Altered Cytokine Research Articles

Altered cytokine and chemokine profile linked to autoantibody and pathogen reactivity in mothers of autistic children.

Maternal autoimmunity, and more specifically, the production of specific maternal autoantibodies, has been associated with altered offspring neurodevelopment. Maternal autoantibody-related (MAR) autism is a subtype of autism that is linked to gestational exposure to certain combinations of autoantibodies to proteins known to be important for fetal neurodevelopment. We wanted to address whether mothers with autism-specific patterns of autoantibodies have a skewed cytokine and chemokine profile during an immune response to infection. To do so, we examined a subset of mothers from the Early Markers for Autism (EMA) study who either produced known patterns of MAR autoantibodies (MAR+) or did not (MAR-). We compared the cytokine/chemokine profiles of MAR+ and MAR- mothers in the context of positive immunoglobulin G (IgG) reactivity to several viral and parasitic agents. We observed that MAR+ mothers have a higher level of proinflammatory cytokine interferon-gamma regardless of IgG status. Additionally, when comparing MAR+ and MAR- mothers in the context of the different pathogens, MAR+ mothers consistently had increases in multiple proinflammatory cytokines and chemokines.

Pro-inflammatory cytokine alterations in recent onset anorexia nervosa adolescent female patients before and after 6 months of integrated therapy: A case-control study.

Anorexia nervosa (AN) is a complex disorder affecting mainly, but not only, teenagers. Researchers agree that AN is deeply associated with a pro-inflammatory state following an impaired immune system, resulting from altered levels of cytokines such as IL-1β and TNF-α, also impacted by the frequent depressive states. Thus, this case-control study aimed to evaluate the relationship between patients suffering from AN undergoing specialized eating disorder treatment for AN and pro-inflammatory cytokines. To reach our purpose, we assessed eating-related psychopathology and depressive symptoms and measured serum concentration of pro-inflammatory cytokines IL-1β, IL-6, IL-8, and TNF-α before and after 6 months of integrated therapy (which included psychopharmacotherapy, psychotherapy, and nutritional treatment), to define whether selected pro-inflammatory cytokines could be considered a pathophysiological marker of the disorder. A sample of 16 young female patients with early diagnosis of AN, and without any previous treatment, and 22 healthy controls matched by age, sex, and socioeconomic status were enrolled. After 6 months of integrated therapy, a significant decrease of all selected pro-inflammatory cytokines was detected. In addition, an improvement in the anxiety-depressant aspects was also noted. In conclusion, the results obtained suggest that pro-inflammatory cytokines are indeed related to the pathophysiology of AN. However, further investigations, involving larger samples of patients with distinct subtypes of AN, are essential to confirm the current findings.

Diagnostic value of cytokines in severe childhood Mycoplasma pneumoniae pneumonia combined with Adenovirus infection

BackgroundTo explore the alterations of inflammatory markers and immune-related cytokines in children infected with Mycoplasma pneumoniae (MP) combined with Adenovirus (ADV).MethodsThe study population consisted of 201 children with MPP, and they were grouped according to whether they were coinfected with ADV infection and critically ill. Additionally, comparative analyses were performed. The diagnostic value of different indicators and combined indicators for SMPP combined with ADV was assessed using ROC curves.ResultsThere was no difference between group A1 and group A2, group B1 and group B2 in terms of age, gender, duration of hospitalisation and fever. The levels of calcitoninogen(PCT), lactate dehydrogenase concentration(LDH), interleukin(IL)-6, IL-8, IL-10, IL-4, IL-12P70, and IFN-γ in group A were higher than group B. The severe group (A1, B1) was significantly higher than the mild group (A2, B2) in terms of D-dimer, CRP, PCT, LDH, IL-6, IL-8, IL-10, IL-17a and number of patients with pleural effusion, solid lung changes. Among the individual indexes of D-dimer, CRP, N%,LDH, and PCT, the AUC of the combined test was 0.977, which was higher than that of the individual indicators. Among IL-6, IL-8, IL-10, and IL-17a, the AUC of the combined assay was 0.802, which was higher than that of the individual indicators.ConclusionMP combined with ADV infection was associated with increased expression levels of IL-6, IL-8, IL-10, IL-4, IL-12P70, IFN-γ, and LDH. IL-6, IL-8, IL-10, IL-17a, LDH, PCT, CRP, and D-dimer could be used as predictors of SMPP and the combined test can improve the diagnostic value.

Identification of RNF213 as a Potential Suppressor of Local Invasion in Intrahepatic Cholangiocarcinoma

Intrahepatic cholangiocarcinoma (ICC) is a lethal cancer with poor survival especially when it spreads. The histopathology of its rare intraductal papillary neoplasm of the bile duct type (IPNB) characteristically shows cancer cells originating within the confined bile duct space. These cells eventually invade and infiltrate the nearby liver tissues, making it a good model to study the mechanism of local invasion, which is the earliest step of metastasis. To discover potential suppressor genes of local invasion in ICC, we analyzed the somatic mutation profiles and performed clonal evolution analyses of the 11 pairs of macrodissected locally invasive IPNB tissues (LI-IPNB) and IPNB tissues without local invasion from the same patients. We identified a protein-truncating variant in an E3 ubiquitin ligase, RNF213 (c.6967C>T; p.Gln2323X; chr17: 78,319,102 [hg19], exon 29), as the most common protein-truncating variant event in LI-IPNB samples (4/11 patients). Knockdown of RNF213 in HuCCT1 and YSCCC cells showed increased migration and invasion, and reduced vasculogenic mimicry but maintained normal proliferation. Transcriptomic analysis of the RNF213-knockdown vs control cells was then performed in the HuCCT1, YSCCC, and KKU-100 cells. Gene ontology enrichment analysis of the common differentially expressed genes revealed significantly altered cytokine and oxidoreductase-oxidizing metal ion activities, as confirmed by Western blotting. Gene Set Enrichment Analysis identified the most enriched pathways being oxidative phosphorylation, fatty acid metabolism, reactive oxygen species, adipogenesis, and angiogenesis. In sum, loss-of-function mutation of RNF213 is a common genetic alteration in LI-IPNB tissues. RNF213 knockdown leads to increased migration and invasion of ICC cells, potentially through malfunctions of the pathways related to inflammation and energy metabolisms.

Inflammatory Markers in Children and Adolescents with Functional Somatic Disorders: A Systematic Review.

Functional somatic disorders (FSDs) are common in children and adolescents. Recent findings suggest that low-grade inflammation has a role in the development and maintenance of pediatric FSDs. This systematic review included studies with original data on systemic inflammatory markers in children and adolescents with an FSD compared to individuals without an FSD. The literature search identified 1374 articles. After assessment, a total of 15 studies met the inclusion criteria. In total, 41 serum or plasma cytokines were assayed in a population of 696 children and adolescents. Altered cytokine levels in patients with FSDs were reported in 12 studies, whereas three studies found no significant differences when comparing patients with FSDs and controls. The cytokine levels were significantly elevated in nine studies (i.e., IL-2, IL-6, IL-8, IL-12 (p70), CRP, hsCRP, IP-10, MCP-1, sTIM-3, sCD25 and TNF-α). The findings indicate that inflammatory response may have a role in the pathophysiology of pediatric FSDs. However, the included studies showed limited quality with potential risk of bias, small study populations and a narrow spectrum of included FSDs, which limits the generalizability of the results. To further explore the potential link between inflammatory markers and pediatric FSDs, future research using a longitudinal study design is recommended.

In vitro mRNA-S maternal vaccination induced altered immune regulation at the maternal-fetal interface.

Maternal-fetal immunology is intricate, and the effects of mRNA-S maternal vaccination on immune regulation at the maternal-fetal interface require further investigation. Our study endeavors to elucidate these immunological changes, enhancing our comprehension of maternal and fetal health outcomes. By analyzing immune profiles and cytokine responses, we aim to provide valuable insights into the impact of mRNA-S vaccination on the delicate balance of immune regulation during pregnancy, addressing critical questions in the field of reproductive pharmacology. This investigation sought to examine the prospective influence of mRNA-S-based vaccines and extracellular vesicles (EVs) containing the Spike (S) protein at the maternal-fetal interface. Our primary emphasis was on evaluating their effects on maternal decidua cells and fetal chorion trophoblast cells (hFM-CTCs). We validated the generation of EVs containing the S protein from small human airway epithelial cell lines (HSAECs) following mRNA-S vaccine exposure. We assessed the expression of angiotensin-converting enzyme 2 (ACE2) gene and protein in fetal membranes and the placenta, with specific attention to decidual cells and fetal membrane chorion cells. To assess cellular functionality, these cells were exposed to both recombinant S protein and EVs loaded with S proteins (eSPs). Our findings revealed that cells and EVs subjected to mRNA-S-based vaccination exhibited altered protein expression levels of S proteins. At the feto-maternal interface, both placental and fetal membrane tissues demonstrated similar ACE-2 expression levels. Among individual cellular layers, syncytiotrophoblast cells in the placenta and chorion cells in the fetal membrane exhibited elevated ACE-2 expression. Notably, EVs derived from HSAECs activated the MAPK pathway in decidual cells. Additionally, decidual cells displayed a substantial increase in gene expression of chemokines like CXCL-10 and CXCL-11, as well as proinflammatory cytokines such as IL-6 in response to eSPs. However, the levels of Ccl-2 and IL-1β remained unchanged in decidual cells under the same conditions. Conversely, hFM-CTCs demonstrated significant alterations in the proinflammatory cytokines and chemokines with respect to eSPs. In conclusion, our study indicates that mRNA-S-based maternal vaccination during pregnancy may influence the maternal-fetal interface's COVID-19 interaction and immune regulation. Further investigation is warranted to assess safety and implications.

A microbiota derived metabolite and pediatric celiac disease pathogenesis

Abstract Celiac Disease (CD) is an autoimmune condition triggered by gluten ingestion and defined by small intestine inflammation leading to villous atrophy in genetically predisposed individuals. 20-40% of the general population possess the predisposing HLA-DQ2 or HLA-DQ8 alleles, however only 1-2% of the population develops CD, indicating that there are additional environmental factors at play in the pathogenesis of the disease. In a prospective cohort study using fecal and plasma samples from children at ages 2.5 and 5 years, before the onset of celiac disease (CD progressors), we found that CD progressors have an altered gut microbiome, plasma metabolome and cytokine profile years before diagnosis. IgA sequencing revealed an increased IgA response and unique microbial targets of IgA. One metabolite increased in CD progressors is taurodeoxycholic acid (TDCA), a secondary bile acid produced by gut microbes. Treating C57BL/B6 mice with TDCA caused villous atrophy as well as upregulated CD4+T-cells in intraepithelial lymphocytes and natural killer cells in the lamina propria (LP). TDCA increased the expression of Qa-1 and NKG2D on T-cells. The DQ8-Dd-villin-IL-15tg mouse model of CD possesses the predisposing HLA-DQ8 molecule and overexpresses IL-15 in the LP. Treating these mice with TDCA caused the villi/crypt ratio to decrease in the treatment group of pooled villi. Our results indicate that TDCA and TDCA-producing bacteria could potentially contribute to the pathogenesis of CD.

Direct effect of ultra diluted ethanolic extract of Apis mellifica on Escherichia coli and Staphylococcus aureus in Gallus gallus domesticus embryo model

Urinary tract infection and other infections caused by multi-drug resistance strains have increased significantly, creating a need to investigate alternative medicine for therapeutic purposes. Our aim is to determine whether Apis mellifica 6C (an alternative ultra-diluted medicine) can counteract the detrimental impact of Escherichia coli ATCC 25922, Escherichia coli MDR and Staphylococcus aureus ATCC 25923 in Gallus gallus domesticus embryos with regard to their morbid anatomical changes and cytokine alterations. Anti-microbial activity of Apis mellifica 6C against the ATCC and MDR strains was examined by Agar Disc Diffusion method. The bacterial strains were inoculated on 15th day embryonated chick egg model and the alteration in cytokine gene expressions (IL-10 and IFN-γ) was examined by RT PCR method. In disc diffusion method, Apis mellifica induced zone of inhibition which was prominent in case of all mentioned bacteria. In case of embryo model, the most notable finding is that after being challenged with Apis mellifica 6C, the IFN-γ and IL-10 gene expression of E. coli ATCC, MDR E. coli and S. aureus ATCC were all remarkably decreased than the control set. Similar interesting outcomes were also found in the morbid anatomy of the chick embryo. In cases of urinary tract infection and other infections, Apis mellifica 6C appears to be efficient and beneficial.

The influence of neonatal BCG vaccination on in vitro cytokine responses to Plasmodium falciparum

BackgroundBacillus Calmette–Guérin (BCG) vaccination has off-target protective effects against infections unrelated to tuberculosis. Among these, murine and human studies suggest that BCG vaccination may protect against malaria. We investigated whether BCG vaccination influences neonatal in vitro cytokine responses to Plasmodium falciparum. Blood samples were collected from 108 participants in the Melbourne Infant Study BCG for Allergy and Infection Reduction (MIS BAIR) randomised controlled trial (Clinical trials registration NCT01906853, registered July 2013), seven days after randomisation to neonatal BCG (n = 66) or no BCG vaccination (BCG-naïve, n = 42). In vitro cytokine responses were measured following stimulation with P. falciparum-infected erythrocytes (PfIE) or E. coli.ResultsNo difference in the measured cytokines were observed between BCG-vaccinated and BCG-naïve neonates following stimulation with PfIE or E. coli. However, age at which blood was sampled was independently associated with altered cytokine responses to PfIE. Being male was also independently associated with increased TNF-a responses to both PfIE and E. coli.ConclusionThese findings do not support a role for BCG vaccination in influencing in vitro neonatal cytokine responses to P. falciparum. Older neonates are more likely to develop P. falciparum-induced IFN-γ and IFN-γ-inducible chemokine responses implicated in early protection against malaria and malaria pathogenesis.

Diet-induced metabolic and immune impairments are sex-specifically modulated by soluble TNF signaling in the 5xFAD mouse model of Alzheimer's disease

Emerging evidence indicates that high-fat, high carbohydrate diet (HFHC) impacts central pathological features of Alzheimer's disease (AD) across both human incidences and animal models. However, the mechanisms underlying this association are poorly understood. Here, we identify compartment-specific metabolic and inflammatory dysregulations that are induced by HFHC diet in the 5xFAD mouse model of AD pathology. We observe that both male and female 5xFAD mice display exacerbated adiposity, cholesterolemia, and dysregulated insulin signaling. Independent of biological sex, HFHC diet also resulted in altered inflammatory cytokine profiles across the gastrointestinal, circulating, and central nervous systems (CNS) compartments demonstrating region-specific impacts of metabolic inflammation. Interestingly, inhibiting the inflammatory cytokine, soluble tumor necrosis factor (TNF) with the brain-permeant soluble TNF inhibitor XPro1595 was able to restore aspects of HFHC-induced metabolic inflammation, but only in male mice. Targeted transcriptomics of CNS regions revealed that inhibition of soluble TNF was sufficient to alter expression of hippocampal and cortical genes associated with beneficial immune and metabolic responses. Collectively, these results suggest that HFHC diet impairs metabolic and inflammatory pathways in an AD-relevant genotype and that soluble TNF has sex-dependent roles in modulating these pathways across anatomical compartments. Modulation of energy homeostasis and inflammation may provide new therapeutic avenues for AD.

High-fat diet elicits sex-based differences in liver inflammatory cytokines and redox homeostasis.

Sex differences in metabolic dysfunction-associated steatotic liver disease (MASLD) have been reported. Oxidative stress and inflammation are involved in the progression of MASLD. Thus, we aimed to evaluate liver redox homeostasis and inflammation in male and female rats fed a high-fat diet (HFD). Male and female Wistar rats were divided into the following groups: standard chow diet (SCD) or HFD during 12 weeks. HFD groups of both sexes had higher hepatocyte injury, with no differences between the sexes. Portal space liver inflammation was higher in females-HFD compared to females-SCD, whereas no differences were observed in males. Lobular inflammation and overall liver inflammation were higher in HFD groups, regardless of sex. TNF-α, IL-6, and IL-1β levels were higher in males-HFD compared to males-SCD, but no differences were observed in females. Catalase activity was higher in males compared to females, with no differences between the SCD and HFD groups of both sexes. Glutathione peroxidase activity was higher in females compared to males, with no differences between the SCD and HFD groups in both sexes. Lipid peroxidation was higher in female-SCD when compared to male-SCD, and in both male- and female-HFD compared to SCD groups. Furthermore, both cytoplasmic and nuclear NRF2 staining were lower in the HFD group compared to the SCD group in males. However, female-HFD exhibited reduced nuclear NRF2 staining compared to the female-SCD group. In conclusion, our study demonstrated that while both male and female rats developed metabolic dysfunction-associated steatohepatitis after 12 weeks of HFD, the alterations in inflammatory cytokines and redox balance were sexually dimorphic.

The Pathophysiological, Genetic, and Hormonal Changes in Preeclampsia: A Systematic Review of the Molecular Mechanisms.

Preeclampsia, a serious complication of pregnancy, involves intricate molecular and cellular mechanisms. Fetal microchimerism, where fetal cells persist within maternal tissues and in circulation, acts as a mechanistic link between placental dysfunction and maternal complications in the two-stage model of preeclampsia. Hormones, complements, and cytokines play pivotal roles in the pathophysiology, influencing immune responses, arterial remodeling, and endothelial function. Also, soluble HLA-G, involved in maternal-fetal immune tolerance, is reduced in preeclampsia. Hypoxia-inducible factor 1-alpha (Hif-α) dysregulation leads to placental abnormalities and preeclampsia-like symptoms. Alterations in matrix metalloproteinases (MMPs), endothelins (ETs), chemokines, and cytokines contribute to defective trophoblast invasion, endothelial dysfunction, and inflammation. Preeclampsia's genetic complexity includes circRNAs, miRNAs, and lncRNAs. CircRNA_06354 is linked to early-onset preeclampsia by influencing trophoblast invasion via the hsa-miR-92a-3p/VEGF-A pathway. The dysregulation of C19MC, especially miR-519d and miR-517-5p, affects trophoblast function. Additionally, lncRNAs like IGFBP1 and EGFR-AS1, along with protein-coding genes, impact trophoblast regulation and angiogenesis, influencing both preeclampsia and fetal growth. Besides aberrations in CD31+ cells, other potential biomarkers such as MMPs, soluble HLA-G, and hCG hold promise for predicting preeclampsia and its complications. Therapeutic interventions targeting factors such as peroxisome PPAR-γ and endothelin receptors show potential in mitigating preeclampsia-related complications. In conclusion, preeclampsia is a complex disorder with a multifactorial etiology and pathogenesis. Fetal microchimerism, hormones, complements, and cytokines contribute to placental and endothelial dysfunction with inflammation. Identifying novel biomarkers and therapeutic targets offers promise for early diagnosis and effective management, ultimately reducing maternal and fetal morbidity and mortality. However, further research is warranted to translate these findings into clinical practice and enhance outcomes for at-risk women.

Investigating the synergistic effects of amitriptyline and H. pylori eradication on depressive-like behaviors and inflammatory cytokines in mice

BackgroundRecent research has highlighted the potential role of Helicobacter pylori in the pathogenesis of psychiatric disorders. This study aimed to evaluate the potential synergistic effects of an antidepressant drug and H. pylori eradication therapy in a mouse model. MethodsMale C57BL/6 mice were divided into four groups: control, H. pylori infection, antidepressant treatment, and combined treatment. H. pylori infection was induced by oral gavage with a clinically relevant strain, and the antidepressant drug was administered via intraperitoneal injections. Behavioral tests including the forced swim test, sucrose preference test, and open field test were conducted to assess depressive-like behaviors and locomotor activity. ResultsThe study demonstrated that H. pylori infection induced depressive-like behaviors in mice, as evidenced by increased immobility time in the forced swim test and reduced sucrose preference. Antidepressant treatment alone partially ameliorated these behavioral changes. Strikingly, the combined treatment of the antidepressant drug and H. pylori eradication therapy led to a significantly greater reduction in depressive-like behaviors compared to either treatment alone. Furthermore, the combined treatment group exhibited increased locomotor activity in the open field test, suggesting a potential improvement in overall psychomotor functioning. ELISA assays revealed alterations in inflammatory cytokines in the H. pylori-infected mice, which were partially attenuated by the combined treatment. ConclusionThe study provides novel evidence for the potential synergistic effects of an antidepressant drug and H. pylori eradication therapy in alleviating depressive-like behaviors in a mouse model.

No side effects on rabbit retina or vitreous microenvironment by nd:YAG laser vitreolysis.

To explore the safety of Neodymium:Yttrium-aluminum-garnet (Nd:YAG) laser vitreolysis based on the histological examination of the retina and the alteration of vitreous cytokines in the rabbits. Nine male New Zealand rabbits underwent Nd:YAG laser vitreolysis of 10mJ x 500 pulses in the left eyes, while the right eyes were used as controls. Intraocular pressure, color fundus photography, and ultrasound B scan were measured before, as well as 1day, 4 weeks, and 12 weeks after Nd:YAG laser vitreolysis. Three rabbits were euthanized 1day, 4 weeks, and 12 weeks after treatment, respectively. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and hematoxylin-eosin (H&E) staining were used to look for pathological changes in the retina. An enzyme-linked immunosorbent assay (ELISA) was utilized to detect the expression of vascular endothelial growth factor (VEGF) and some inflammatory cytokines, including interferon inducible protein 10 (IP-10), monocyte chemoattractant protein 1 (MCP-1) and interlenkin 6 (IL-6) in the vitreous humor. The ascorbic acid (AsA) and total reactive antioxidant potential (TRAP) in the vitreous humor were also measured. Following Nd:YAG laser vitreolysis, the levels of VEGF, IP-10, MCP-1, IL6, AsA, and TRAP in the vitreous humor did not change substantially (P > 0.05). There were no detectable pathological changes in the retinal tissues, and no apoptotic signal was found. Rabbits tolerate Nd:YAG laser vitreolysis without observable impact on retinal tissue or the microenvironment of the vitreous.

Necroptosis could serve as an indicator of therapeutic resistance in viral induced well-differentiated oral squamous cell carcinoma?

Goal of the perspectiveExploring necroptosis as an indicator of therapeutic resistance in viral-induced well-differentiated oral squamous cell carcinoma (OSCC) is to elucidate its potential role in predicting treatment outcomes and guiding therapeutic decisions. By understanding the relationship between necroptosis levels and therapeutic resistance, oncologists can aim to identify novel biomarkers and therapeutic targets that could improve patient management and outcomes in viral-induced OSCC. DiscussionViral-induced oral squamous cell carcinoma (OSCC) presents with disrupted cellular functions, dysregulation of apoptotic pathways, evasion of programmed cell death and resistance to conventional anticancer treatments. Concurrently, alterations in pro-inflammatory cytokines and chemokines drive tumorigenesis in viral-induced squamous cell carcinoma, impairing anti-viral immune responses. ConclusionMonitoring necroptosis levels in viral-induced OSCC offers insights into therapy resistance, as high levels may indicate reduced responsiveness to standard treatments. Understanding the role of necroptosis in therapy resistance could pave the way for the development of targeted therapies that exploit necroptosis pathways to overcome resistance and improve treatment outcomes in viral-induced OSCC.

Abstract CT191: First-in-human, dose escalation and expansion study of MT-6402, a novel engineered toxin body (ETB) targeting PD-L1, in patients with PD-L1 expressing relapsed/refractory advanced solid tumors: Interim data

Abstract MT-6402 is a PD-L1-targeted ETB capable of directly killing PD-L1 expressing cells by internalization of a de-immunized Shiga-like toxin A subunit (SLTA), resulting in ribosomal destruction. Targeting PD-L1 expressing tumor cells may directly drive tumor regression, whereas targeting PD-L1 expressing immune cells may release immunosuppression and drive tumor immune recognition. MT-6402 also delivers an HLA-A*02 restricted cytomegalovirus (CMV) class I antigen into PD-L1 expressing cells (antigen seeding) that can be recognized by existing CMV-specific cytotoxic T cells. A first-in-human dose escalation (Part A) and expansion (Part B) study with a weekly intravenous administration of MT-6402 in 4-week cycles was initiated in 2021. Safety and tolerability are primary objectives. Efficacy, pharmacokinetics, and pharmacodynamic data are also collected. As of 10Dec2023, 53 total patients (pts) with PD-L1-expressing advanced solid tumors received ≥ 1 dose of MT-6402: 48 pts in Part A ranging in dose 16 to 100 µg/kg and 5 pts in Part B at 63 µg/kg, just below the maximum tolerated dose (MTD) of 83 µg/kg. MT-6402 was well tolerated in Part A, completed Sept2023. 5 dose limiting toxicities have been reported: a Grade (G)3 maculopapular rash at 24 µg/kg, a G3 infusion related reaction at 63 µg/kg, a G1 cardiac troponin T increase leading to dosing hold for ≥2 weeks at 83 µg/kg, a G3 maculopapular rash at 100 µg/kg, and a G1 cardiac troponin T increase at 100 µg/kg. There were no G4 or G5 drug-related adverse events. In Part B, pts with PD-L1 scores of TPS ≥ 50% will be treated at MTD or lower and 5 pts have been treated at 63 µg/kg. Signs of antitumor activity have been reported including a long-lasting PR with 70% tumor reduction have been observed in a pt with CPI-refractory nasopharyngeal carcinoma on treatment 14+ cycles at 63 µg/kg. This pt has a PD-L1 TPS score of 2% indicating immune cell clearance may have driven the response. The most common cancer in Part A is Squamous Cell Carcinoma of the Head and Neck (10 pts). Pharmacodynamic effects include a significant reduction in peripheral PD-L1+ immune cells, indicating a PD-L1 target-specific effect. Substantial alterations in serum cytokines associated with the tumor microenvironment were noted after each dose in most pts in a dose dependent manner. Most pts display increased CD8/CD4 ratios with IL-2 and TNFα cytokine release, indicative of immune activation due to elimination of immune cells. CMV-specific CD8 T-cells exhibited a pattern of extravasation from the periphery in HLA-A*02+/CMV+ pts suggesting antigen seeding. These results describe a novel approach to checkpoint modulation by MT-6402 with targeted cell killing and altered tumor immunophenotype, particularly in HLA-A*02/CMV+ pts. These results provide rationale for continued development of MT-6402. Citation Format: Brian A. Van Tine, Eugene Ahn, Rebecca A. Redman, Minal A. Barve, William J. Edenfield, Julio Peguero, Victoria M. Villaflor, Drew W. Rasco, Steven F. Powell, Admasu T. Mamuye, Chris B. Moore, Joshua M. Pelham, Soratree Charoenthongtrakul, David R. Spigel. First-in-human, dose escalation and expansion study of MT-6402, a novel engineered toxin body (ETB) targeting PD-L1, in patients with PD-L1 expressing relapsed/refractory advanced solid tumors: Interim data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT191.

Altered serum cytokines in patients with symptomatic disk herniation and depressive symptoms.

An increasing number of studies have indicated the important role of cytokines in the development of depressive disturbances (DD). In medically ill patients, cytokines can provoked sickness behavior, the signs of which resemble DD. This results in alterations in behavior to limit energy expenditure and redirect it to cope with particular diseases. The aim of our study was to investigate the role of pro-inflammatory IL-6, TNF-α, and IL-1β and anti-inflammatory IL-10 and TGF-β in DD observed in patients suffering from pain caused by disk herniation (DH) qualified for surgery. The intensity of DD assessed by using Beck Depression Inventory, pain intensity, and functional impairment were evaluated in 70 patients with DH who were qualified for surgery. Pro-inflammatory serum levels of TNF-α, IL-1, IL-6, anti-inflammatory TGF-β, and IL-10 were measured. Elevated serum levels of TGF-β, IL-10, and IL-6 were found in the group with moderate and severe depressive symptoms (SD) compared with the groups with mild (MD) or no depressive symptoms (ND). TGF-β levels were negatively correlated with pain intensity, as assessed using the Present Pain Intensity scale in SD. Functional impairment measured using the Oswestry Disability Index was the most advanced in SD group. Results of our study can suggest association between depressive disturbances and anti-inflammatory cytokines TGF-β and IL-10. Functional impairment of SD group is more severe but serum levels of TGF-β and IL-10, which are involved in the healing processes, are increased.

Synergistic effects of Ω-3 polyunsaturated fatty acid supplementation and programmed cell death protein 1 blockade on tumor growth and immune modulation in a xenograft model of esophageal cancer

Esophageal cancer, especially esophageal squamous cell carcinoma (ESCC), remains a significant global health challenge with limited survival rates. This study aimed to elucidate the combined effects of immune-modulating nutrition (IMN) with Ω-3 polyunsaturated fatty acid (PUFA) supplementation and anti-programmed cell death protein 1 (PD-1) treatment on tumor growth and immune responses in a xenograft model of ESCC. A total of 36 C57BL/6 mice were used to construct a xenograft model using the mouse esophageal cancer cell line AKR. Mice were subjected to treatment with anti- PD-1 antibody combined with either Ω-3 PUFA-rich or Ω-3 PUFA-deficient nutrition. Tumor growth, immune markers, cytokine profiles, and metabolic changes were evaluated. The combination of anti-PD-1 and Ω-3 PUFA supplementation significantly inhibited tumor growth more effectively than anti-PD-1 treatment alone. Enhanced expression of immune markers PD-L1 and CD3 was observed in Ω-3 PUFA-fed mice. Additionally, compared with anti-PD-1 therapy and anti-PD-1 plus Ω-3 PUFA-deficient nutrition, Ω-3 PUFAs intensified alterations in key chemokines and cytokines, including elevated IL-12, IFN-γ, and GM-CSF levels, and reduced CXCL12 levels. However, Ω-3 PUFAs did not significantly alter the glycolysis and tryptophan metabolic program induced by anti-PD-1. Our findings indicated the potential synergetic therapeutic benefits of combining anti-PD-1 treatment with Ω-3 PUFA supplementation in ESCC, which offered promising avenue for further research.

462 Stem Cell-Loaded Implantable Intrathecal Bioreactors for the Treatment of Spinal Cord Injury: A Porcine Model Pilot Study

INTRODUCTION: Stem cells promote spinal cord injury (SCI) recovery by secreting paracrine factors that orchestrate endogenous healing mechanisms. However, effects in clinical trials are modest and there are no approved stem cell therapies to treat SCI. Major barriers include cell washout, immune attack, and oncogenic potential. METHODS: ITBs were implanted in three pigs. One pig received a cell-loaded ITB without injury (Cells), another received a cell-loaded ITB with injury (Cells + SCI), and another received a sham ITB with injury (SCI). SCIs were induced by weight drop at T5. ITBs were implanted cranial to the injury and sutured under the dura then loaded with human mesenchymal stem cells or sham cell media. Cerebrospinal fluid (CSF) was collected for 6 days following surgery through a lumbar drain. Cytokines in the CSF were measured by ELISA and the ITB was retrieved for cell viability staining. RESULTS: Upon retrieval, stem cells were alive on viability staining of the ITB. CSF levels of the pro-inflammatory cytokines IFNy and IL-1a were increased in the SCI condition compared to the Cells and Cells + SCI conditions. Pro-inflammatory cytokines peaked on post-operative day 5 and remained high. Anti-inflammatory cytokines IL-1ra, VEGF, and TGFβ were elevated in the SCI + Cells condition and depressed in the SCI condition compared to the Cells condition. Anti-inflammatory cytokines peaked on post-operative day 3 and decreased by day 6. CONCLUSIONS: In this pilot study, stem cells survived in an implantable ITB and altered cytokine levels in the CSF of pigs with SCI. Cell-loaded ITBs reduced pro-inflammatory cytokines and increased anti-inflammatory cytokines. Implantable ITBs warrant further study as they may represent a potential new delivery option for stem cell therapy.

Different Influence Pattern of Conventional and Alternative Sources of Smoking on Adhesion Molecules and Cytokine Secretion in THP-1 Monocytes.

Tobacco is a carcinogen that is closely associated with the occurrence of lung cancer and head and neck squamous cell carcinoma (HNSCC). The consumption of tobacco is also leading to alterations in different immune cell subtypes. However, the impact of different conventional and alternative smoking sources on human monocytes remains elusive. In this study, we investigated the influence of aqueous extracts of different sources of smoking (cigarettes; heated tobacco product IQOS; e-cigarettes with and without nicotine; nicotine pouches) on different monocytic adhesion molecules, chemokine receptors and checkpoint molecule PD-L1 by flow cytometry. Cytokine expression patterns were evaluated using human cytokine arrays and the human monocyte leukemia cell line THP-1 as a model. Data revealed differential effects of the analyzed conventional and alternative smoking devices on monocyte adhesion molecules and cytokine secretion. The examined smoking devices can be assigned to two differential monocyte activation patterns. Monocytes stimulated with aqueous extracts of cigarettes, e-cigarette without nicotine, and heat not burn product IQOS revealed distinct alterations of surface markers and cytokines compared to the monocyte activation pattern in response to aqueous extracts of nicotine, nicotine pouches, and e-cigarette with nicotine. Our data indicate differential immunological consequences of different conventional and alternative smoking sources with and without nicotine. Further comprehensive analysis as well as in vivo investigations on peripheral blood monocyte subsets from smoking individuals using different smoking sources are required to better understand the impact on monocyte characteristics, especially with regard to the development of cancer.