prognostication and guidance of immunomodulatory treatment is currently limited.