Serum Concentrations Of IFN-γ Research Articles

Improved biodistribution and enhanced immune response of subunit vaccine using a nanostructure formed by self-assembly of ascorbyl palmitate

New adjuvant strategies are needed to improve protein-based subunit vaccine immunogenicity. We examined the potential to use nanostructure of 6-O-ascorbyl palmitate to formulate ovalbumin (OVA) protein and an oligodeoxynucleotide (CpG-ODN) (OCC). In mice immunized with a single dose, OCC elicited an OVA-specific immune response superior to OVA/CpG-ODN solution (OC). Rheological studies demonstrated OCC's self-assembling viscoelastic properties. Biodistribution studies indicated that OCC prolonged OVA and CpG-ODN retention at injection site and lymph nodes, reducing systemic spread. Flow-cytometry assays demonstrated that OCC promoted OVA and CpG-ODN co-uptake by Ly6ChiCD11bhiCD11c+ monocytes. OCC and OC induced early IFN-γ in lymph nodes, but OCC led to higher concentration. Conversely, mice immunized with OC showed higher serum IFN-γ concentration compared to those immunized with OCC. In mice immunized with OCC, NK1.1+ cells were the IFN-γ major producers, and IFN-γ was essential for OVA-specific IgG2c switching. These findings illustrate how this nanostructure improves vaccine's response.

Population Pharmacokinetics of the Anti-Interferon-Gamma Monoclonal Antibody Emapalumab: An Updated Analysis.

Emapalumab is a fully human monoclonal antibody that targets free and receptor-bound interferon-gamma (IFNγ), neutralizing its biological activity. IFNγ levels differ by orders of magnitude between patients with primary hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS; a form of secondary HLH) in systemic juvenile idiopathic arthritis (sJIA). Therefore, this study aimed to develop a population pharmacokinetic model for emapalumab across a patient population with a wide range of total (free and emapalumab-bound) IFNγ levels using observations from patients with primary HLH or MAS in sJIA in clinical trials. Pharmacokinetic data were pooled (n = 58; 2709 observations) from studies enrolling patients administered emapalumab for primary HLH or MAS in sJIA. Patients with primary HLH were administered emapalumab 1mg/kg (potentially increasing to 3, 6, and up to 10mg/kg based on clinical response) every 3days. Patients with MAS in sJIA were administered emapalumab 6mg/kg, followed by 3mg/kg every 3days until day 15 and twice weekly until day 28. An earlier population PK model was re-parameterized using this data. The final model for emapalumab comprised a 2-compartment model with first-order elimination. Emapalumab clearance remains constant when the total IFNγ concentration (free and emapalumab-bound) is < ~ 10,000pg/ml but increases proportionally to total IFNγ concentration above this threshold. Emapalumab clearance was estimated to be 0.00218, 0.00308, 0.00623 and 0.01718 l/h at total serum IFNγ concentrations of 103, 104, 105 and 106pg/ml, respectively, with corresponding terminal half-lives of 19.2, 13.8, 7.18 and 3.12days for a 1-year-old patient weighing 10kg with primary HLH. The median terminal half-life for emapalumab in patients with MAS in sJIA was estimated to be 24.0 (range, 6.13-32.4)days, which is similar to observations in healthy volunteers. Emapalumab pharmacokinetics in patients with primary HLH and MAS in sJIA were described by a two-compartment model with fixed allometric exponents and an age-related effect. Differences in total IFNγ levels between patients with primary HLH and MAS may affect emapalumab pharmacokinetics, suggesting that each indication may require different dosing to rapidly control hyperinflammation. Clinicaltrials.gov identifiers: NCT01818492, NCT03311854 and NCT02069899.

Blood Biomarker and Physical Activity Correlations in Persons with Parkinson’s Disease

Parkinson’s disease (PD) is a debilitating disease that reduces an individual’s quality of life (QOL). PD has a complex pathophysiology, but inflammation is a major contributor. Inflammation is a biological process that removes harmful stimuli and initiates the healing cascade. Researchers commonly use inflammatory markers, such as tumor necrosis factor-alpha (TNFα),interferon-gamma (IFNγ), and interleukin 1-beta (IL1β), to study PD pathologies. While PD is irreversible, physical activity is a non-pharmacological treatment exhibiting beneficial outcomes related to PD and inflammation. To determine if exercise frequency affects the quality of life (QOL) and the magnitude of change in inflammatorybiomarkers associated with PD. Researchers recruited 10 individuals diagnosed with PD to participate in a cross-sectional study. Participants completed four questionnaires to determine their current physical activity (PA) level and QOL. Blood samples were analyzed to determine differences in serum TNFα, IFNγ, and IL1β concentrations between different PA levels of persons with PD. With an alpha level of 0.05, this project only yielded two significant results: an unexpected positive relationship between IL1β and PA level and an expected negative relationship between IL1β and QOL. Although they were not significant, several results trended in the expected directions. Discussion: Observed trends indicated that increasing physical activity decreases inflammatory blood biomarker levels and increases QOL while increasing sedentary behavior increases inflammatory blood biomarker levels and decreases QOL.

Clinical study of the cytokine panel in the diagnosis of ocular chronic graft-versus-host disease

Objective: To investigate the association between cytokines and ocular chronic graft-versus-host disease (cGVHD) and identify specific biomarkers for ocular cGVHD to enhance clinical diagnosis, treatment, and evaluation. Methods: A mouse model of cGVHD was established to explore the correlation between cGVHD and serum cytokines. Based on the findings from the animal experiments and literature review, a panel of 16 cytokine combinations was identified. Enzyme-linked immunosorbent assay (ELISA) was used to compare the cytokine concentrations in the serum and tear samples from patients who underwent allogeneic hematopoietic stem cell transplantation from June 2017 to March 2022 at the Medical Center of Hematology, Xinqiao Hospital, Army Medical University. Results: ① Compared with the control group, mice with cGVHD exhibited elevated serum IL-1β, IL-6, IL-8, IL-17, IFN-γ, CX3CL1, CXCL11, CXCL13, CCL11, and CCL19 concentrations (all P<0.05). ② Analysis of the cytokine profiles of the serum and tear samples revealed that compared with patients without ocular cGVHD, those with ocular cGVHD exhibited increased serum IL-8 [P=0.032, area under the curve (AUC) =0.678]; decreased serum IL-10 (P=0.030, AUC=0.701) ; elevated IL-8, IFN-γ, CXCL9, and CCL17 in tear samples; and lower IL-10 and CCL19 in tear samples (all P<0.05, all AUC>0.7). Moreover, cytokines in tear samples showed correlations with ocular surface parameters related to ocular cGVHD. Conclusions: Tear fluid demonstrates greater specificity and sensitivity as a biomarker for diagnosing ocular cGVHD than serum biomarkers. Among the identified cytokines in tear samples, IL-8, IL-10, IFN-γ, CXCL9, CCL17, and CCL19 serve as diagnostic biomarkers for ocular cGVHD post-transplantation, offering practical reference value for diagnosis.

Phase I study targeting newly diagnosed grade 4 astrocytoma with bispecific antibody armed T cells (EGFR BATs) in combination with radiation and temozolomide

PurposeThe purpose of this study was to determine the safety, feasibility, and immunologic responses of treating grade 4 astrocytomas with multiple infusions of anti-CD3 x anti-EGFR bispecific antibody (EGFRBi) armed T cells (EGFR BATs) in combination with radiation and chemotherapy.MethodsThis phase I study used a 3 + 3 dose escalation design to test the safety and feasibility of intravenously infused EGFR BATs in combination with radiation and temozolomide (TMZ) in patients with newly diagnosed grade 4 astrocytomas (AG4). After finding the feasible dose, an expansion cohort with unmethylated O6-methylguanine-DNA methyltransferase (MGMT) tumors received weekly EGFR BATs without TMZ.ResultsThe highest feasible dose was 80 × 109 EGFR BATs without dose-limiting toxicities (DLTs) in seven patients. We could not escalate the dose because of the limited T-cell expansion. There were no DLTs in the additional cohort of three patients with unmethylated MGMT tumors who received eight weekly infusions of EGFR BATs without TMZ. EGFR BATs infusions induced increases in glioma specific anti-tumor cytotoxicity by peripheral blood mononuclear cells (p < 0.03) and NK cell activity (p < 0.002) ex vivo, and increased serum concentrations of IFN-γ (p < 0.03), IL-2 (p < 0.007), and GM-CSF (p < 0.009).ConclusionTargeting AG4 with EGFR BATs at the maximum feasible dose of 80 × 109, with or without TMZ was safe and induced significant anti-tumor-specific immune responses. These results support further clinical trials to examine the efficacy of this adoptive cell therapy in patients with MGMT-unmethylated GBM.ClinicalTrials.gov Identifier: NCT03344250

Changes in the Cytokine Profile in Patients During COVID-19 Infection

Abstract COVID-19 has proven to be a disease that affects not only the respiratory tract but also leads to a state of generalized systemic hyperinflammation and overall immune dysregulation. An important role in its pathogenesis is the disturbance of many cytokines – a condition which, in its most pronounced form, is also called a „cytokine storm“. Objective To evaluate the serum cytokine levels during COVID-19 infection as potential biomarkers for the severity and course of infection. Materials and methods By design, the study is a retrospective cross-sectional, in which the serum concentrations of 10 pro- and anti-inflammatory cytokines (IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, TNF-α, and GM-CSF) were investigated in 36 individuals (divided into 3 groups by severity – with a mild form of the infection/presymptomatic, moderately severe and severe/critical) within two periods – before and after the second week from the onset of symptoms of the disease. Results In the period up to the 2nd week, the serum concentrations of IFN-γ (p = 0.029), IL-1β (p = 0.017), and IL-5 (p = 0.014) showed a statistically significant correlation with the disease severity, however in the later stage of the disease the cytokine levels did not show any clinical value. Conclusion Cytokine testing could be used to predict the severity of COVID-19 infection which could support individual therapeutic decisions. Analysis of a larger group of patients is needed to unfold the full potential of such testing.

Clinical Study on Cytokines Panel in the Diagnosis of Ocular Chronic Graft-Versus-Host Disease

Background Chronic graft-versus-host disease (cGVHD) is a common complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT), affecting 30-70% of patients after allo-HSCT. Sixty to ninety percent of cGVHD patients suffer from ocular chronic GVHD (ocGVHD), which is characterized by new-onset dry, “gritty”, or painful eyes, cicatricial conjunctivitis, keratoconjunctivitis sicca, and confluent areas of punctate keratopathy, significantly affecting patients' quality of life. Nevertheless, the clinical diagnosis of ocGVHD relies heavily on observing symptoms and clinical signs. Treatment is typically initiated during the symptomatic stage, by which time the damage to the ocular tissues may be irreversible. Consequently, it is crucial to investigate methods of early diagnosis for early intervention. Methods The cGVHD mouse model was established to explore the correlation between cGVHD and serum cytokines. Based on the findings from animal experiments and literature review, a panel of 16 cytokine combinations was identified. Enzyme-linked immunosorbent assay (ELISA) was employed to compare the levels of cytokines in serum and tear samples obtained from patients who underwent allogeneic hematopoietic stem cell transplantation. The inclusion criteria were set as post-allo-HSCT patients between the ages of 18 and 60 who were willing to participate in the study. The visual acuity, ocular pressure, Ocular Surface Disease Index (OSDI) score, Schirmer's test without anesthesia, corneal fluorescein staining (CFS), and fluorescein tear breakup time (FTBUT) were evaluated. The tear sample was collected via Schirmer's strips. Qualitative data were compared with the chi-square test. The Spearman test was used to analyze correlations (ChiCTR2200062516). Results In comparison to the control group, cGVHD mice exhibited elevated concentrations of serum IL-1β, IL-6, IL-8, IL-17, IFN-γ, CX3CL1, CXCL11, CXCL13, CCL11, and CCL19 (P&amp;lt;0.05). A total of 26 post-allo-HSCT ocGVHD patients (38±11y; range 19-57y) and 27 patients without ocGVHD (34±9y; range 20-52y) were recruited. Between patients with and without ocGVHD, there were significant differences in ocular surface parameters (p&amp;lt;0.0001). Analysis of serum and tear cytokine profiles in patients revealed that, when compared to patients without ocular cGVHD, those with ocular cGVHD exhibited increased serum IL-8 levels (P=0.0319, AUC value=0.678), decreased serum IL-10 levels (P=0.0305, AUC value=0.701), elevated tear fluid levels of IL-8, IFN-γ, CXCL9, and CCL17, and lower tear fluid levels of IL-10 and CCL19 (P&amp;lt;0.05, AUC values were &amp;gt;0.7). Moreover, the correlation analysis between tear cytokine levels and ophthalmic indices showed that 3 cytokines were correlated with ophthalmic indices: IL-10, IFN-γ and CXCL9, indicating the superior diagnostic capabilities and correlation with ocGVHD severity. (Figure 1) Conclusions Tear fluid demonstrates greater specificity and sensitivity as biomarkers for diagnosing ocular cGVHD compared to serum biomarkers. Among the identified tear cytokines, IL-8, IL-10, IFN-γ, CXCL9, CCL17, and CCL19 can serve as diagnostic biomarkers for ocular cGVHD post-transplantation offering practical reference value for diagnosis. IL-10, IFN-γ and CXCL9 levels could evaluate the severity of ocGVHD. In addition, large-scale prospective studies are warranted to confirm our findings.

Added γ-oryzanol boosted anti-inflammatory effects of canola oil in adult subjects with type 2 diabetes: a randomized controlled clinical trial.

This study was conducted to examine the effects of daily intake of γ-oryzanol (ORZ)-fortified canola oil, as compared with plain canola and sunflower oils, on certain inflammatory and oxidative stress biomarkers in adult subjects with Type 2 Diabetes (T2D). We randomly allocated 92 adult subjects with T2D from both sexes to one of the following groups to receive: (a) ORZ-fortified canola oil (ORZO; n1 = 30); (b) unfortified canola oil (CANO; n2 = 32); or (c) sunflower oil (SUFO; n3 = 30) for 12weeks. Dietary and laboratory evaluations were performed initially and finally. Serum hs-CRP concentrations significantly decreased in ORZO group (from 3.1 ± 0.2 to 1.2 ± 0.2 mg/L), as compared with CANO (p = 0.003) and SUFO (p < 0.001) groups. Serum IL-6 significantly decreased just in ORZO (-22.8%, p = 0.042) and CANO groups (-19.8%, p = 0.038). However, the between-group differences were not significant. Serum IL-1β slightly decreased in ORZO (-28.1%, p = 0.11) and increased in SUFO (+ 20.6%, p = 0.079) but between-group difference was statistically significant (p = 0.017). Serum IFN-γ concentrations decreased significantly only in ORZO (from 3.3 ± 0.08 to 2.9 ± 0.21 IU/mL, p = 0.044). Salivary IgA concentrations increased significantly in all three intervention groups. Notwithstanding, only the difference between ORZO and CANO groups was statistically significant (p = 0.042). Similarly, circulating malondialdehyde concentrations significantly decreased in all three groups but with no between-group significant difference. Daily consumption of ORZ-fortified canola oil, compared with unfortified canola and sunflower oils, for 12 weeks resulted in boosting of certain anti-inflammatory effects of canola oil. These findings may have preventive implications for both clinicians and policy makers. This clinical trial was registered at clinicaltrials.gov (03.08.2022; NCT05271045).

Potential risk of tamoxifen: gut microbiota and inflammation in mice with breast cancer.

Tamoxifen is an effective anti-tumor medicine, but evidence has been provided on tamoxifen-related inflammation as well as its impact on gut microbiota. In this study, we aimed to investigate tamoxifen-induced gut microbiota and inflammation alteration. We established a BC xenograft mouse model using the MCF-7 cell line. 16S rRNA gene sequencing was used to investigate gut microbiota. qRT-PCR, western blotting, and cytometric bead array were used to investigate inflammation-related biomarkers. Various bioinformatic approaches were used to analyze the data. Significant differences in gut microbial composition, characteristic taxa, and microbiome phenotype prediction were observed between control, model, and tamoxifen-treated mice. Furthermore, protein expression of IL-6 and TLR5 was up-regulated in tamoxifen-treated mice, while the mRNA of Tlr5 and Il-6, as well as protein expression of IL-6 and TLR5 in the model group, were down-regulated in the colon. The concentration of IFN-γ, IL-6, and IL12P70 in serum was up-regulated in tamoxifen-treated mice. Moreover, correlation-based clustering analysis demonstrated that inflammation-negatively correlated taxa, including Lachnospiraceae-UCG-006 and Anaerotruncus, were enriched in the model group, while inflammation-positively correlated taxa, including Prevotellaceae_UCG_001 and Akkermansia, were enriched in the tamoxifen-treated group. Finally, colon histologic damage was observed in tamoxifen-treated mice. Tamoxifen treatment significantly altered gut microbiota and increased inflammation in the breast cancer xenograft mice model. This may be related to tamoxifen-induced intestinal epithelial barrier damage and TLR5 up-regulation.

An optimized IL-12-Fc expands its therapeutic window, achieving strong activity against mouse tumors at tolerable drug doses

Interleukin-12 (IL-12) has emerged as one of the most potent cytokines for tumor immunotherapy due to its ability to induce interferon γ (IFNγ) and polarize Th1 responses. Clinical use of IL-12 has been limited by a short half-life and narrow therapeutic index. We generated a monovalent, half-life-extended IL-12-Fc fusion protein, mDF6006, engineered to retain the high potency of native IL-12 while significantly expanding its therapeutic window. Invitro and invivo activity of mDF6006 was tested against murine tumors. To translate our findings, we developed a fully human version of IL-12-Fc, designated DF6002, which we characterized invitro on human cells and invivo in cynomolgus monkeys in preparation for clinical trials. The extended half-life of mDF6006 modified the pharmacodynamic profile of IL-12 to one that was better tolerated systemically while vastly amplifying its efficacy. Mechanistically, mDF6006 led to greater and more sustained IFNγ production than recombinant IL-12 without inducing high, toxic peak serum concentrations of IFNγ. We showed that mDF6006's expanded therapeutic window allowed for potent anti-tumor activity as single agent against large immune checkpoint blockade-resistant tumors. Furthermore, the favorable benefit-risk profile of mDF6006 enabled effective combination with PD-1 blockade. Fully human DF6002, similarly, demonstrated an extended half-life and a protracted IFNγ profile in non-human primates. An optimized IL-12-Fc fusion protein increased the therapeutic window of IL-12, enhancing anti-tumor activity without concomitantly increasing toxicity. This research was funded by Dragonfly Therapeutics.

Radio-adaptive Response Induced by Low-dose Ionizing Radiation in Innate Immunity for Radiotherapy.

Radio-adaptive response (RAR) is a mechanism by which low doses of ionizing radiation (IR) protect cells from subsequent high doses. This study aimed to compare the immuno-radiological effects of 0.25, 0.5, and 5 Gy to 0.25 or 0.5 Gy as priming and 5 Gy as challenging doses. Thirty-five rats were irradiated whole-body with 0.25 and 0.5 Gy followed by 5 Gy, and the same single IR doses with non-irradiated animals serving as controls. Serum interferon-gamma (INF-γ), interleukin-1beta (IL-1β), tumor necrosis factor-alpha (TNF-α), nitric oxide (NO), and malondialdehyde (MDA) levels were measured 4 d post both priming and challenge doses. A 0.25-Gy priming dose significantly (P < 0.05) reduced serum TNF-α, MDA, and NO levels compared to all single-irradiated groups. Surprisingly, there was no difference in IFN-γ serum levels between the RAR-induced and non-irradiated groups (P ≥ 0.05). Compared to the same low priming dose (0.25 and 0.5 Gy), the effect of the challenging dose (5 Gy) remains unchanged or decreases. Serum IFN-γ, MDA, and NO concentrations, on the other hand, were significantly (P < 0.05) lower in the 0.5 Gy pre-challenging dose, whereas IL1β had no effect (P ≥ 0.05) compared to 5 Gy alone. The post-RAR group had significantly (P < 0.05) lower oxidative stress indicators than the other irradiation groups. The findings suggested that priming with low IR could help mitigate the negative effects on the hematopoietic system. Finally, RAR has significantly impacted endogenous cytokines, oxidative stress biomarkers, and lipid peroxidation parameters. RAR can improve patients' radiological safety profiles by mitigating adverse radiotherapy effects.

Changes and correlations of T-cell coinhibitory molecule programmed death-1 and interferon-γ in pediatric immune thrombocytopenia.

Immune thrombocytopenia (ITP) is an acquired autoimmune disease characterized by abnormalities of T cells subsets. Programmed death-1 (PD-1) is a co-signaling inhibitory molecule in T cells that is involved in many autoimmune diseases. Here we aimed to measure changes in PD-1 expression and serum interferon-γ (IFN-γ) levels before and 1 month after treatment in pediatric patients with newly diagnosed ITP. We measured PD-1+ CD4+ T cells percentages using flow cytometry and the serum IFN-γ levels by enzyme-linked immunosorbent assay in 40 pediatric patients with ITP and 20 healthy controls. Compared with healthy controls, the PD-1+ CD4+ T cells percentages and serum IFN-γ levels were significantly higher in ITP patients before and 1 month after therapy. A correlation study revealed that PD-1+ CD4+ T cells percentage was negatively associated with platelet count and positively associated with IFN-γ level in patients with ITP. Furthermore, serum IFN-γ levels were significantly decreased in patients after treatment, but no significant change was detected in the percentage of PD-1+ CD4+ T cells before or 1 month after therapy. PD-1+ CD4+ T cells expression and IFN-γ levels were increased in patients with ITP. These preliminary data suggest a potential role of PD-1+ CD4+ T cells as mediators of ITP. We also found a correlation between PD-1+ CD4+ T cells and both platelet counts and IFN-γ levels. These findings suggest a potential role of PD-1+ CD4+ T cells and IFN-γ in the pathogenesis of ITP. Further studies investigating PD-1 expression in different T-cell subsets, serum IFN-γ concentrations, and antiplatelet antibodies levels over a longer duration after therapy initiation could delineate the precise role of PD-1 in ITP pathogenesis. Consequently, novel nontraditional therapeutic strategies for ITP patients may become available.

Effect of exogenous galectin-9, a natural TIM-3 ligand, on the severity of TNBS- and DSS-induced colitis in mice.

Inflammatory bowel disease (IBD) have a complex pathogenesis that is yet to be completely understood. However, a strong correlation between Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling and IBD has been observed. T-cell immunoglobulin and mucin domain-containing-3 (Tim-3) has been reported to regulate TLR4/NF-κB by interacting with Galectin-9 (Gal-9), and recombinant Gal-9 can activate Tim-3; however, its potential properties in IBD and the underlying mechanism remain unclear. This study aimed to determine how Gal-9 affects experimental colitis in mice. Dextran sodium sulfate (DSS) and 2,4,6-trinitrobenzene sulfonic acid (TNBS) were used to establish colitis in mice, and the severity of the illness was assessed based on body weight, colon length, and histology. Therefore, we explored the effects of Gal-9 treatment on colitis. Furthermore, we analyzed the effect of Gal-9 on the expression of Tim-3 and TLR4/NF-κB pathway in colonic tissues and the serum levels of interferon-gamma (IFN-γ), interleukin (IL)-1β, and IL-6. Tim-3 expression in the colon was notably decreased in mice with TNBS-induced colitis, whereas TLR4/NF-kB expression was significantly increased. Intraperitoneal injection of Gal-9 dramatically decreased the disease activity index and attenuated the level of intestinal mucosal inflammation in TNBS-induced colitis mice (p<0.05). Intraperitoneal administration of Gal-9 significantly increased Tim-3 expression in the colon and decreased the serum concentrations of IFN-γ, IL-1β, and IL-6. Additionally, Gal-9 treatment significantly downregulated the expression of TLR4 signaling pathway-related proteins. In contrast, Gal-9 did not reduce the severity of DSS-induced colitis. In summary, exogenous Gal-9 increased Tim-3 expression, inhibited the TLR4/NF-κB pathway, and alleviated TNBS-induced colitis in mice but not DSS-induced colitis in mice, revealing its potential therapeutic ramifications for IBD.

Serum Concentrations of Some Thelper1-Derived Cytokines in Generalized Erythema Multiforme

BACKGROUND: Erythema multiforme (EM) is an acute mucocutaneous syndrome characterized by typical and/or atypical target lesions on the skin. The etiology is still not clear, but EM may be related to infection or medication. Clinically, there are cases of EM with atypical target lesions with generalized distribution without, or with minimal, mucosal lesions. The causes remain unknown. However, T helper cells 1 (Th1) may play an important role in EM. AIMS: The aim of the study was to investigate serum concentrations of some Th1-derived cytokines in generalized EM or generalized EM -like eruptions. METHODS: This was a sectional and descriptive study conducted at the National Hospital of Dermatology and Venereology, in Hanoi, Vietnam, from April 2017 to August 2019. There were 33 EM patients, and 32 healthy controls (HCs) participated. Serum interleukin (IL)-2, interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α) levels were measured using the fluorescence covalent microbead immunosorbent assay (ProcartaPlex Immunoassay Panels kit, Thermo Fisher Scientific, USA). The Mann–Whitney U-test was used to compare the serum IL levels of the two groups. Differences were considered to be statistically significant at p &lt; 0.05. RESULTS: The mean age of the EM patients was 42.2 ± 17.5 years, ranging from 19 to 76 years old. Men accounted for 30.3%, women accounted for 69.7%. There were 22 patients with &lt;1 week of onset, accounting for 66.7%; 11 patients with 1 week and those with more than 1 week accounted for 33.3%. There were 60.6% of patients using drugs before the onset. Most patients had pruritus (97%), and all had diffusely distributed skin lesions. Only 15.2% of the patients had mucosal lesions. There are 30.3% of patients with fever. The serum IFN-γ concentration of the EM group was 5.35 ± 9.88 pg/mL, higher than that of the HCs group (0.35 ± 0.77 pg/mL), the difference was statistically significant with p = 0.01 (Mann–Whitney U). The concentrations of IL-2 and TNF-α of the HCs were 24.32 ± 27.94 pg/mL and 109.74 ± 126.73 pg/mL, respectively, higher than those of the EM group (3.37 ± 5.94 pg/mL and 5.86 ± 11.88 pg/mL, respectively). The difference was statistically significant with p &lt; 0.001. Age did not correlate with serum concentrations of cytokines in the EM group. CONCLUSION: In generalized EM, serum concentrations of IFN-γ are statistically significantly higher than those of HCs but serum concentrations of IL-2 and TNF-α were lower. There is no correlation between age and serum concentrations of cytokines in generalized erythema multiform.

Antitumor effect of CAR-T cells targeting transmembrane tumor necrosis factor alpha combined with PD-1 mAb on breast cancers

BackgroundOur previous study showed that transmembrane tumor necrosis factor alpha (tmTNF-α) is overexpressed in primary breast cancers including triple-negative breast cancers (TNBCs). Chimeric antigen receptor engineered-T (CAR-T) cells have been...

Tylvalosin Tartrate Improves the Health Status of Swine Herds during Immunization with Porcine Reproductive and Respiratory Syndrome Virus-Inactivated Vaccine

Porcine reproductive and respiratory syndrome (PRRS) is a devastating disease that affects pigs and is responsible for severe economic losses. The commercial PRRSV-inactivated vaccine (CH-1a strain) in China was recently selected to control PRRS in large populations of PRRS-positive sows and was found to effectively reduce the rate of stillbirth abortion based on clinical observations. However, stress from vaccine inoculation (e.g., fever, anorexia, abortions, and slow body weight gain) usually appears after immunization on many swine farms. In this study, we fed piglets a diet medicated with tylvalosin tartrate during PRRSV-inactivated vaccine immunization. We found that tylvalosin tartrate attenuated the increase in total white blood cells induced by immunization at day one post-immunization (DPI) and induced an increase in monocyte counts after seven DPI. There was also attenuation in the intensity of the inflammatory response induced by vaccination and elevation of serum IFN-γ concentrations at three and seven DPI after immunization. The administration of tylvalosin tartrate could also attenuate the reduction in the percentage of CD8+ T cells induced by PRRSV-inactivated vaccine immunization at seven DPI. These results demonstrated that in addition to tylvalosin tartrate being able to control respiratory and enteric bacterial infections in swine farms, it can also improve the stress status of swine herds during PRRSV-inactivated vaccine immunization.

Red Ginseng Extract and γ-Aminobutyric Acid Synergistically Enhance Immunity Against Cancer Cells and Antitumor Metastasis Activity in Mice.

The effects of combined administration of red ginseng (RG) extracts and gamma-aminobutyric acid (GABA) on immunostimulatory activity and tumor metastasis inhibition were investigated in mice. For the immunostimulatory activity, splenocyte proliferation, natural killer (NK) cell activity, including the production of granzyme B (GrB) and interferon gamma (IFN-γ), and serum level of cytokine such as IFN-γ, interleukin (IL)-17, and IL-21 were assessed. Peyer's patch cells obtained from mice administered with RG+GABA were cultured, and the cytokine level in the culture supernatant and bone marrow (BM) cell proliferation activity were examined. The proliferative activity of splenocytes was significantly higher in the RG-GABA treatment group than in RG or GABA alone (P < .05). In the experimental tumor metastasis model, oral administration of RG+GABA showed a higher antitumor metastatic effect compared to that of RG or GABA alone. Oral administration of RG+GABA significantly augmented NK cell-mediated cytotoxicity against YAC-1 tumor cells. In addition, the production of GrB and IFN-γ was stimulated in the culture supernatant of NK cells and YAC-1 cells. Serum concentrations of IFN-γ, IL-17, and IL-21 in mice with RG+GABA were significantly higher compared to the corresponding blood levels in mice administered with RG or GABA alone. The RG+GABA group showed significant BM cell proliferation and increased production of IL-6 and granulocyte-macrophage colony-stimulating factor compared to that in the monotherapy groups. Therefore, RG may have a synergistic effect with GABA for enhancing the host defense system such as BM proliferation and NK cell activity in a tumor metastasis model.

Evaluation of dendritic cell-targeting T7 phages as a vehicle to deliver avian influenza virus H5 DNA vaccine in SPF chickens.

There is a growing demand for effective technologies for the delivery of antigen to antigen-presenting cells (APCs) and their immune-activation for the success of DNA vaccines. Therefore, dendritic cell (DC)-targeting T7 phages were used as a vehicle to deliver DNA vaccine. In this study, a eukaryotic expression plasmid pEGFP-C1-HA2-AS containing the HA2 gene derived from the avian H5N1 virus and an anchor sequence (AS) gene required for the T7 phage packaging process was developed. To verify the feasibility of phage delivery, the plasmid encapsulated in DC-targeting phage capsid through the recognition of AS was evaluated both in vitro and in vivo. The pEGFP-C1-HA2-AS plasmid could evade digestion by DNase I by becoming encapsulated into the phage particles and efficiently expressed the HA2 antigen in DCs with the benefit of DC-targeting phages. For chickens immunized with the DC-targeting phage 74 delivered DNA vaccine, the levels of IgY and IgA antibodies, the concentration of IFN-γ and IL-12 cytokines in serum, the proliferation of lymphocytes, and the percentage of CD4+/CD8+ T lymphocytes isolated from peripheral blood were significantly higher than chickens which were immunized with DNA vaccine that was delivered by non-DC-targeting phage or placebo (p<0.05). Phage 74 delivered one-fiftieth the amount of pEGFP-C1-HA2-AS plasmid compared to Lipofectin, however, a comparable humoral and cellular immune response was achieved. Although, the HA2 DNA vaccine delivered by the DC-targeting phage induced enhanced immune responses, the protection rate of virus challenge was not evaluated. This study provides a strategy for development of a novel avian influenza DNA vaccine and demonstrates the potential of DC-targeting phage as a DNA vaccine delivery vehicle.

Disseminated nontuberculous mycobacterial infection with cryptic immunodeficiency mimicking malignancy: a case report

BackgroundNontuberculous mycobacteria (NTM) usually invades vulnerable hosts. Disseminated NTM (dNTM) infection can affect nearly all organs and be easily misdiagnosed as metastatic carcinoma or other systemic diseases, especially in seemingly immunocompetent hosts. Identification of underlying immunodeficiency is critical for the diagnosis and treatment of dNTM. Adult-onset immunodeficiency (AOID) with anti-IFN-γ autoantibodies has recently been recognized as a crucial but frequently neglected risk factor for dNTM infection. Frequent relapses of infection are common in AOID patients despite appropriate anti-infective treatment and B-cell-depleting therapy has shown some promising results. Herein, we report a case of dNTM infection mimicking malignancy in an AOID patient who was successfully treated with rituximab.Case presentationA middle-aged male presented with fever, productive cough, multifocal skin abscesses and multiple osteolytic lesions with pathological fractures. Chest CT revealed consolidation of the lingula while bronchoscopy showed a mass completely blocking the airway opening of the inferior lingual segment. Metagenomic next-generation sequencing and mycobacterial culture of skin pus and bronchoalveolar lavage fluid reported Mycobacterium Colombiense, confirming the diagnosis of dNTM infection. However, anti-NTM antibiotics alone failed to prevent disease relapse and progression. Further evaluation indicated undetectable serum IFN-γ concentration and high-titer autoantibodies against IFN-γ, suggesting that AOID was the underlying reason for dNTM. Rituximab was added to treatment and successfully controlled the infection without relapse at one-year follow-up.ConclusionWe reported a rare case of disseminated Mycobacterium Colombiense infection manifested with pulmonary mass, pathological fracture and dermapostasis in a host with AOID. Our case demonstrated that AOID should be screened when patients get the episode of disseminated NTM infection particularly when other risk factors are excluded. Besides prolonged anti-NTM therapy, AOID-associated NTM infection should be treated with B-cell-depleting therapy to prevent recurrence.

Effect of Dietary Pomelo Peel Powder on Growth Performance, Diarrhea, Immune Function, Antioxidant Function, Ileum Morphology, and Colonic Microflora of Weaned Piglets.

This trial evaluated how dietary-accommodated pomelo peel powder (PPP) affected average daily feed intake (ADFI) and average daily gain (ADG), diarrhea, antioxidation, and colonic microbial in weaned piglets. Thirty piglets weaned at 28 d were divided into three groups: a basal diet (CON); a CON containing 75 mg/kg chlortetracycline (CTC); and a CON containing 8 g/kg (PPP). This trial had a period of 28 days. Piglets supplemented with PPP had higher ADFI and ADG than piglets in CTC and CON (p &lt; 0.05). The diarrhea rate in PPP and CTC was lower than in CON in the 3rd and 4th weeks (p &lt; 0.05). Serum superoxide dismutase and glutathione peroxidase enzyme activities, and total antioxidant capacity in PPP were higher than those in CON (p &lt; 0.05). Serum interleukin (IL)-4, insulin-like growth factor-I, immunoglobulin (Ig)A, and IgG concentrations in the PPP and CTC groups were higher than those in the CON group (p &lt; 0.05). Serum IL-1β, IL-8, IL-17, and interferon (IFN)-γ concentrations and the cecal pH in PPP were lower than those in CON (p &lt; 0.05). Serum IL-1β, IFN-γ, and IgA concentrations of piglets in PPP were lower than in CTC (p &lt; 0.05). The villus height and villus height/crypt depth of the ileum of piglets in PPP and CTC were higher than those in CON (p &lt; 0.05), but there was no difference between PPP and CTC (p &gt; 0.05). The Firmicutes and Cyanobacteria relative abundances in PPP and CTC (p &lt; 0.05) were lower than those in CON, whereas the Bacteroidetes relative abundances in PPP and CTC were higher than those in CON. The Prevotellaceae relative abundance in CTC was higher than in CON (p &lt; 0.05), whereas the Lactobacillaceae relative abundance in CTC was lower than in CON (p &lt; 0.05). The Ruminococcaceae relative abundance in PPP was higher than in CON (p &lt; 0.05), whereas the Veillonellaceae relative abundance in PPP was lower than in CON (p &lt; 0.05). PPP can improve ADFI and ADG, relieve diarrhea, and enhance the colonic microflora of weaned piglets. Therefore, PPP is expected to replace CTC as a feed additive to alleviate weaning stress and ensure normal growth and development of piglets.