Interleukin-7 Levels Research Articles

Purinergic signaling displays a pro-inflammatory profile in lymphoid immune organs of Oreochromis niloticus experimentally infected by Providencia rettgeri: The role of pathophysiology

The pathophysiological mechanisms associated with immune responses to the opportunistic bacterial pathogen Providencia rettgeri in fish species are unknown. The aim of this study was to evaluate whether purinergic signaling generates anti-inflammatory or pro-inflammatory profiles in lymphoid immune organs of the Nile tilapia (Oreochromis niloticus) experimentally infected by P. rettgeri. Adenosine triphosphate (ATP) and adenosine diphosphate (ADP) hydrolysis activities in the spleen and triphosphate diphosphohydrolase (NTPDase) in the head kidney decreased in experimentally P. rettgeri-infected Nile tilapia on days seven and fourteen post-infection (PI) compared to the control group. At these same time points, splenic and head kidney adenosine deaminase (ADA) activity, and levels of ATP, interleukin-15 (IL-15) and metabolites of nitric oxide (NOx) increased in infected animals compared to their respective control groups; this was also observed for serum ATP levels. No significant difference was observed between groups regarding 5′-nucleotidase activity. These results suggest that purinergic signaling in lymphoid immune organs of Nile tilapia exerts a pro-inflammatory profile in response to P. rettgeri infection. This response contributes to the inhibition of immune and inflammatory responses by reduction of ATP hydrolysis and augmentation of ATP in the extracellular environment as well as augmentation in adenosine deamination and its possible reduction in the extracellular environment, leading to a self-sustained pro-inflammatory cycle, corroborated by excessive content of ATP (extracellular milieu), IL-15 and NOx levels. Purinergic signaling may thereby contribute to the pathophysiology of P. rettgeri infection.

Effect of a novel long-acting interleukin-7 agonist, NT-I7, on survival in mouse models of glioma.

e13516 Background: Glioblastoma is one of the most devastating cancers, with a 5-year overall survival < 10%. Patients are routinely treated with radiation therapy (RT) and temozolomide (TMZ). These treatments can cause prolonged severe lymphopenia which is associated with shorter survival. Interleukin-7 (IL-7) is a cytokine that preferentially supports growth and survival of CD4+ and CD8+ lymphocytes. IL-7 levels were inappropriately low in glioblastoma patients treated with chemoradiation who developed severe treatment-related lymphopenia (TRL). NT-I7 (rhIL-7-hyFc, from NeoImmuneTech, Inc.) is a long-acting cytokine consisting of recombinant human IL-7 fused to a hybrid Fc (hyFc) region of IgD and IgG4. Similarly to murine IL-7, human IL-7 also induces proliferation of murine cell lines. Consequently, NT-I7 can be studied using comparable dosing in both mice and humans. We hypothesized that administration of NT-I7 could mitigate TRL and improve survival. Methods: We developed a murine glioma model with chemoradiation induced lymphopenia. The C57BL/6 mice were injected intracranially with mouse glioma cells (GL261) expressing luciferase. Tumor-bearing mice were treated with clinically-relevant RT (2 Gy for 5 consecutive days) and concomitant TMZ (33mg/kg daily during RT) to induce lymphopenia. NT-I7 was given subcutaneously at 10 mg/kg one day after completion of RT/TMZ. Peripheral blood samples were collected on days 1, 3, 7, 14- and 28-days post-RT/TMZ. Lymphocyte counts including CD3, CD4, CD8, and CD19 were analyzed by flow cytometry. Tumor growth was monitored by bioluminescence imaging and mouse survival was monitored daily. Results: We found that 1) NT-I7 significantly improved lymphocyte count recovery post RT/TMZ; 2) mice receiving NT-I7 lived significantly longer than controls. Presently, we are elucidating the mechanisms of survival benefit found by NT-I7 administration. Conclusions: Overall, our data suggest that NT-I7 may be a feasible solution for immune reconstitution and may synergize anti-tumor effect with standard chemoradiation in glioma. Further studies are ongoing to confirm these findings in a different glioma model and to evaluate whether NT-I7 can alter tumor micro-environment.

Identification of Low-Abundance Urinary Biomarkers in Lupus Nephritis Using Electrochemiluminescence Immunoassays.

To investigate the utility of a sensitive platform using electrochemiluminescence (ECL) for the identification of low-abundance urinary protein biomarkers in lupus nephritis (LN). Forty-eight urine samples were obtained from subjects in 2 independent cohorts, each consisting of 3 groups (matched for age, sex, and race) of 8 patients with active LN (renal Systemic Lupus Erythematosus Disease Activity Index [SLEDAI] >0), 8 patients with inactive SLE (renal SLEDAI 0), and 8 healthy controls. Samples were tested using a preexisting 40-plex ECL panel. A custom 5-plex ECL panel was then developed for further validation studies and used to test 140 urine samples (from 44 patients with active LN, 41 patients with inactive SLE, 28 healthy controls, and 27 patients with other kidney diseases). Levels of 17 urinary proteins were elevated (P < 0.05 by 2-tailed Mann-Whitney U test) in samples from patients with active LN compared to samples from patients with inactive SLE and healthy controls in cohort 1, while 9 were similarly elevated in cohort 2. Of these, interleukin-7 (IL-7), IL-12p40, IL-15, interferon-γ-inducible protein 10 (IP-10), and thymus and activation-regulated chemokine (TARC) were chosen for further validation. These 5 proteins were undetectable by enzyme-linked immunosorbent assay (ELISA). Hence, a custom 5-plex ECL panel was developed and used to validate the results from the initial 40-plex screening panel. Urinary IL-7, IL-12p40, IL-15, IP-10, and TARC levels were again significantly elevated in patients with active LN compared to those with inactive SLE and healthy controls, and correlated well with the renal SLEDAI and physician's global assessment of disease activity (R > 0.67, P < 0.05). All 5 urinary proteins were more frequently elevated in LN compared to controls with other chronic kidney diseases, although overall group differences attained significance only for urinary IL-7 and IL-15. Urinary levels of IL-7, IL-12p40, IL-15, IP-10, and TARC are potentially useful diagnostic tools in LN. The use of ECL assays may allow detection of urinary biomarkers that are below ELISA detection limits.

Serum interleukin 15 in anorexia nervosa: Comparison to normal weight and obese girls

Background: Interleukin 15 (IL-15) plays a key role in the muscle-fat interaction, reducing adipose tissue mass without changes in the lean body mass and reduction of food intake. Here we assess serum IL-15 levels in girls with anorexia nervosa (AN) relative to obese and normal weight female adolescents.Methods: Serum IL-15 concentrations were evaluated using a commercially available ELISA kit in 32 Polish girls with restrictive AN, 29 girls with obesity (O), and 21 healthy controls (C). Anthropometric measurements (weight, height, BMI) and laboratory assays (serum fasting glucose, insulin, HOMA-IR, total cholesterol, HDL, LDL, triglycerides, and C-reactive protein (CRP)) were performed.Results: Mean serum IL-15 in the AN group was significantly higher than in C, but lower than in O. In all examined girls, significant positive correlations between IL-15 and body weight, BMI, insulin, HOMA, LDL, triglycerides and CRP were noted. We also observed an inverse relationship between IL-15 and HDL.Conclusions: Our study demonstrated that serum IL-15 concentrations in adolescent girls with AN and obesity are significantly elevated in comparison to normal weight controls. However, the role of IL-15 in the pathogenesis of AN and obesity remains still unclear.

Breast milk interleukin-7 and thymic gland development in infancy.

Interleukin-7 (IL-7) is known to be important for lymphocyte development. We sought to investigate the maternal breast milk IL-7 expression to explore its impact on thymus development in infants. We conducted a prospective study on three groups of healthy infants classified into exclusively breast-fed (n = 19), formula-fed (n = 17) and mixed-fed (n = 19) infants. They were investigated at 2, 4 and 6 months of age for thymic indices by ultrasonography, T lymphocyte subsets enumeration by flowcytometry and breast milk IL-7 levels. Thymic indices were higher at the age of 2 and 6 months in the exclusively breast-fed infants (mean ± SD 22.4 ± 2.1, 26.2 ± 2.7 mm3, respectively) and mixed-fed infants (mean ± SD 22 ± 3.2, 25 ± 3.2, respectively) as compared to formula-fed infants (mean ± SD 17.9 ± 3.7, 21.6 ± 3.9 respectively); p < 0.001. In the exclusively breast-fed infants, IL-7 levels correlated positively to thymic indices and CD3+ T cell numbers at 2months of age. Positive correlations were elicited in the mixed-fed group at 2, 4 and 6months of age for thymic indices and at 6months for CD3+ cells. Breast milk and/or its IL-7 content have a significant positive impact on thymic development. Our conclusions are limited by the sample size and short duration of follow-up. What is known is that breast milk has a trophic role in thymic development and contains IL-7. What is new is that there is positive correlation between breast milk IL-7 concentration and thymic development and lymphocyte output; variation of IL-7 levels with type of feeding (exclusive breast feeding/mixed breast and formula feeding) and with time postnatally.

Effects of indoor coal fine particulate matter on the expression levels of inflammatory factors in ovalbumin-induced mice.

Objective: Cooking and heating with coal is the main source of household air pollution in acid rain-plagued areas of China and is a leading contributor to disease burden. In this study, we investigated the adverse effects of exposure to indoor fine particulate matter emission from coal combustion on the expression levels of inflammatory factors in ovalbumin (OVA)-induced mice. Methods: Forty BALB/c male mice were randomly divided into four groups (control group, PM2.5 group, OVA group, and OVA + PM2.5 group; n = 10) and treated with ovalbumin (OVA) or PM2.5, alone or together. Interleukin-4 (IL-4), interleukin-7 (IL-7), interleukin-8 (IL-8), interleukin-17 (IL-17), transforming growth factor β1 (TGF-β1), and interferon γ (IFN-γ) protein expression levels were measured in bronchoalveolar lavage fluid (BALF). Additionally, serum immunoglobulin (Ig) IgE and IgG1 levels were measured. The mRNA expression levels of IL-7 and IFN-γ in pulmonary tissue were also analyzed. Bronchoalveolar lavage (BAL), inflammatory cell counts, and histopathological examinations were also performed. Results: Exposure to PM2.5 + OVA induced abnormal pathological changes and inflammatory responses in lungs compared to the control. The levels of IL-4, IL-7, IL-8 and IL-17 in BALF from the OVA + PM2.5 group were higher than those in BALF from the control group, OVA group, and PM2.5 group (P < 0.05). PM2.5 plus OVA significantly raised the serum IgE and IgG1 levels compared with the control group. An increasing IL-7 mRNA trend was found among the treatment groups (P < 0.05). The expression level of IFN-γ mRNA was significantly higher in the control group than in the other 3 groups (P < 0.05). Conclusion: Indoor coal PM2.5 was sufficient by itself to cause inflammatory cellular infiltration of pulmonary tissue, leading to organelle injury and physiological structure change. Additionally, it promoted the occurrence and development of asthma by influencing the expression levels of IL-7 and various relevant inflammatory factors (such as IL-4 and IL-8) and changing the equilibrium between Treg and Th17 cells.

Serum Interleukin-15 is a Marker of Alopecia Areata Severity.

Background:Interleukin-15 (IL-15) is a cytokine that is involved in many inflammatory and autoimmune diseases. Although alopecia areata (AA) is an autoimmune disease, serum levels of IL-15 have not been studied well in AA patients.Aim of the Work:We aims at evaluating the serum levels of IL-15 in active AA.Subject and Methods:This case-control study included 40 AA patients and 40 apparently healthy matched controls. Written informed consents were obtained from all the participants. The scalp was examined to assess sites, number, and size of alopecia patches, and the severity of AA lesions was assessed using the Severity of Alopecia Tool score (SALT score) which determine the percentage of hair loss in the scalp. The body was carefully examined to detect any alopecia patches in any hairy area. Nail examination was carried out to detect any nail involvement. Serum IL-15 levels were measured using an ELISA kits.Results:Serum levels of IL-15 in patients were significantly higher than those in the control group (P < 0.001). Serum levels in alopecia totalis were significantly higher than those with one or two patches, and serum levels in patients with both scalp and body involvement were significantly elevated than the levels of patients with either scalp or body involvement. There was a statistically significant positive correlation between SALT score and serum levels of IL-15 (P < 0.001).Conclusion:Serum IL-15 may be a marker of AA severity.

Comprehensive Cytokine Profiling of Patients with Advanced Systemic Mastocytosis Treated with Midostaurin

Background: Advanced systemic mastocytosis (AdvSM) comprises a group of hematologic neoplasms primarily driven by the oncogenic KIT D816V mutation. Morbidity and mortality relate to organ damage caused by neoplastic mast cell infiltration and mast cell mediator symptoms. Midostaurin, an oral multikinase/KIT inhibitor, produced reversion of organ damage in 60-70% of AdvSM patients (Gotlib et al, NEJM, 2016; DeAngelo et al, Leukemia, 2018), which was associated with decreases in bone marrow mast cell burden, serum tryptase levels, and splenomegaly in the majority of patients. Similar to myelofibrosis (MF) patients treated with JAK inhibitors, midostaurin improves disease symptoms and quality of life (Gotlib et al, NEJM, 2016). We conducted a cytokine profiling study to better understand the biologic effects of midostaurin in this patient population.Methods: Plasma cytokine levels were analyzed in 19 patients with AdvSM (2 aggressive SM, 10 SM with an associated hematologic neoplasm, and 7 with mast cell leukemia) treated with midostaurin 100 mg twice daily. Seventeen patients were treated on the phase II investigator-initiated trial (DeAngelo et al,Leukemia, 2018), and two were treated on a compassionate-use basis. Cytokine levels were compared to 10 patients with MF (primary MF [n=4]; post PV/ET MF [n=6]), treated with JAK inhibitors (ruxolitinib, fedratinib, or momelotinib) and 10 healthy patients whose age range matched the SM group. Plasma samples were obtained pretreatment, and after 4-8 weeks of therapy. Each patient sample was evaluated for 62 cytokines using a Luminex assay (eBioscience) performed at the Stanford Human Immune Monitoring Center. Sparse partial least squares discriminant analysis (SPLS-DA) was used to identify the most predictive cytokines from the expression data that help classify patient samples based on disease states, and SPLS regression was used to identify cytokines correlated with survival (Rohart et al, mixOmics. R package version 6.3.2). Overall survival was calculated from the time of initiation of midostaurin to time of death.Results: Plasma levels of several cytokines were higher at baseline in AdvSM and MF patients compared to healthy controls (Fig 1A-B). In patients with AdvSM and MF, pretreatment levels of leptin (false discovery rate (FDR) < 0.002), epidermal growth factor (EGF; FDR < 2e-5), and brain-derived neurotrophic factor (BDNF; FDR < 3.5e-7) were lower than healthy controls. Using SPLS-DA, we identified a distinct baseline cytokine expression profile that could classify patient samples as either AdvSM, MF, or healthy with an error rate of less than 0.10 (Fig 1C). The six most predictive cytokines were nerve growth factor, EGF, BDNF, interferon alpha, intercellular adhesion molecule-1 (ICAM1), and leukemia inhibitory factor. Corroborating prior data (Verstovsek et al, NEJM 2010), we found that several plasma cytokine levels significantly decreased in MF patients after 1-2 cycles of JAK inhibition (Fig 1B). Although we observed similar decreases in plasma cytokine levels for AdvSM patients on midostaurin (Fig 1A), the results were more variable and did not reach statistical significance. AdvSM patients that responded to midostaurin (major or partial response per Valent criteria) expressed a different baseline cytokine expression profile when compared to non-responders. SPLS-DA was able to distinguish these two classes of patients with an error rate of 0.35 (Fig 1D). SPLS regression identified baseline levels of interleukin-7 (IL7), ICAM1, interleukin 12 subunit p40 (IL12p40), EGF, and platelet-derived growth factor BB (PDGFBB) as potential predictors of survival for patients with AdvSM treated with midostaurin. High pretreatment levels of IL7 (109 months (m) vs. 33 m; p=0.01), EGF (92 m vs. 34 m; p=0.04), and PDGFBB (80 m vs. 37 m; p=0.09) and low pretreatment levels of ICAM1 (91 m vs. 19 m; p=0.02) and IL12p40 (91 m vs. 19 m; p=0.03) were associated with increased survival.Conclusions: Cytokine expression profiling can distinguish patients with AdvSM or MF from healthy controls. Compared to the use of JAK inhibitors in MF, midostaurin's activity in AdvSM appears less related to reversion of pro-inflammatory cytokines. Investigation of a larger cohort of patients is needed to determine whether such analyses of plasma cytokines will provide added value to new scoring prognostic systems of AdvSM that incorporate clinical and molecular data. [Display omitted] DisclosuresDeAngelo:Glycomimetics: Research Funding; Amgen: Consultancy; ARIAD: Consultancy, Research Funding; Takeda: Honoraria; BMS: Consultancy; Incyte: Consultancy, Honoraria; BMS: Consultancy; ARIAD: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria; Shire: Honoraria; Amgen: Consultancy; Pfizer Inc: Consultancy, Honoraria; Blueprint Medicines: Honoraria, Research Funding. George:Blueprint Medicines: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Gotlib:Deciphera: Consultancy, Honoraria, Research Funding; Kartos: Consultancy; Promedior: Research Funding; Gilead: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Blueprint Medicines: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

ZEB2 and LMO2 Drive Immature T-Cell Lymphoblastic Leukemia Via Distinct Oncogenic Mechanisms

ZEB2, a E-box binding homeobox transcription factor, is able to induce epithelial-to-mesenchymal transition in the context of solid tumors. As such, its expression is correlated with cancer cell invasion, dissemination and metastasis, but also with the acquisition of cancer stem cell properties and therapy resistance.Using conditional knockout mice, we previously have shown that ZEB2 is an essential hematopoietic transcription factors, indispensable for normal embryonic(1) and adult(2) hematopoiesis. In addition, using conditional overexpressing mice we have demonstrated that ZEB2 is a bona fide driver of an immature subtype of T-ALL with increased leukemia-initiating potential(3).Here, we investigated the effects of ZEB2 overexpression on normal T-cell differentiation. Already from young age, ZEB2-overexpressing mice have a smaller thymus, with increased percentages of early T-cell precursors. Detailed flow cytometric analysis indicate a T-cell differentiation delay at the beta-selection checkpoint, with accumulation of DN3 (CD4- CD8- CD44- CD25+) cells. Using in vitro differentiation assays on OP9-DL1 stromal cells, we demonstrate that the perturbed T-cell differentiation is independent of the thymic micro-environment. Lowering the dose of exogenous interleukin-7 levels in the culture media can partially rescue this phenotype, which suggests that ZEB2-overexpressing thymocytes are delayed in T-cell differentiation due to their inability to downregulate the interleukin-7 receptor (IL7R) levels.Both the perturbed T-cell differentiation, and the latency/penetrance of immature subtype of the T-ALL formed in ZEB2-overexpressing mice is similar to what has been described for LMO2-overexpressing mice. Based on this phenocopy, we hypothesized that ZEB2 and LMO2 induce immature T-ALL via converging oncogenic pathway and/or via regulating similar crucial genes for the T-cell differentiation program. However, in contrast to LMO2, ZEB2-overexpresssing pre-leukemic thymocytes do not display aberrant self-renewal potential as demonstrated by transplantation experiments in sublethal irradiated syngeneic hosts. In addition, by using multiple Cre-transgenic lines, allowing the expression of ZEB2 at different stages of T-cell differentiation, we demonstrate that the oncogenic potential of ZEB2 is independent of the perturbed T-cell differentiation observed during the early stage of the disease.Based on these results we conclude that ZEB2 and LMO2 both drive the development of an immature subtype of T-ALL, but via distinct oncogenic mechanisms.(1) Goossens S. et al., Blood 2011 May 26; 117(21):5620-30.(2) Li J. et al., Blood 2017 Jan 26; 129(4):460-472.(3) Goossens S. et al., Nat Commun. 2015 Jan 7;6:5794. DisclosuresNo relevant conflicts of interest to declare.

Inflammatory Biomarkers, Depressive Symptoms and Falls Among the elderly in Panama.

Background: Falls are common among elderly adults, and are predictors of hospitalization, institutionalization and mortality.Objective: The objective of the present study was to examine the relationship between blood-based markers of inflammation and fall events in a sample of elderly Hispanic adults.Method: Data were collected from 190 participants enrolled in the Panama Aging Research Initiative study who completed baseline clinical and cognitive assessments. A non-fasting blood sample was obtained. Self-reported falls were classified as no falls, single falls or recurrent (two or more) falls reported in the 12 months prior to baseline evaluations. Serum levels of C Reactive Protein (CRP), T-lymphocyte secreting protein (I-309), interleukin 10 (IL-10), interleukin 6 (IL-6) and interleukin 7 (IL-7) were measured. Global cognition was assessed with the Mini Mental State Examination and depressive symptoms were assessed with the Geriatric Depression Scale (GDS-30). Multinomial logistic regression was used to assess the link between inflammation and fall events.Results: Depressive symptoms, limitations in Instrumental Activities of Daily Living (IADL), IL-7 and I-309 were significantly related to fall events. Elevated levels of IL-7 increased the likelihood of single and recurrent falls, while increased levels of I-309 were associated only with recurrent falls. Greater IADL limitations and depressive symptoms were associated with an increased likelihood of recurrent falls.Conclusion: There is a lack of research investigating the relationship between inflammatory biomarkers and fall events. These results provide evidence of risk factors for falls in Hispanic older adults, and could serve to guide public health professionals to establish clinical guidelines to reduce fall risks.

Preinfusion polyfunctional anti-CD19 chimeric antigen receptor T cells are associated with clinical outcomes in NHL

AbstractAfter treatment with chimeric antigen receptor (CAR) T cells, interleukin-15 (IL-15) elevation and CAR T-cell expansion are associated with non-Hodgkin lymphoma (NHL) outcomes. However, the association of preinfusion CAR product T-cell functionality with clinical outcomes has not been reported. A single-cell analysis of the preinfusion CD19 CAR product from patients with NHL demonstrated that CAR products contain polyfunctional T-cell subsets capable of deploying multiple immune programs represented by cytokines and chemokines, including interferon-γ, IL-17A, IL-8, and macrophage inflammatory protein 1α. A prespecified T-cell polyfunctionality strength index (PSI) applied to preinfusion CAR product was significantly associated with clinical response, and PSI combined with CAR T-cell expansion or pretreatment serum IL-15 levels conferred additional significance. Within the total product cell population, associations with clinical outcomes were greater with polyfunctional CD4+ T cells compared with CD8+ cells. Grade ≥3 cytokine release syndrome was associated with polyfunctional T cells, and both grade ≥3 neurologic toxicity and antitumor efficacy were associated with polyfunctional IL-17A–producing T cells. The findings in this exploratory study show that a preinfusion CAR product T-cell subset with a definable polyfunctional profile has a major association with clinical outcomes of CAR T-cell therapy. This trial was registered at www.clinicaltrials.gov as #NCT00924326.

Specific alterations in the circulating levels of the SIRT1, TLR4, and IL7 proteins in patients with dementia

Sirtuins have gained considerable attention as epigenetic regulators for slowing aging and age-related disorders. The growing association between neurodegeneration and inflammation has led researchers to investigate interactions of sirtuins with inflammatory markers in neurodegenerative diseases. We analyzed SIRT1's association with chronic inflammation in dementia as an age-related neurodegenerative condition through Toll-like receptor 4 (TLR4) and interleukin-7 (IL7) for the first time. In the present study, we observed a significant increase in the level of SIRT1 in patients with all types of dementia. Interestingly, the level of TLR4 protein was significantly lower in only the patients with Alzheimer's disease (AD) compared to the healthy elderly subjects. There was no significant change in the level of IL7 between the diseased and healthy elderly subjects. A significant positive correlation between SIRT1 level and age in healthy elderly subjects was evident according to Pearson's correlation test. However, this correlation was not observed in the dementia patients. Furthermore, the positive correlation between the levels of IL7 and TLR4 in the healthy elderly subjects was absent in the dementia patients. However, there was no direct association between the examined single nucleotide polymorphisms (SNPs) and dementia at the molecular level. According to logistic regression analysis, dementia risk increases 1.16 times due to an increase in the SIRT1 level and 24.23 times due to a decrease in the TLR4 level. Interestingly, a high level in the total antioxidant status (TAS) increases the risk of dementia approximately 33.32 times. Therefore, the current study, for the first time, provides a much better molecular understanding of the interaction between decreasing TLR4 levels and increasing SIRT1 levels in dementia, especially in AD. Furthermore, it highlights the importance of epigenetics in several age-related diseases and suggests that developing novel therapies to prevent or slow down the progression of dementia may support healthy aging.

Effect of intradialytic isometric exercise with or without neuromuscular electrical stimulation to IL-15, TNF-α regulation, and functional capacity in chronic kidney disease patient

One of the etiology of limited functional capacity in chronic renal disease patient is muscle wasting. Increasing of Tumor Necrosis Factor Alpha (TNF-α) in chronic renal disease causes muscle wasting. Strengthening exercise is recommended by ACSM but it is hard to be done. Contraction of skeletal muscle will express interleukin-15 (IL-15) which is important for metabolism and skeletal muscle function. Isometric exercise and Neuromuscular electrical stimulation (NMES) are easy to be applied intradialytic and can fascilitate muscle contraction and has strengthening effect, but their effect in chronic kidney disease patient have not been largely reported yet. This study aimed to prove that intradialytic isometric exercise with or without NMES can modulate IL-15, TNF-α expression and improve functional capacity in chronic kidney disease patient. Twenty-five chronic kidney disease patient underwent hemodialysis was randomly divided into 3 groups, control group, isometric group, and isometric and NMES group, received treatment twice a week, for 6 weeks. The subjects were examined for five times sit to stand test (FTSTS), IL-15 and TNF-α test by immunoassay before and after intervention. There was increased of FTSTS in isometric group ( P = 0.007) and also combined isometric and NMES group ( P = 0.001). TNF-α in isometric group was increased ( P = 0.003) and also in combined isometric and NMES group ( P = 0.025). Compared to the control group, TNF-α was change significantly in isometric group (0.017) and also in combined isometric and NMES group (0.020). There was no significant difference in IL-15 levels pre-and post-experimental in all three groups ( P > 0.05). Intradialytic isometric exercise with or without NMES for 6 weeks can improve functional capacity and also regulates TNF-α.

Optimized administration of hetIL-15 expands lymphocytes and minimizes toxicity in rhesus macaques

The common γ-chain cytokine interleukin-15 (IL-15) plays a significant role in regulating innate and adaptive lymphocyte homeostasis and can stimulate anti-tumor activity of leukocytes. We have previously shown that the circulating IL-15 in the plasma is the heterodimeric form (hetIL-15), produced upon co-expression of IL-15 and IL-15 Receptor alpha (IL-15Rα) polypeptides in the same cell, heterodimerization of the two chains and secretion. We investigated the pharmacokinetic and pharmacodynamic profile and toxicity of purified human hetIL-15 cytokine upon injection in rhesus macaques. We compared the effects of repeated hetIL-15 administration during a two-week dosing cycle, using different subcutaneous dosing schemata, i.e. fixed doses of 0.5, 5 and 50 µg/kg or a doubling step-dose scheme ranging from 2 to 64 µg/kg. Following a fixed-dose regimen, dose-dependent peak plasma IL-15 levels decreased significantly between the first and last injection. The trough plasma IL-15 levels measured at 48 h after injections were significantly higher after the first dose, compared to subsequent doses. In contrast, following the step-dose regimen, the systemic exposure increased by more than 1 log between the first injection given at 2 µg/kg and the last injection given at 64 µg/kg, and the trough levels were comparable after each injection. Blood lymphocyte cell count, proliferation, and plasma IL-18 levels peaked at day 8 when hetIL-15 was provided at fixed doses, and at the end of the cycle following a step-dose regimen, suggesting that sustained expansion of target cells requires increasing doses of cytokine. Macaques treated with a 50 µg/kg dose showed moderate and transient toxicity, including fever, signs of capillary leak syndrome and renal dysfunction. In contrast, these effects were mild or absent using the step-dose regimen. The results provide a new method of optimal administration of this homeostatic cytokine and may have applications for the delivery of other cytokines.

Serum interleukin 15 levels in patients with seropositive myasthenia gravis do not correlate with disease severity

AimTo assess interleukin 15 (IL-15) serum levels in patients with seropositive myasthenia gravis (MG); searching for potential relationship between IL-15 levels and clinical features such as gender, age at onset, clinical presentation or treatment received. BackgroundIL-15 plays pivotal role in T-cell dependent autoimmunity. Increased IL-15 serum levels have been reported in several autoimmune diseases including MG patients from Japan. Patients and methodsSera of 42 seropositive MG patients (66.7% women), mean age 50.6±23.7 years) have been tested by ELISA for IL-15 levels. ResultsThere were no statistically significant differences between IL-15 serum levels in MG patients in comparison with controls as well as between subgroups of MG patients (early vs. late onset and thymoma MG). Mean/median IL-15 serum levels were similar in MG patients treated with corticosteroids (CS) and CS naïve. Outliers (very high values) were seen only in untreated generalized MG patients. ConclusionsSerum interleukin 15 levels in patients with seropositive myasthenia gravis do not correlate with disease severity.

Increased soluble IL-7 receptor concentrations associate with improved IL-7 therapy outcomes in SIV-infected ART-treated Rhesus macaques.

The use of interleukin-7 (IL-7) as an immunorestorative therapeutic has proven effective in HIV infection, cancer and bone marrow transplantation. Mediating its activity through membrane-bound IL-7 receptor α (mCD127), IL-7 therapy increases T-cell numbers and survival. A soluble form, sCD127, is found in plasma, and we have previously identified increased plasma sCD127 concentrations in HIV infection. Furthermore, patients with high sCD127 exhibited the best viral control, implicating a role for IL-7 or sCD127 directly in improved virologic/immunologic outcomes. The role of the cytokine IL-7 in elevating sCD127 levels was addressed here through assessment of retrospective samples obtained from SIV-infected antiretroviral (ART)-treated Rhesus macaques. IL-7 was administered in clustered weekly doses, allowing for an assessment prior, during and following IL-7 administration. The levels of sCD127 remained relatively unchanged during both early SIV infection and following initiation of ART. However, treatment with IL-7 increased sCD127 concentrations in most animals, transiently or persistently, paralleling increased T-cell numbers, correlating significantly with CD8+ T-cell levels. In addition, proliferating CD4+ or CD8+ T-cells (measured by Ki67) increased in association with elevated sCD127 concentrations. Finally, a high concentration of sCD127 in IL7-treated animals was associated with increased retention of T-cells (measured by BrDU). In addition, a lack, or loss of viral control was associated with more pronounced and frequent elevations in plasma sCD127 concentrations with IL-7 therapy. In summary, plasma sCD127 levels in SIV-infected ART-treated macaques was associated with therapeutic IL-7 administration, with higher sCD127 levels in macaques demonstrating the best T-cell responses. This study furthers our knowledge regarding the interrelationship between increased IL-7 levels and elevated sCD127 levels that may have implications for future IL-7 immunotherapeutic approaches in HIV-infected patients.

The relationship between plasma interleukin-15 levels and sarcopenia in outpatient older people.

Sarcopenia is a geriatric syndrome in which there is a decrease in muscle mass, muscle strength, and muscle function. Interleukin-15 (IL-15), a myokine released by skeletal muscle, has effects on both muscle and adipose tissue. We evaluated the relationship between plasma IL-15 level and sarcopenia. We evaluated a total of 160 outpatient older people, and 80 of whom had sarcopenia. Sarcopenia was defined according to the European Working Group on Sarcopenia in Older People criteria. Plasma IL-15 was measured by enzyme-linked immunosorbent assay. Activities of daily living, nutritional and exercise status, co-morbidities, body mass index, waist circumference, sensitive C-reactive protein, IL-6, and vitamin D levels were also evaluated. IL-15 levels were significantly higher in control subjects [5.1 (2.75-18.69)] compared to sarcopenic participants [3.91 (2.07-15.56)] (p < 0.001). Plasma IL-15 levels were independently and inversely associated with sarcopenia in multivariate regression analysis [OR: 0.74 (CI 95% 0.6-0.91) p = 0.005]. Age [OR: 1.13 (CI 95% 1.01-1.27) p = 0.03] and BMI [OR: 0.68 (CI 95% 0.51-0.92)] were also associated with sarcopenia in multivariate regression analysis. A low level of plasma IL-15 is associated with sarcopenia in outpatient older people. Further longitudinal and prospective studies are needed to evaluate changes in IL-15 over time together with muscle mass and strength or therapeutic potential of IL-15.

The level changes and clinical value of serum nerve growth factor and interleukin-15 in children with mycoplasma pneumoniae pneumonia

Objective To investigate the level changes and clinical value of serum nerve growth factor(NGF)and interleukin-15(IL-15)in children with mycoplasma pneumoniae pneumonia. Methods A retrospective study was performed on 90 patients with mycoplasma pneumoniae pneumonia(MPP)who were admitted from July 2014 to April 2015.At the same time, another 90 medical healthy children were selected as the control group in the same period.The serum NGF, IL-15 level changes.The serum NGF and IL-15 level changes in different onset age children with MPP and healthy children, and in critically ill children and children with mild acute phase were compared. Results Acute onset of nerve growth factor in serum and recovery period, the NGF and IL-15 were higher than those in the control group, and the difference was statistically significant(P<0.05); nerve growth factor in serum of children with acute exacerbation, NGF and IL-15 level were significantly higher than those of children in the recovery period, and the difference was statistically significant(P<0.05); in group of children with severe acute exacerbation, serum NGF and IL-15 level were significantly higher than those in children with mild group, and the difference was statistically significant(P<0.05); in group of children with severe recovery of nerve growth factor, the serum NGF, IL-15 levels were significantly higher than those in children with mild group, and the difference was statistically significant(P<0.05). Conclusion Serum NGF and IL-15 are checking sensitive index in MPP children, which can be used to evaluate the disease severity in MPP children, it is worth clinical promotion. Key words: Pneumonia; Mycoplasma pneumonia; Interleukin-15; Nerve growth factor

Lamotrigine decreases MRP8 and IL-7 in rat models of intractable epilepsy secondary to focal cortical dysplasia.

The aim of the present study was to examine the effect of lamotrigine and the expression of myeloid-related protein 8 (MRP8) and interleukin-7 (IL-7) in the treatment of focal cortical dysplasia with secondary intractable epilepsy. In this study, rats with focal cortical dysplasia with secondary intractable epilepsy (constructed by our laboratory) were selected and used for experimentation, 21-day Sprague-Dawley rats were randomly divided into the control group (38 rats), the observation group I (39 rats), and the observation group II (38 rats). Rats in the observation group I received daily intraperitoneal injection of 0.02 mg/kg lamotrigine, and those in the observation group II and the control group received daily intraperitoneal injection of 0.02 mg/kg normal saline. Expression quantities of MRP8 and IL-7 in the hippocampus sample tissues of mice in the control group, observation group I, and observation group II were measured via fluorescence quantitative polymerase chain reaction assay, western blot analysis, enzyme-linked immunosorbent assay, and immunohistochemistry 48 h later. MRP8 and IL-7 gene mRNA levels of the control group, the observation group I and the observation group II had no significant differences (P>0.05). The expression quantity on the protein level of MRP8 and IL-7 showed no significant differences (P>0.05) between the observation group I (7.91±1.3, 3.86±0.38) and the control group (7.52±1.03, 3.62±0.29). The expression quantity of MRP8 and IL-7 showed significant differences (P<0.05) between observation group II (27.47±1.13, 19.45±0.48) and observation group I (7.91±1.3, 3.86±0.38). It was found that MRP8 and IL-7 were focused on the nerve cell membrane of hippocampus of rats in the observation group by immunohistochemistry experiments. In conclusion, the results from the present study show that lamotrigine can be used to treat rats with focal cortical dysplasia with secondary intractable epilepsy by reducing the expression levels of MRP8 and IL-7 in the body, providing a new therapeutic target to the follow-up treatment of focal cortical dysplasia with secondary intractable disease.

High salivary soluble L-selectin and interleukin-7 levels in Asian Indian patients with primary Sjögren’s syndrome

In present study, we aimed to study salivary soluble L-selectin (sL-selectin), interleukin-7(IjL-7), and lymphotoxin-α levels in primary Sjögren's syndrome (pSS) and their clinical as well as serological correlations. pSS patients fulfilling either the American European Consensus Group (AECG) and/or the American college of Rheumatology (ACR) criteria were recruited. Age- and sex-matched hospital staff were recruited as healthy controls. Unstimulated saliva was collected by the spitting method; sL-selectin, IL-7, and lymphotoxin-α were measured in the saliva using commercial ELISA kits. Forty-three patients with pSS and 31 healthy controls were included in the study. Increased levels of sL-selectin and IL-7 were found in the saliva of patients as compared to controls. Lymphotoxin-α was undetectable in the saliva of pSS patients and controls. Salivary sL-selectin positively correlated with rheumatoid factor (r=0.47; p<0.003). No other variable including ESSDAI was significantly associated with salivary sL-selectin and IL-7 levels. Indian patients with primary Sjögren's syndrome have higher salivary sL-selectin and IL-7 levels than healthy controls.