Science.gov

Sample records for localized th1 th2

  1. Trpm4 differentially regulates Th1 and Th2 function by altering calcium signaling and NFAT localization

    PubMed Central

    Weber, K. Scott; Hildner, Kai; Murphy, Kenneth M.; Allen, Paul M.

    2010-01-01

    T helper cell subsets have unique calcium (Ca2+) signals when activated with identical stimuli. The regulation of these Ca2+ signals and their correlation to the biological function of each T cell subset remains unclear. Trpm4 is a Ca2+-activated cation channel that we found is expressed at higher levels in Th2 cells compared to Th1 cells. Inhibition of Trpm4 expression increased Ca2+ influx and oscillatory levels in Th2 cells and decreased influx and oscillations in Th1 cells. This inhibition of Trpm4 expression also significantly altered T cell cytokine production and motility. Our experiments revealed that decreasing Trpm4 levels divergently regulates nuclear localization of NFATc1. Consistent with this, gene profiling did not show Trpm4 dependent transcriptional regulation and T-bet and GATA-3 levels remain identical. Thus, Trpm4 is expressed at different levels on T helper cells and plays a distinctive role in T cell function by differentially regulating Ca2+ signaling and NFATc1 localization. PMID:20656926

  2. Differential effects of myelin basic protein-activated Th1 and Th2 cells on the local immune microenvironment of injured spinal cord.

    PubMed

    Hu, Jian-Guo; Shi, Ling-Ling; Chen, Yue-Juan; Xie, Xiu-Mei; Zhang, Nan; Zhu, An-You; Jiang, Zheng-Song; Feng, Yi-Fan; Zhang, Chen; Xi, Jin; Lü, He-Zuo

    2016-03-01

    Myelin basic protein (MBP) activated T cells (MBP-T) play an important role in the damage and repair process of the central nervous system (CNS). However, whether these cells play a beneficial or detrimental role is still a matter of debate. Although some studies showed that MBP-T cells are mainly helper T (Th) cells, their subtypes are still not very clear. One possible explanation for MBP-T immunization leading to conflicting results may be the different subtypes of T cells are responsible for distinct effects. In this study, the Th1 and Th2 type MBP-T cells (MBP-Th1 and -Th2) were polarized in vitro, and their effects on the local immune microenvironment and tissue repair of spinal cord injury (SCI) after adoptive immunization were investigated. In MBP-Th1 cell transferred rats, the high levels of pro-inflammatory cells (Th1 cells and M1 macrophages) and cytokines (IFN-γ, TNF-α, -β, IL-1β) were detected in the injured spinal cord; however, the anti-inflammatory cells (Th2 cells, regulatory T cells, and M2 macrophages) and cytokines (IL-4, -10, and -13) were found in MBP-Th2 cell transferred animals. MBP-Th2 cell transfer resulted in decreased lesion volume, increased myelination of axons, and preservation of neurons. This was accompanied by significant locomotor improvement. These results indicate that MBP-Th2 adoptive transfer has beneficial effects on the injured spinal cord, in which the increased number of Th2 cells may alter the local microenvironment from one primarily populated by Th1 and M1 cells to another dominated by Th2, Treg, and M2 cells and is conducive for SCI repair. PMID:26772636

  3. Th1/Th2 cytokine expression in diabetic retinopathy.

    PubMed

    Cao, Y L; Zhang, F Q; Hao, F Q

    2016-01-01

    Diabetic retinopathy (DR), an important complication of diabetes mellitus (DM), is not well understood. T helper cell balance (Th1/Th2) is involved in various autoimmune diseases; however, its role in DR is not understood. This study explores changes in Th1 and Th2 cytokine expression during DR. Blood samples were collected from 25 healthy volunteers (normal control group), 35 patients with type 2 DM (T2DM group) without DR, and 30 cases of T2DM patients with DR (DR group). Real-time PCR was used to measure mRNA expression of IL-2 and TNF-α, secreted from Th1 cells, and of IL-4 and IL-10, secreted from Th2 cells. We used ELISA to detect cytokine expression in serum to analyze the correlation between Th1 and Th2 cytokines. IL-2 and TNF-αmRNA and protein expression levels in the T2DM and DR groups were significantly higher than in the normal control group (P < 0.05). Compared with the T2DM group, the DR group had higher IL-2 and TNF-αlevels (P < 0.05). IL-4 and IL-10 levels were lower in the DR group compared with the normal and T2DM groups (P < 0.05), while T2DM showed no difference compared with the normal control (P > 0.05). IL-2 and TNF-αwere negatively correlated with IL-4 and IL-10 in the DR group, respectively. We found that Th1 cytokine secretion was higher and Th2 cytokines secretion was lower during DR, leading to a Th1/ Th2 imbalance, suggesting that Th1/Th2 imbalance is a side effect for DR occurrence and development. PMID:27525838

  4. In situ hybridization to detect and localize signature cytokines of T-helper (Th) 1 and Th2 immune responses in chicken tissues.

    PubMed

    Kidane, Fana Alem; Bilic, Ivana; Mitra, Taniya; Wernsdorf, Patricia; Hess, Michael; Liebhart, Dieter

    2016-07-01

    The avian immune system has been shown to possess a repertoire of cytokines directing T-helper (Th) 1 and Th2 types of immune responses similar to that in mammals. The objective of this study was to establish in situ hybridization (ISH) for the localization of mRNA of selected signal cytokines, chicken interferon-γ (ChIFN-γ), chicken interleukin (ChIL)-4 and ChIL-13 in fixed tissues. RNA probes were generated to hybridize to 488, 318, and 417bp of the respective target mRNA. Probe concentrations ranging from 100ng/ml to 400ng/ml were shown to be suitable to label cells that expressed these cytokines. The specificity of every probe was verified using the respective sense probe. ChIFN-γ, ChIL-4 and ChIL-13 positive cells were observed in the lymphocytic infiltrations of liver and in the periarteriolar lymphatic sheaths of spleen collected from specific-pathogen-free chickens. ISH of these cytokines in a severely inflamed liver due to infiltration with the parasite Histomonas meleagridis revealed the expression of both ChIFN-γ and ChIL-13 mRNA in the mononuclear infiltrates. In conclusion, ChIFN-γ, ChIL-4 and ChIL-13 mRNA were efficiently localized by ISH, which supplies a valid technique to characterize immune responses in fixed tissues. PMID:27269792

  5. Modulating the Th1/Th2 balance in inflammatory arthritis.

    PubMed

    Müller, B; Gimsa, U; Mitchison, N A; Radbruch, A; Sieper, J; Yin, Z

    1998-01-01

    The balance between Th1 and Th2 cells regulates the choice between inflammatory and antibody-mediated immune responses. To an increasing extent this balance is thought to involve the participation of antigen-presenting cells, rather than the entirely autonomous activity of T cells and their cytokines. Here we survey current opinion concerning the working of this balance, and its condition in rheumatoid arthritis and the other inflammatory arthritides. The contrast between Lyme arthritis and reactive arthritis is particularly illuminating, since one is triggered by extracellular and the other by intracellular infection. We describe current approaches to the modulation of this balance. Guided by the principles that genetic polymorphism is likely to identify relevant genes, that any cytokine gene picked up by a virus must matter and that natural immunosuppressive activity at mucosal surfaces should be worth exploiting, we identify as particularly worthy of attention: (i) IL-10, (ii) inhibitors of IL-12 production, (iii) inhibitors of CD40 ligand expression and (iv) oral and nasal tolerance. Other protective T cell subsets are touched on, and the impact of oligonucleotide arrays mentioned. PMID:9836376

  6. Th1 or Th2 balance regulated by interaction between dendritic cells and NKT cells.

    PubMed

    Onoé, Kazunori; Yanagawa, Yoshiki; Minami, Keita; Iijima, Norifumi; Iwabuchi, Kazuya

    2007-01-01

    If Th1 or Th2 polarization could be artificially manipulated, effective immune responses would be generated depending on nature of the targets. In this study we attempted to regulate CD40 expressions on dendritic cells (DCs) in order to modify the T cell response. It was found that reducing agents selectively inhibited surface expression of CD40 on DCs. This finding may provide a new strategy of DC-mediated modulation of the Th1/Th2 balance. It was also shown that NKT-produced Th1/Th2 cytokine balance was under control of negative feedback loop through DCs. Th1 cytokine-pretreated DCs mainly induced Th2 cytokine production, whereas Th2 cytokine-pretreated DCs induced Th1 cytokine production by alpha-galactosylceramide-stimulated NKT cells. The negative feedback regulation system could be applicable to therapeutics of various diseases based on immunological disorders. PMID:17917039

  7. Expression of Th1- Th2- and Th17-associated cytokines in laryngeal carcinoma

    PubMed Central

    Xu, Xiaoqun; Wang, Rui; Su, Qinghong; Huang, Haiyan; Zhou, Peng; Luan, Junwen; Liu, Jingsheng; Wang, Junfu; Chen, Xuemei

    2016-01-01

    T-helper (Th) 0 cell differentiation into Th1 or Th2 cells is dependent on a number of transcription factors that act at specific time points to regulate gene expression. Th17 cells, a subset of interleukin (IL)-17-producing T cells distinct from Th1 or Th2 cells, are considered to exhibit a critical function in inflammation and autoimmune diseases, as well as cancer development. In the present study, the expression of Th1-, Th2- and Th17-associated cytokines in laryngeal cancer and pericarcinoma tissues obtained from 57 laryngeal carcinoma patients was investigated. The association between Th1, Th2 and Th17 infiltration and tumor development was also evaluated. Reverse transcription-polymerase chain reaction and western blotting results revealed that the mRNA and protein expression of Th2 cytokines was lower, while the expression of Th1 and Th17 cytokines was higher in tumor tissues than in pericarcinoma tissues. Furthermore, the early stage cancer patients exhibited a higher level of interferon-γ, IL-2 and IL-17 mRNA expression than those at advanced stages. Cancer tissues exhibited higher Th17 cytokine expression than pericarcinoma tissues. By contrast, Th1 cytokine expression was increased in pericarcinoma tissues compared with cancer tissues. These results indicate that high expression of Th1- and Th17-associated cytokines in laryngeal carcinoma may contribute to suppression of cancer development and a relatively good prognosis. PMID:27588143

  8. Immunomodulation Mechanism of Antidepressants: Interactions between Serotonin/Norepinephrine Balance and Th1/Th2 Balance

    PubMed Central

    Martino, Matteo; Rocchi, Giulio; Escelsior, Andrea; Fornaro, Michele

    2012-01-01

    Neurotransmitters and hormones regulate major immune functions, including the selection of T helper (Th)1 or Th2 cytokine responses, related to cell-mediated and humoral immunity, respectively. A role of imbalance and dynamic switching of Th1/Th2 system has been proposed, with relative displacement of the immune reserve in relation to complex interaction between Th1/Th2 and neuro-hormonal balance fluctuations, in the pathogenesis of various chronic human diseases, probably also including psychiatric disorders. Components of the stress system such as norepinephrine (NE) and glucocorticoids appear to mediate a Th2 shift, while serotonin (5-HT) and melatonin might mediate a Th1 shift. Some antidepressants would occur affecting these systems, acting on neurotransmitter balance (especially the 5-HT/NE balance) and expression levels of receptor subtypes, which in turn affect cytokine production and relative Th1/Th2 balance. It could be therefore hypothesized that the antidepressant-related increase in NE tone enhances the Th2 response, while the decrease in NE tone or the increase in 5-HT tone enhances the Th1 response. However, the neurotransmitter and Th1/Th2 balance modulation could be relative, aiming to restore physiological levels a previous imbalance in receptor sensitivity and cytokine production. The considerations on neuro-immunomodulation could represent an additional aid in the study of pathophysiology of psychiatric disorders and in the choice of specific antidepressants in specific clusters of symptoms, especially in comorbidity with internal pathologies. Furthermore limited data, reviewed here, have shown the effectiveness of some antidepressants as pure immunomodulators. However, these considerations are tentative and require experimental confirmation or refutation by future studies. PMID:23204981

  9. Sex-Based Selectivity of PPARγ Regulation in Th1, Th2, and Th17 Differentiation

    PubMed Central

    Park, Hong-Jai; Park, Hyeon-Soo; Lee, Jae-Ung; Bothwell, Alfred L. M.; Choi, Je-Min

    2016-01-01

    Peroxisome proliferator-activated receptor gamma (PPARγ) has recently been recognized to regulate adaptive immunity through Th17 differentiation, Treg functions, and TFH responses. However, its role in adaptive immunity and autoimmune disease is still not clear, possibly due to sexual differences. Here, we investigated in vitro treatment study with the PPARγ agonist pioglitazone to compare Th1, Th2, and Th17 differentiation in male and female mouse splenic T cells. Pioglitazone treatment significantly inhibited various effector T cell differentiations including Th1, Th2, and Th17 cells from female naïve T cells, but it selectively reduced IL-17 production in male Th17 differentiation. Interestingly, pioglitazone and estradiol (E2) co-treatment of T cells in males inhibited differentiation of Th1, Th2, and Th17 cells, suggesting a mechanism for the greater sensitivity of PPARγ to ligand treatment in the regulation of effector T cell differentiation in females. Collectively, these results demonstrate that PPARγ selectively inhibits Th17 differentiation only in male T cells and modulates Th1, Th2, and Th17 differentiation in female T cells based on different level of estrogen exposure. Accordingly, PPARγ could be an important immune regulator of sexual differences in adaptive immunity. PMID:27548145

  10. Mangiferin Attenuates Th1/Th2 Cytokine Imbalance in an Ovalbumin-Induced Asthmatic Mouse Model

    PubMed Central

    Hou, Guang-Han; Du, Jun; Huang, Xin; Lu, Yi; Keller, Evan T.; Zhang, Jian; Deng, Jia-Gang

    2014-01-01

    Mangiferin is a major bioactive ingredient in Mangifera indica Linn. (Anacardiaceae) leaves. Aqueous extract of such leaves have been used as an indigenous remedy for respiratory diseases like asthma and coughing in traditional Chinese medicine. However, underlying molecular mechanisms of mangiferin on anti-asthma remain unclear. In our present study, we investigated the anti-asthmatic effect of mangiferin on Th1/Th2 cytokine profiles and explored its underlying immunoregulatory mechanism in mouse model of allergic asthma. Mangiferin significantly reduced the total inflammatory cell counts and eosinophil infiltration, decreased the production of ovalbumin-specific IgE in serum and PGD2 in BALF. The antibody array analysis showed that mangiferin down-regulated the levels of one group of cytokines/chemokines including Th2-related IL-4, IL-5, IL-13, and others IL-3, IL-9, IL-17, RANTES, TNF-α, but simultaneously up-regulated Th1-related IFN-γ, IL-2 and IL-10 and IL-12 expression in serum. Thus it attenuates the imbalance of Th1/Th2 cells ratio by diminishing the abnormal mRNA levels of Th1 cytokines (IFN-γ and IL-12) and Th2 cytokines (IL-4, IL-5 and IL-13). Finally, mangiferin substantially inhibited the activation and expression of STAT-6 and GATA-3 in excised lung tissues. Our results suggest that mangiferin can exert anti-asthmatic effect. The underlying mechanism may attribute to the modulation of Th1/Th2 cytokine imbalance via inhibiting the STAT6 signaling pathway. PMID:24955743

  11. Localized Th1-, Th2-, T Regulatory Cell-, and Inflammation-Associated Hepatic and Pulmonary Immune Responses in Ascaris suum-Infected Swine Are Increased by Retinoic Acid▿ †

    PubMed Central

    Dawson, Harry; Solano-Aguilar, Gloria; Beal, Madeline; Beshah, Ethiopia; Vangimalla, Vandana; Jones, Eudora; Botero, Sebastian; Urban, Joseph F.

    2009-01-01

    Pigs infected with Ascaris suum or controls were given 100 μg (low-dose) or 1,000 μg (high-dose) all-trans retinoic acid (ATRA)/kg body weight in corn oil or corn oil alone per os on days after inoculation (DAI) −1, +1, and +3 with infective eggs. Treatment with ATRA increased interleukin 4 (IL4) and IL12p70 in plasma of infected pigs at 7 DAI and augmented bronchoalveolar lavage (BAL) eosinophilia observed at 7 and 14 DAI. To explore potential molecular mechanisms underlying these observations, a quantitative real-time reverse transcription (RT)-PCR array was used to examine mRNA expression in tissue. Ascaris-infected pigs had increased levels of liver mRNA for T-helper-2 (Th2)-associated cytokines, mast cell markers, and T regulatory (Treg) cells, while infected pigs given ATRA had higher IL4, IL13, CCL11, CCL26, CCL17, CCL22, and TPSB1 expression. Gene expression for Th1-associated markers (IFNG, IL12B, and TBX21), the CXCR3 ligand (CXCL9), IL1B, and the putative Treg marker TNFRSF18 was also increased. Expression of IL4, IL13, IL1B, IL6, CCL11, and CCL26 was increased in the lungs of infected pigs treated with ATRA. To determine a putative cellular source of eosinophil chemoattractants, alveolar macrophages were treated with IL4 and/or ATRA in vitro. IL4 induced CCL11, CCL17, CCL22, and CCL26 mRNA, and ATRA increased the basal and IL4-stimulated expression of CCL17 and CCL22. Thus, ATRA augments a diverse Th1-, Th2-, Treg-, and inflammation-associated response in swine infected with A. suum, and the increased BAL eosinophilia may be related to enhanced induction of eosinophil chemokine activity by alveolar macrophages. PMID:19332534

  12. Nanoparticle clearance is governed by Th1/Th2 immunity and strain background

    PubMed Central

    Jones, Stephen W.; Roberts, Reid A.; Robbins, Gregory R.; Perry, Jillian L.; Kai, Marc P.; Chen, Kai; Bo, Tao; Napier, Mary E.; Ting, Jenny P.Y.; DeSimone, Joseph M.; Bear, James E.

    2013-01-01

    Extended circulation of nanoparticles in blood is essential for most clinical applications. Nanoparticles are rapidly cleared by cells of the mononuclear phagocyte system (MPS). Approaches such as grafting polyethylene glycol onto particles (PEGylation) extend circulation times; however, these particles are still cleared, and the processes involved in this clearance remain poorly understood. Here, we present an intravital microscopy–based assay for the quantification of nanoparticle clearance, allowing us to determine the effect of mouse strain and immune system function on particle clearance. We demonstrate that mouse strains that are prone to Th1 immune responses clear nanoparticles at a slower rate than Th2-prone mice. Using depletion strategies, we show that both granulocytes and macrophages participate in the enhanced clearance observed in Th2-prone mice. Macrophages isolated from Th1 strains took up fewer particles in vitro than macrophages from Th2 strains. Treating macrophages from Th1 strains with cytokines to differentiate them into M2 macrophages increased the amount of particle uptake. Conversely, treating macrophages from Th2 strains with cytokines to differentiate them into M1 macrophages decreased their particle uptake. Moreover, these results were confirmed in human monocyte–derived macrophages, suggesting that global immune regulation has a significant impact on nanoparticle clearance in humans. PMID:23778144

  13. Development of a functional cDNA array for evaluation of the Th1/Th2 balance.

    PubMed

    Yamaguchi, Aki; Koda, Toshiaki; Abe, Hiroyuki; Sato, Masayoshi; Li, Jie; Sakai, Tomoaki; Togashi, Yuji; Shinohara, Yukito; Ikeda, Hiroaki; Nishimura, Takashi

    2005-10-15

    The immune balance controlled by CD4(+) helper T cell subsets (T helper 1 (Th1) and T helper 2 (Th2)) is crucial for immunoregulation and its imbalance causes various immune diseases including infections, allergic disorders and autoimmune diseases. Therefore, it is of great importance to develop a system of diagnosing Th1/Th2 imbalances for curing immune diseases. Here we developed a functional cDNA array filter useful for assessing the Th1/Th2 balance in mice. To overcome the disadvantages of conventional microarrays carrying thousands of genes, we prepared an array filter containing 40 Th1-specific and 32 Th2-specific genes, which were selected from over 8700 genes based on (i) the specificity of expression in Th1 or Th2 cells and (ii) an expression level which is high enough for detection using a DNA array. This array filter provided a prompt and precise evaluation for the skewing of the Th1/Th2 balance combined with our calculation algorithm. The bias toward Th1 or Th2 was evaluated visually at a glance by aligning the genes on the filter. Moreover, we succeeded in evaluating the skewing of the Th1/Th2 balance in vivo during acute graft versus host disease (GVHD). Thus, this array filter will provide a novel tool for evaluation of the Th1/Th2 balance in a variety of immune diseases. PMID:15993951

  14. Th1, Th2 and Treg/T17 cytokines in two types of proliferative glomerulonephritis.

    PubMed

    Stangou, M; Bantis, C; Skoularopoulou, M; Korelidou, L; Kouloukouriotou, D; Scina, M; Labropoulou, I T; Kouri, N M; Papagianni, A; Efstratiadis, G

    2016-01-01

    IgA nephropathy (IgAN) and focal segmental necrotizing glomerulonephritis (FSNGN) are characterized by proliferation of native glomerular cells and infiltration by inflammatory cells. Several cytokines act as mediators of kidney damage in both diseases. The aim of the present study was to investigate the role of Th1, Th2 and Treg/T17 cytokines in these types of proliferative glomerulonephritis. Simultaneous measurement of Th1 interleukin (IL-2, IL-12, tumor necrosis factor-alpha [TNF-α], interferon-gamma [INF-γ]), Th2 (IL-4, IL-5, IL-6, IL-10, IL-13), Treg/T17 transforming growth factor-beta 1 (TGF-β1, granulocyte-macrophage colony-stimulating factor [GM-CSF], IL-17) cytokines and C-C chemokines Monocyte chemoattractant protein-1 (MCP-1, macrophage inflammatory protein-1 [MIP-1] β) was performed in first-morning urine samples, at the day of renal biopsy, using a multiplex cytokine assay. Cytokine concentrations were correlated with histological findings and renal function outcome. Urinary excretion of Th1, Th2 and Treg/Th17 cytokines were significantly higher in FSNGN compared to IgAN patients. In IgAN patients (n = 50, M/F: 36/14, M age: 40.7 [17-67] years), Th1, Th2 and T17 cytokines correlated significantly with the presence of endocapillary proliferation, while in FSNGN patients (n = 40, M/F: 24/16, M age: 56.5 [25-80] years), MCP-1 and TGF-β1 had a positive correlation with severe extracapillary proliferation (P = 0.001 and P = 0.002, respectively). Urinary IL-17 was the only independent parameter associated with endocapillary proliferation in IgAN and with MCP-1 urinary excretion in FSNGN. Response to treatment was mainly predicted by IL-6 in IgAN, and by Th2 (IL-4, IL-6), Treg (GM-CSF) cytokines and MIP-1 β in FSNGN. Th1, Th2 and T17 cytokines were directly implicated in renal pathology in IgAN and possibly through MCP-1 production in FSNGN. IL-17 and IL-6 seem to have a central role in inflammation and progression of kidney injury. PMID:27194829

  15. Th1, Th2 and Treg/T17 cytokines in two types of proliferative glomerulonephritis

    PubMed Central

    Stangou, M.; Bantis, C.; Skoularopoulou, M.; Korelidou, L.; Kouloukouriotou, D.; Scina, M.; Labropoulou, I. T.; Kouri, N. M.; Papagianni, A.; Efstratiadis, G.

    2016-01-01

    IgA nephropathy (IgAN) and focal segmental necrotizing glomerulonephritis (FSNGN) are characterized by proliferation of native glomerular cells and infiltration by inflammatory cells. Several cytokines act as mediators of kidney damage in both diseases. The aim of the present study was to investigate the role of Th1, Th2 and Treg/T17 cytokines in these types of proliferative glomerulonephritis. Simultaneous measurement of Th1 interleukin (IL-2, IL-12, tumor necrosis factor-alpha [TNF-α], interferon-gamma [INF-γ]), Th2 (IL-4, IL-5, IL-6, IL-10, IL-13), Treg/T17 transforming growth factor-beta 1 (TGF-β1, granulocyte-macrophage colony-stimulating factor [GM-CSF], IL-17) cytokines and C-C chemokines Monocyte chemoattractant protein-1 (MCP-1, macrophage inflammatory protein-1 [MIP-1] β) was performed in first-morning urine samples, at the day of renal biopsy, using a multiplex cytokine assay. Cytokine concentrations were correlated with histological findings and renal function outcome. Urinary excretion of Th1, Th2 and Treg/Th17 cytokines were significantly higher in FSNGN compared to IgAN patients. In IgAN patients (n = 50, M/F: 36/14, M age: 40.7 [17–67] years), Th1, Th2 and T17 cytokines correlated significantly with the presence of endocapillary proliferation, while in FSNGN patients (n = 40, M/F: 24/16, M age: 56.5 [25–80] years), MCP-1 and TGF-β1 had a positive correlation with severe extracapillary proliferation (P = 0.001 and P = 0.002, respectively). Urinary IL-17 was the only independent parameter associated with endocapillary proliferation in IgAN and with MCP-1 urinary excretion in FSNGN. Response to treatment was mainly predicted by IL-6 in IgAN, and by Th2 (IL-4, IL-6), Treg (GM-CSF) cytokines and MIP-1 β in FSNGN. Th1, Th2 and T17 cytokines were directly implicated in renal pathology in IgAN and possibly through MCP-1 production in FSNGN. IL-17 and IL-6 seem to have a central role in inflammation and progression of kidney injury. PMID:27194829

  16. Ginsenoside Rd elicits Th1 and Th2 immune responses to ovalbumin in mice.

    PubMed

    Yang, Zhigang; Chen, Aqin; Sun, Hongxiang; Ye, Yiping; Fang, Weihuan

    2007-01-01

    Ginsenoside Rd (Rd), a saponin isolated from the roots of panax notoginseng, was evaluated for inducing Th1 or Th2 immune responses in mice against ovalbumin (OVA). ICR mice were immunized subcutaneously with OVA 100 microg alone or with OVA 100 microg dissolved in saline containing alum (200 microg), or Rd (10, 25 or 50 microg) on days 1 and 15. Two weeks later (day 28), concanavalin A (Con A)-, lipopolysaccharide (LPS)- and OVA-stimulated splenocyte proliferation was determined using MTT assay, and OVA-specific antibody titers and levels of cytokines in serum were measured by ELISA and microparticle-based flow cytometric immunoassay, as well as peripheral blood T-lymphocyte subsets analyzed using flow cytometer. Rd significantly enhanced the Con A-, LPS-, and OVA-induced splenocyte proliferation in the OVA-immunized mice. OVA-specific IgG, IgG1, and IgG2b antibody titers in serum were significantly enhanced by Rd compared with OVA control group. Meanwhile, Rd also significantly promoted the production of the Th1 and Th2 cytokines in OVA-immunized mice. Further, the effects of Rd on expression of cytokine mRNA in Con A-stimulated mice splenocytes were evaluated by RT-PCR analysis. Rd significantly enhanced the interleukin-2 (IL-2), interferon-gamma (IFN-gamma), IL-4, and IL-10 mRNA expression in mice splenocyte induced by Con A. These results suggested that Rd had immunological adjuvant activity, and elicited a Th1 and Th2 immune response by regulating production and gene expression of Th1 cytokines and Th2 cytokines. PMID:16950547

  17. Th-1, Th-2 Cytokines Profile among Madurella mycetomatis Eumycetoma Patients.

    PubMed

    Nasr, Amre; Abushouk, Amir; Hamza, Anhar; Siddig, Emmanuel; Fahal, Ahmed H

    2016-07-01

    Eumycetoma is a progressive and destructive chronic granulomatous subcutaneous inflammatory disease caused by certain fungi, the most common being Madurella mycetomatis. The host defence mechanisms against fungi usually range from an early non-specific immune response to activation and induction of specific adaptive immune responses by the production of Th-1 and Th-2 cytokines. The aim of this study is to determine the levels of Th-1 and Th-2 cytokines in patients infected with Madurella mycetomatis, and the association between their levels and disease prognosis. This is a descriptive cross-sectional study conducted at the Mycetoma Research Centre, University of Khartoum, Sudan, where 70 patients with confirmed M. mycetomatis eumycetoma were enrolled; 35 with, and 35 without surgical excision. 70 healthy individuals from mycetoma endemic areas were selected as controls. The levels of serum cytokines were determined by cytometric bead array technique. Significantly higher levels of the Th-1 cytokines (IFN-γ, TNF-α, IL-1β and IL-2) were recorded in patients treated with surgical excision, compared to those treated without surgical excision. In contrast, the Th-2 cytokines (IL-4, IL-5, IL-6 and IL-10) were significantly lower in patients treated with surgical excision compared to those treated without surgical excision. In conclusion, the results of this study suggest that cell-mediated immunity can have a role to play in the pathogenesis of eumycetoma. PMID:27434108

  18. Th-1, Th-2 Cytokines Profile among Madurella mycetomatis Eumycetoma Patients

    PubMed Central

    Nasr, Amre; Abushouk, Amir; Hamza, Anhar; Siddig, Emmanuel; Fahal, Ahmed H.

    2016-01-01

    Eumycetoma is a progressive and destructive chronic granulomatous subcutaneous inflammatory disease caused by certain fungi, the most common being Madurella mycetomatis. The host defence mechanisms against fungi usually range from an early non-specific immune response to activation and induction of specific adaptive immune responses by the production of Th-1 and Th-2 cytokines. The aim of this study is to determine the levels of Th-1 and Th-2 cytokines in patients infected with Madurella mycetomatis, and the association between their levels and disease prognosis. This is a descriptive cross-sectional study conducted at the Mycetoma Research Centre, University of Khartoum, Sudan, where 70 patients with confirmed M. mycetomatis eumycetoma were enrolled; 35 with, and 35 without surgical excision. 70 healthy individuals from mycetoma endemic areas were selected as controls. The levels of serum cytokines were determined by cytometric bead array technique. Significantly higher levels of the Th-1 cytokines (IFN-γ, TNF-α, IL-1β and IL-2) were recorded in patients treated with surgical excision, compared to those treated without surgical excision. In contrast, the Th-2 cytokines (IL-4, IL-5, IL-6 and IL-10) were significantly lower in patients treated with surgical excision compared to those treated without surgical excision. In conclusion, the results of this study suggest that cell-mediated immunity can have a role to play in the pathogenesis of eumycetoma. PMID:27434108

  19. Th1 and Th2 cell-associated cytokines in experimental visceral leishmaniasis.

    PubMed Central

    Miralles, G D; Stoeckle, M Y; McDermott, D F; Finkelman, F D; Murray, H W

    1994-01-01

    In experimental Leishmania donovani infection in BALB/c mice, initial susceptibility gives way to T-cell-dependent acquired resistance and eventual control over visceral infection. Since various cytokines appear to underlie the host response to Leishmania infection, we examined infected liver tissue for gene expression of cytokines associated with Th1 (gamma interferon [IFN-gamma] and interleukin-2 [IL-2]) and Th2 cells (IL-4 and IL-10). By Northern (RNA) blot analysis, only IFN-gamma mRNA expression was detected in livers of infected euthymic mice. To determine whether activation of Th1 cells develops selectively in this model, qualitative PCR analysis was used. These results indicated that mRNAs for IFN-gamma, IL-2, IL-4, and IL-10 were all induced by L. donovani infection. The potentially negative Th2 cell-associated response did not appear to play a functional role, however, since resistance was acquired, anti-IL-4 monoclonal antibody treatment did not accelerate control over visceral infection, and serum immunoglobulin E levels remained low. As judged by PCR analysis, IL-4 and IL-10 mRNAs were also expressed under three other conditions without apparent effect: in naive euthymic mice treated with IL-2, which induces leishmanicidal activity; in rechallenged immune mice, which resist reinfection; and in nude mice, which fail to control L. donovani. These results suggest that, like other Leishmania species, L. donovani infection may trigger a potentially suppressive Th2 cell-associated cytokine response. However, in T-cell-intact mice able to control L. donovani, this response either is insufficient to influence outcome or more likely is overshadowed by the Th1 cell response. Images PMID:8112840

  20. HLA-DRBeta1, circulating Th1/Th2 cytokines and immunological homunculus in coronary atherosclerosis.

    PubMed

    Mostafazadeh, Amrollah; Saravi, Mehrdad; Niaki, Haleh Akhavan; Drabbels, Jos; Gholipour, Haji Mohammad; Minagar, Milad; Mosavi, Ezatola; Jalali, Farzad; Bijani, Ali

    2011-03-01

    Coronary atherosclerotic disease is one of the most endangering health disorder worldwide. This study was designed to investigate the correlation between HLA-DR1 alleles and circulating Th1/Th2 type cytokines in coronary atherosclerosis. By Elisa, Th1/Th2 type cytokines were determined in serum samples of 31 subjects with unstable angina, 27 subjects with chronic stable angina and 24 individuals as normal control. By SSP-PCR, more than 100 alleles of HLA-DRBeta1 were typed in 24 subjects who had skewed serum levels of Th1/Th2 type cytokines. Lipid profiles were determined by the routine methods of clinical laboratory in all subjects. The mean serum concentration of IL-10 in normal control subjects was higher in comparison to the patient groups.0.33±0.59 pg/ml versus 0.064±0.3 pg/ml in unstable angina pectoris group (p<0.028) and 0.22±0.6 pg/ml in chronic stable subjects. There was no statistically significant difference among the groups in serum levels of other desired cytokines (IFN-Gamma, IL-4). 33.33% of normal control subjects were HLA-DR16 positive whereas none of the subjects with chronic stable angina or individuals with unstable angina pectoris was positive for this antigen. The mean concentration of serum LDL-cholesterol in normal control group was high 142.046±35.40 (pg/ml).This preliminary study shows that the atherogenic effect of the LDL- cholesterol may be dampened by HDL-cholesterol through anti inflammatory cytokine IL-10 and HLA-DR16, a phenomenon interpretable via immunological homunculus theory. PMID:21358010

  1. Th1, Th2, and Th17 Cytokine Involvement in Thyroid Associated Ophthalmopathy.

    PubMed

    Shen, Jie; Li, Zhangfang; Li, Wenting; Ge, Ying; Xie, Min; Lv, Meng; Fan, Yanfei; Chen, Zhi; Zhao, Defu; Han, Yajuan

    2015-01-01

    To determine serum cytokine profiles in Graves' disease (GD) patients with or without active and inactive thyroid associated ophthalmopathy (TAO), we recruited 65 subjects: 10 GD only (without TAO), 25 GD + active TAO, 20 GD + TAO, and 10 healthy controls. Liquid chip assay was used to measure serum Th1/Th2/Th17 cytokines including IFN-γ (interferon-gamma), TNF-α (tumor necrosis factor-alpha), IL-1α (interleukin-1 alpha), IL-1Ra (IL-1 receptor antagonist), IL-2, IL-4, IL-6, and IL-17 and two chemokines: RANTES (regulated upon activation, normal T cell expressed and secreted) and IP-10 (IFN-γ-induced protein 10). Serum levels of TSH (thyroid stimulating hormone) receptor autoantibodies (TRAb) were measured using an enzyme linked immunosorbent assay. Compared with healthy controls, TAO patients showed significantly elevated serum levels of IFN-γ, TNF-α, IL-1α, IL-4, IL-6, IL-17, and IP-10. Comparing active and inactive TAO, serum Th1 cytokines IFN-γ and TNF-α were elevated in active TAO, while serum Th2 cytokine IL-4 was elevated in inactive TAO. Serum Th17 cytokine IL-17 was elevated in GD but reduced in both active and inactive TAO. A positive correlation was found between TRAb and IFN-γ, TNF-α, IL-1α, IL-2, IL-4, and IL-6. Taken together, serum Th1/Th2/Th17 cytokines and chemokines reflect TAO disease activity and may be implicated in TAO pathogenesis. PMID:26089587

  2. Effect of ultra violet irradiation on the interplay between Th1 and Th2 lymphocytes

    PubMed Central

    Abo Elnazar, Salma Y.; Ghazy, Amany A.; Ghoneim, Hossam E.; Taha, Abdul-Rahman M.; Abouelella, Amira M.

    2015-01-01

    Although ultraviolet (UV) radiation is used to treat several types of diseases, including rickets, psoriasis, eczema, and jaundice, the prolonged exposure to its radiation may result in acute and chronic health effects particularly on the skin, eyes, and the immune system. Aim: This study was carried out to show the effect of UV on both of the lymphoproliferative response and their capacity to produce IL-12 and IL-10 in mice. Methods: Mice were exposed to whole body UVB and tested for the effect of recovery times on lymphocyte proliferation and cytokine production. In addition, direct irradiation of spleens and lymphocyte suspension was carried out. Basal and mitogens-stimulated lymphocyte proliferation was assessed by MTT assay while IL-10 and IL-12 were measured using ELISA. Results: There was a significant suppression in lymphocyte proliferation in comparison with control. IL-12 level was significantly reduced while the level of IL-10 was increased. Con A and PWM mitogens had no significant changes in IL-10 while Con A caused a highly significant increase in IL-12 at day 6 of recovery in UVB body irradiation. Conclusion: Exposure to UVB radiation could cause a state of immune suppression and shifts Th1/Th2 cell response. This effect is closely associated with the reduction of Th1 cytokines’ expression and increase in Th2 cytokines’ levels. PMID:25852558

  3. TH1/TH2 paradigm extended: macrophage polarization as an unappreciated pathogen-driven escape mechanism?

    PubMed

    Muraille, Eric; Leo, Oberdan; Moser, Muriel

    2014-01-01

    The classical view of the Th1/Th2 paradigm posits that the pathogen nature, infectious cycle, and persistence represent key parameters controlling the choice of effector mechanisms operating during an immune response. Thus, efficient Th1 responses are triggered by replicating intracellular pathogens, while Th2 responses would control helminth infection and promote tissue repair during the resolution phase of an infectious event. However, this vision does not account for a growing body of data describing how pathogens exploit the polarization of the host immune response to their own benefit. Recently, the study of macrophages has illustrated a novel aspect of this arm race between pathogens and the immune system, and the central role of macrophages in homeostasis, repair and defense of all tissues is now fully appreciated. Like T lymphocytes, macrophages differentiate into distinct effectors including classically (M1) and alternatively (M2) activated macrophages. Interestingly, in addition to represent immune effectors, M1/M2 cells have been shown to represent potential reservoir cells to a wide range of intracellular pathogens. Subversion of macrophage cell metabolism by microbes appears as a recently uncovered immune escape strategy. Upon infection, several microbial agents have been shown to activate host metabolic pathways leading to the production of nutrients necessary to their long-term persistence in host. The purpose of this review is to summarize and discuss the strategies employed by pathogens to manipulate macrophage differentiation, and in particular their basic cell metabolism, to favor their own growth while avoiding immune control. PMID:25505468

  4. CD4+ T-cell subsets in inflammatory diseases: beyond the Th1/Th2 paradigm.

    PubMed

    Hirahara, Kiyoshi; Nakayama, Toshinori

    2016-04-01

    CD4(+)T cells are crucial for directing appropriate immune responses during host defense and for the pathogenesis of inflammatory diseases. In addition to the classical biphasic model of differentiation of T-helper 1 (Th1) and Th2 cells, unexpected increases in the numbers of CD4(+)T-cell subsets, including Th17, Th9, T follicular-helper (Tfh) and T-regulatory (Treg) cells, have been recognized. In the present review, we focus on how these various T-helper cell subsets contribute to the pathogenesis of immune-mediated inflammatory diseases. In particular, we focus on multiple sclerosis, psoriasis and asthma as typical model diseases in which multiple T-helper cell subsets have recently been suggested to play a role. We will also discuss various unique sub-populations of T-helper cells that have been identified. First, we will introduce the heterogeneous T-helper cell subsets, which are classified by their simultaneous expression of multiple key transcription factors. We will also introduce different kinds of memory-type Th2 cells, which are involved in the pathogenesis of chronic type-2 immune-related diseases. Finally, we will discuss the molecular mechanisms underlying the generation of the plasticity and heterogeneity of T-helper cell subsets. The latest progress in the study of T-helper cell subsets has forced us to reconsider the etiology of immune-mediated inflammatory diseases beyond the model based on the Th1/Th2 balance. To this end, we propose another model--the pathogenic T-helper population disease-induction model--as a possible mechanism for the induction and/or persistence of immune-mediated inflammatory diseases. PMID:26874355

  5. Analysis of Serum Th1/Th2 Cytokine Levels in Patients with Acute Mumps Infection

    PubMed Central

    Malaiyan, Jeevan; Ramanan, Padmasani Venkat; Subramaniam, Dinesh; Menon, Thangam

    2016-01-01

    Background: The mumps virus is frequently the causative agent of parotitis. There has been no study on serum cytokine levels of acute mumps parotitis except for a few which document cytokine levels in cerebrospinal fluid of mumps meningitis. It is with this notion, our study aimed to find Th1/Th2 cytokine levels from patients with acute mumps parotitis. Materials and Methods: Concentrations of mumps-specific IgM, mumps, measles, rubella-specific IgG antibody, and Th1/Th2 cytokines, namely interferon-γ (IFN-γ), interleukin-2 (IL-2), IL-4, and IL-10 were measured simultaneously in serum from 74 patients (42 pediatric and 32 adult cases), 40 healthy subjects (20 pediatric and 20 adults) and in the supernatant of peripheral blood mononuclear cells stimulated with mumps virus genotype C which served as the positive control. Statistical significance was analyzed between each group by means of Mann–Whitney U-test, Kruskal–Wallis test, and Spearman's rank correlation coefficient test. Results: IgM positivity confirmed acute infection in all 74 patients and of these 67 were vaccinated cases; however, very few of them (10/67) were positive for mumps IgG. We found that IFN-γ, IL-2, and IL-10 showed a statistically significant increase in both pediatric and adult patients with acute mumps infection when compared to healthy controls and values were comparable to the positive control. Conclusion: The Th1 cells play important roles during the acute phase of mumps parotitis. PMID:27293364

  6. CD30 antigen: not a physiological marker for TH2 cells but an important costimulator molecule in the regulation of the balance between TH1/TH2 response.

    PubMed

    Pellegrini, Patrizia; Berghella, Anna Maria; Contasta, Ida; Adorno, Domenico

    2003-01-01

    Understanding the physiological role of CD30 would be an important step forward in transplants because CD30+ T cells can be induced by alloantigens even in the presence of immunosuppressives such as cyclosporine (Csa) and hence can act as regulatory cells in allograft. The results of functional studies on purified T CD30+ cell populations led us to hypothesize that the CD30 costimulator molecule is not a specific marker for TH2 cells in normal conditions, as has been suggested, but rather a marker for an important immunoregulatory subpopulation that regulates the balance between TH1 and TH2 (TH1/TH2) type response. To substantiate this hypothesis we studied the TH1/TH2 cytokine network in peripheral whole blood cultures stimulate with M44 CD30 ligand (CD30L), an agonistic monoclonal antibody (mAb). Four types of whole blood culture were used: the first had been stimulated with anti-CD3 mAb which generates a CD30 cytokine profile similar to alloreactive stimulation; the second with anti-CD3 mAb+M81 (an anti-CD30L mAb) to inhibit CD30/CD30L interaction; the third with anti-CD3+anti-interleukin (IL)4 mAbs to counteract IL4 activity and the fourth with anti-CD3+anti-interferon (IFN)gamma mAbs to counteract IFNgamma activity. Network interactions between soluble CD30 (sCD30, a maker of CD30 expression), sBcl2 (a marker of cell survival) and TH1/TH2 cytokines (IFNgamma, IL2, IL12p70, IL12p40, IL4, IL5 and IL10) were then studied in the supernatants obtained. Our results confirm the hypothesis above by showing that CD30 signals trigger functional mechanisms responsible for changes in levels of production of several important TH1 and TH2 cytokines involved in the regulation of the physiological balance between TH1/TH2 functions. The CD30-stimulated network, in fact, induces IFNgamma production linked to TH1 activity (-->TH1) which is subsequently integrated by IL4 production linked to TH2 activity (-->TH2). This production appears to be regulated, respectively, by IL12p40

  7. Th1/Th2 Cytokine Profile and Its Diagnostic Value in Mycoplasma pneumoniae Pneumonia

    PubMed Central

    Li, Wei; Liu, Yu-jie; Zhao, Xiao-le; Shang, Shi-qiang; Wu, Lang; Ye, Qing; Xu, Hui

    2016-01-01

    Background: The levels of Th1/Th2 cytokine can alter in pathogenic infection in children with pneumonia. Objectives: To evaluate Th1/Th2 cytokine profile and its diagnostic value in M. pneumoniae pneumonia in children. Patients and Methods: Children with M. pneumoniae mono-infection and 30 healthy children were tested with cytokines assay. We used real time PCR to detect M. pneumoniae in children with pneumonia. Results: M. pneumoniae test was positive in 2188 (16.62%) out of 13161 pneumonia children. Children aged 5 - 9 years had the highest rate and summer was a season with high rate of M. pneumoniae incidence in Zhejiang province. During the course of study, in 526 pneumonia children with M. pneumoniae mono-infection and 30 healthy children cytokines assay was performed. IL-2 level of M. pneumoniae pneumonia children was lower than that of healthy children (median levels, pg/mL: IL-2: 3.2 vs. 5.7, P = 0.00), while IL-4, IL-10 and IFN-γ were higher than in healthy children (median levels, pg/mL: IL-4: 3.2 vs. 1.5, P = 0.00; IL-10: 5.6 vs. 2.5, P = 0.001; IFN-γ: 20.4 vs. 4.8, P = 0.001). Conclusions: IL-2 decreases and IL-4, IL-10 and IFN-γ increase in children with M. pneumoniae pneumonia, which has a promising prospect in diagnosis of this disease in clinical practice. PMID:26848377

  8. TH1/TH2 balance in concomitant immediate and delayed-type hypersensitivity diseases.

    PubMed

    de Mello, Luane Marques; Bechara, Monique Isabel Silveira; Solé, Dirceu; Rodrigues, Virmondes

    2009-06-01

    In spite of the observation of mutual inhibitory properties of TH1 and TH2 CD4+ cells, a group of patients developed simultaneously immediate and delayed-type hypersensitivity reactions that are theoretically antagonistic. Patients presenting concomitant hypersensitivity reactions were evaluated for cytokine production. PBMC from 45 patients and 13 non-atopic individuals were cultured with mite allergen and mitogen and the supernatants obtained were evaluated for cytokine production by ELISA. The analysis of the cytokines levels revealed increased production of pro-inflammatory cytokine TNF-alpha in the non-atopic individuals after specific and mitogen stimulus. The IL-4 was largely observed on serum samples and IL-5 levels were higher in the double sensitized group (group DerpNi) after PHA stimulus. The IL-13 levels were increased in sensitized groups (Derp and DerpNi groups) after PHA stimuli. Atopic patients (Derp and DerpNi groups) presented lowest levels IFN-gamma and the analysis of TGF-beta production after rDER P I stimulation have shown increased levels among sensitized patients to Dermatophagoides pteronyssinus mite. IL-10 levels did not differ after antigen stimulation but basal production was higher on Derp and DerpNi groups. Furthermore, negative correlations were observed between IFN-gamma levels and IL-4, IL-13 and IL-10. This study has shown patients able to react, concomitantly, to the two types of antigens - rDER P I and NiSO4, present distinct pattern of cytokine production. The increased levels of IL-13 in the sensitive individuals to mite antigen (rDER P I) and IFN-gamma in NiSO4 sensitized individuals confirm the role of the type TH2 response in the atopies and TH1 type in DCA. PMID:19433108

  9. Th1/Th2 cytokines in Type 1 diabetes: Relation to duration of disease and gender

    PubMed Central

    Vaseghi, Hajar; Jadali, Zohreh

    2016-01-01

    Background: T-cells are important in the pathogenesis of Type 1 diabetes (T1D). However, the exact role of T-cell subpopulations in this pathway remains unknown. The purpose of this study was to assess the expression pattern of T helper 1 (Th1) interferon-gamma (IFN-γ) and Th2 interleukin-4 (IL-4) cytokines and their relationship with sex and disease duration in T1D patients. Materials and Methods: This study was conducted on 21 T1D patients and 22 healthy subjects. Gene expression analysis of peripheral blood mononuclear cells (PBMCs) was performed using real-time reverse transcriptase polymerase chain reaction. Results: IFN-γ gene expression was significantly lower in T1D patients compared with controls (P < 0.05). Conversely, IL-4 mRNAs were significantly increased in the PBMCs from patients as compared to controls (P < 0.05). There was no significant difference in the expression of IL-4 and IFN-γ between men and women with T1D (P > 0.05) while IL-4 mRNA expression in male patients was about 1.9 folds higher than female patients. Moreover, IFN-γ mRNA expression in female patients was about 1.8 folds lower than male patients. Patients were divided into two groups regarding their disease duration: <10 years and >10 years. A significant increase in the IL-4 expression was observed between two groups of patients compared to controls (P < 0.0001). Conversely, there was a significant difference in the expression of IFN-γ only between patients with more than 10 years of disease duration (P = 0.02). Conclusion: These data propose supplementary implications for the role of Th1/Th2 imbalance in T1D immunopathogenesis. Moreover, factors such as sex and disease duration may have some influence on cytokine mRNA expression. PMID:27186546

  10. The influence of leptin on Th1/Th2 balance in obese children with asthma*

    PubMed Central

    Youssef, Doaa Mohammed; Elbehidy, Rabab Mohamed; Shokry, Dina Mahamoud; Elbehidy, Eman Mohamed

    2013-01-01

    OBJECTIVE: In individuals with asthma, obesity induces the production of leptin and is associated with disease severity. Our objective was to evaluate the levels of serum leptin and their effect on Th1/Th2 balance in obese and non-obese children with asthma, as well as to investigate the association between serum leptin levels and clinical outcomes. METHODS: We evaluated 50 atopic children with physician-diagnosed moderate-to-severe persistent asthma and 20 controls. The children with asthma were divided into two groups, by body mass index percentile: obese (n = 25) and non-obese (n = 25). From all subjects, we collected peripheral blood samples in order to determine the levels of leptin, IFN-γ, and IL-4. Asthma severity was assessed by an asthma symptom score, and the results were correlated with the parameters studied. RESULTS: Serum leptin levels were significantly higher in the obese asthma group than in the non-obese asthma group, as well as being significantly higher in the children with asthma than in the controls, whereas IFN-γ levels were significantly higher and IL-4 levels were significantly lower in the obese asthma group than in the non-obese asthma group. In addition, the obese asthma group showed higher asthma symptom scores and significantly lower FEV1 (% of predicted) than did the non-obese asthma group. There was a significant positive correlation between leptin and IFN-γ levels only in the obese asthma group. CONCLUSIONS: Although leptin is involved in the pathogenesis of asthma in obese and non-obese children, its effect is more pronounced in the former. In the presence of high leptin levels, only obese children with asthma exhibited Th1 polarization, with higher IFN-γ levels and greater asthma severity. PMID:24310629

  11. Brain Granulomas in Neurocysticercosis Patients Are Associated with a Th1 and Th2 Profile

    PubMed Central

    Restrepo, Blanca I.; Alvarez, Jorge I.; Castaño, Jorge A.; Arias, Luis F.; Restrepo, Margarita; Trujillo, Judith; Colegial, Carlos H.; Teale, Judy M.

    2001-01-01

    Neurocysticercosis (NCC) is a common central nervous system (CNS) infection caused by Taenia solium metacestodes. Despite the well-documented importance of the granulomatous response in the pathogenesis of this infection, there is limited information about the types of cells and cytokines involved. In fact, there has been limited characterization of human brain granulomas with any infectious agent. In the present study a detailed histological and immunohistochemical analysis of the immune response was performed on eight craniotomy specimens where a granuloma surrounded each T. solium metacestode. The results indicated that in all the specimens there was a dying parasite surrounded by a mature granuloma with associated fibrosis, angiogenesis, and an inflammatory infiltrate. The most abundant cell types were plasma cells, B and T lymphocytes, macrophages, and mast cells. Th1 cytokines were prevalent and included gamma interferon, interleukin-18 (IL-18), and the immunosuppressive, fibrosis-promoting cytokine transforming growth factor β. The Th2 cytokines IL-4, IL-13, and IL-10 were also present. These observations indicate that a chronic immune response is elicited in the CNS environment with multiple cell types that together secrete inflammatory and anti-inflammatory cytokines. In addition, both collagen type I and type III deposits were evident and could contribute to irreversible nervous tissue damage in NCC patients. PMID:11401999

  12. Cerebrospinal fluid Th1/Th2 cytokine profiles in children with enterovirus 71-associated meningoencephalitis.

    PubMed

    Li, Huajun; Li, Shuxian; Zheng, Jianfeng; Cai, Chunyan; Ye, Bin; Yang, Jun; Chen, Zhimin

    2015-03-01

    Enterovirus 71 (EV71) infection can cause severe neurological complications including meningoencephalitis (ME) in some patients with hand, foot and mouth disease (HFMD). However, to date no studies have reported changes in cytokine concentrations and their correlations with clinical variables in patients with ME following EV71 infection. In this study, responses of Th1/Th2 cytokine, including IL-2, IL-4, IL-6, IL-10, TNF-α and IFN-γ, in cerebrospinal fluid (CSF) from patients with EV71-related HFMD with ME and patients with febrile convulsions (FC) were analyzed using cytometric bead array technology. It was found that CSF IL-6 and IFN-γ concentrations were significantly higher in patients with EV71-related ME than in those with FC. Additionally, both CSF IL-6 and IFN-γ concentrations were correlated with CSF cytology, fever duration and duration of hospital stay. More interestingly, a positive correlation between CSF IL-6 and IFN-γ concentrations was observed. Finally, receiver operating characteristic analysis revealed that when a cutoff value of 9.40 pg/mL was set for IL-6, the sensitivity and specificity were 84.5% and 85.5%, respectively, for discriminating EV71-related ME from FC. In conclusion, IL-6 and IFN-γ may be associated with EV71-induced neuropathology. PMID:25611005

  13. Th2-Th1 shift with the multiantigenic formulation TERAVAC-HIV-1 in Balb/c mice.

    PubMed

    García-Díaz, Darien; Rodríguez, Ingrid; Santisteban, Yaimín; Márquez, Gabriel; Terrero, Yanet; Brown, Enma; Iglesias, Enrique

    2013-01-01

    In chronic HIV infection a progressive Th1 to Th2/Th0 cytokine-profile shift is related to disease progression. One of the possible benefits of a therapeutic vaccination might be to counterbalance this phenomenon to allow viral replication control under a Th1-type immune response. TERAVAC-HIV-1 is a multiantigenic formulation vaccine candidate against HIV-1 which comprises the recombinant protein CR3 that contains T cell epitopes and the surface and nucleocapsid antigens of Hepatitis B Virus (HBV). Previous studies showed that such virus like particles of the HBV provide a Th1 adjuvant effect. The present studies examined the capacity of TERAVAC to elicit a Th1 response in the presence of an ongoing HIV-specific Th2-type response in Balb/c mice. To examine this issue, we injected subcutaneously the animals with CR3 or viral lysate in alum which resulted in a Th2-type response. The CR3-specific Th2-type response was verified by induction of IL-4 and IL-10 secretion in ex vivo stimulated splenocytes without secretion of IFN-γ and IgG2a antibodies in serum. Further subcutaneous and simultaneous subcutaneous-nasal immunizations of the same mice with TERAVAC promoted IFN-γ secretion and production of IgG2a antibodies in accordance with a Th1-type response. This result suggests a therapeutic benefit of this vaccine candidate in the restoration of the Th1-type HIV-specific cellular response in seropositive patients. PMID:23183092

  14. GATA-3 promotes Th2 responses through three different mechanisms: induction of Th2 cytokine production, selective growth of Th2 cells and inhibition of Th1 cell-specific factors.

    PubMed

    Zhu, Jinfang; Yamane, Hidehiro; Cote-Sierra, Javier; Guo, Liying; Paul, William E

    2006-01-01

    Naïve CD4 T cells can differentiate into at least two different types of T helpers, Th1 and Th2 cells. Th2 cells, capable of producing IL-4, IL-5 and IL-13, are involved in humoral immunity against extracellular pathogens and in the induction of asthma and other allergic diseases. In this review, we summarize recent reports regarding the transcription factors involved in Th2 differentiation and cell expansion, including Stat5, Gfi-1 and GATA-3. Stat5 activation is necessary and sufficient for IL-2-mediated function in Th2 differentiation. Enhanced Stat5 signaling induces Th2 differentiation independent of IL-4 signaling; although it does not up-regulate GATA-3 expression, it does require the presence of GATA-3 for its action. Gfi-1, induced by IL-4, promotes the expansion of GATA-3-expressing cells. Analysis of conditional Gata3 knockout mice confirmed the critical role of GATA-3 in Th2 cell differentiation (both IL-4 dependent and IL-4 independent) and in Th2 cell proliferation and also showed the importance of basal GATA-3 expression in inhibiting Th1 differentiation. PMID:16467870

  15. Effect of cordycepin purified from Cordyceps militaris on Th1 and Th2 cytokines in mouse splenocytes.

    PubMed

    Jeong, Min-Ho; Seo, Min Jeong; Park, Jeong Uck; Kang, Byoung Won; Kim, Kyoung-Sook; Lee, Jae Yun; Kim, Gi-Young; Kim, Jung-In; Choi, Yung Hyun; Kim, Kwang Hyuk; Jeong, Yong Kee

    2012-08-01

    Cordycepin was purified from a mushroom, Cordyceps militaris, and its effect on Th1 and Th2 cytokines was examined. The level of cytokine induction in mouse splenocytes was estimated after co-inoculation of purified cordycepin and LPS. When 5 microg/ml of purified cordycepin was exposed to mouse splenocytes for 72 h, the level of a Th1 cytokine IL-12 increased by 2.9-fold. The addition of the purified cordycepin to splenocytes also increased the level of Th2 cytokines, IL-4 and IL-10, by 1.9- and 1.8- fold, respectively. Therefore, cordycepin increases the cytokine levels and may contribute to the up-regulation of cellular and humoral immunity. PMID:22713995

  16. Effects of pristane alone or combined with chloroquine on macrophage activation, oxidative stress, and TH1/TH2 skewness.

    PubMed

    Ouyang, Qiufang; Huang, Ziyang; Wang, Zhenhua; Chen, Xiaoqing; Ni, Jingqin; Lin, Ling

    2014-01-01

    We investigated the protective role of chloroquine against pristane-induced macrophage activation, oxidative stress, and Th1/Th2 skewness in C57BL/6J mice. Those mice were treated with pristane alone or combined with chloroquine. Hematological and biochemical parameters, macrophage phagocytic function, the oxidant/antioxidant index, cytokine for IFN-γ, TNF-α, IL-4, and IL-6, and the isotypes of IgG2a and IgG1 were determined. And the expression of T-bet/GATA-3 and IL-12/IL-10 mRNA in spleen were analyzed by real-time PCR. We found that pristane treatment for a period of 12 or 24 weeks triggered macrophage activation syndrome, characterized by hemophagocytosis in spleen and peripheral blood, enhanced lipid phagocytosis by peritoneal macrophages in vitro, erythropenia and leucopenia, increased anti-Smith, lactic dehydrogenase, triglyceride, and ferritin, as well as hypercytokinemia of IFN-γ, TNF-α, IL-4, and IL-6. In parallel, a significant increase in lipid peroxidation and a decrease in superoxide dismutase, glutathione, and catalase activity, as well as a skewed Th1/Th2 balance in spleen, were observed. However, chloroquine supplementation showed a remarkable amelioration of these abnormalities. Our data indicate that pristane administration induces macrophage activation, oxidative stress, and Th1/Th2 skewness, which can be attenuated by chloroquine. PMID:25136646

  17. Study of Th1/Th2 balance in peripheral blood mononuclear cells of patients with alopecia areata.

    PubMed

    Sadeghi, Soha; Sanati, Mohammad Hossein; Taghizadeh, Morteza; Mansouri, Parvine; Jadali, Zohreh

    2015-09-01

    Alopecia areata represents an autoimmune pathological process driven primarily by cellular aberrations contained within the immune system, which activates various humoral and cellular elements of the immune response. The aim of this study was to determine the mRNA expression levels of T-bet and GATA-3 as potential inducers of T helper (Th)1 and Th2 differentiation, respectively, as well as Th1(IFN-γ) and Th2(IL-4) cytokine mRNA expression in patients with alopecia areata. Using real-time reverse transcriptase PCR (RT-PCR), the relative amounts of T-bet, GATA-3, IFN-γ, and IL-4 mRNA transcripts were determined in PBMCs from 20 Iranian patients with alopecia areata and compared with those of 20 healthy control subjects. In comparison with the normal group, T-bet and IFN-γ mRNA expression levels were significantly up-regulated in the alopecia areata patients, while GATA-3 and IL-4 mRNA expression levels were down-regulated. Notably, positive correlation (P < 0.05) was found between IFN-γ and T-bet levels in patients and controls. In addition, significant positive correlations existed between GATA-3 and IL-4 (P < 0.05). These results indicate that a Th1/Th2 imbalance exists in alopecia areata, and it may be implicated in the pathogenesis of disease. PMID:26551570

  18. Inhibition of caspase-8 activity promotes protective Th1- and Th2-mediated immunity to Leishmania major infection

    PubMed Central

    Pereira-Manfro, Wânia F.; Ribeiro-Gomes, Flávia L.; Filardy, Alessandra Almeida; Vellozo, Natália S.; Guillermo, Landi V. C.; Silva, Elisabeth M.; Siegel, Richard M.; DosReis, George A.; Lopes, Marcela F.

    2014-01-01

    We investigated how apoptosis pathways mediated by death receptors and caspase-8 affect cytokine responses and immunity to Leishmania major parasites. Splenic CD4 T cells undergo activation-induced apoptosis, and blockade of FasL-Fas interaction increased IFN-γ and IL-4 cytokine responses to L. major antigens. To block death receptor-induced death, we used mice expressing a T cell-restricted transgene for vFLIP. Inhibition of caspase-8 activation in vFLIP mice enhanced Th1 and Th2 cytokine responses to L. major infection, even in the Th1-prone B6 background. We also observed increased NO production by splenocytes from vFLIP mice upon T cell activation. Despite an exacerbated Th2 response, vFLIP mice controlled better L. major infection, with reduced lesions and lower parasite loads compared with WT mice. Moreover, injection of anti-IL-4 mAb in infected vFLIP mice disrupted control of parasite infection. Therefore, blockade of caspase-8 activity in T cells improves immunity to L. major infection by promoting increased Th1 and Th2 responses. PMID:24072877

  19. Th1/Th2 cell dichotomy in acquired immunity to Bordetella pertussis: variables in the in vivo priming and in vitro cytokine detection techniques affect the classification of T-cell subsets as Th1, Th2 or Th0.

    PubMed Central

    Barnard, A; Mahon, B P; Watkins, J; Redhead, K; Mills, K H

    1996-01-01

    In studies of the mechanism of immunity to Bordetella pertussis in a murine respiratory infection model, we have previously demonstrated that natural infection of immunization with a whole cell vaccine induces a potent protective immune response, which is mediated by T-helper type-1 (Th1) cells. In contrast an acellular vaccine generates Th2 cells and is associated with delayed bacterial clearance following respiratory challenge. In the present study we have investigated the apparent Th1/Th2 cell dichotomy in acquired immunity and have examined the factors that affect their induction or detection. The cytokine profiles of B. pertussis-specific T cells in immune animals were determined using antigen-stimulated ex vivo spleen cells or CD4+ T-cell lines and clones established in the presence of interleukin-2 (IL-2) or IL-4. Antigen-specific T cells derived from mice immunized with the acellular vaccine were almost exclusively of the Th2 cell type. In contrast, T-cell lines and clones established following respiratory infection or immunization with the whole cell vaccine were predominantly of the Th1 type. However, a proportion of T cells from convalescent mice, especially when cultured in the presence of IL-4, secreted IL-4 and IL-5 with or without detectable IL-2 and interferon-gamma (IFN-gamma), suggesting that Th0 or Th2 cells were also primed during natural infection in vivo. Furthermore, when mice were assessed 6 months after infection, spleen cells produced significant levels of IL-4 and IL-5, which were not evident at 6 weeks. The route of immunization and the genetic background of the mice were also found to influence the preferential priming of Th1 cells, and this was directly related to the level of protection against respiratory or intracerebral (i.c.) challenge. Our findings underline the critical role of CD4+ Th1 cells in immunity to B. pertussis, but also demonstrate that a number of factors in the in vivo priming and in vitro restimulation can skew the

  20. Oral Administration of p-Hydroxycinnamic Acid Attenuates Atopic Dermatitis by Downregulating Th1 and Th2 Cytokine Production and Keratinocyte Activation

    PubMed Central

    Lee, Hyun-Su; Choi, Eun-Ju; Lee, Kyung-Sik; Kim, Hye-Ran; Na, Bo-Ra; Kwon, Min-Sung; Jeong, Gil-Saeng; Choi, Hyun Gyu; Choi, Eun Young; Jun, Chang-Duk

    2016-01-01

    Atopic dermatitis (AD) is a complex disease that is caused by various factors, including environmental change, genetic defects, and immune imbalance. We previously showed that p-hydroxycinnamic acid (HCA) isolated from the roots of Curcuma longa inhibits T-cell activation without inducing cell death. Here, we demonstrated that oral administration of HCA in a mouse model of ear AD attenuates the following local and systemic AD manifestations: ear thickening, immune-cell infiltration, production of AD-promoting immunoregulatory cytokines in ear tissues, increased spleen and draining lymph node size and weight, increased pro-inflammatory cytokine production by draining lymph nodes, and elevated serum immunoglobulin production. HCA treatment of CD4+ T cells in vitro suppressed their proliferation and differentiation into Th1 or Th2 and their Th1 and Th2 cytokine production. HCA treatment of keratinocytes lowered their production of the pro-inflammatory cytokines that drive either Th1 or Th2 responses in AD. Thus, HCA may be of therapeutic potential for AD as it acts by suppressing keratinocyte activation and downregulating T-cell differentiation and cytokine production. PMID:26959360

  1. Oral Administration of p-Hydroxycinnamic Acid Attenuates Atopic Dermatitis by Downregulating Th1 and Th2 Cytokine Production and Keratinocyte Activation.

    PubMed

    Lee, Hyun-Su; Choi, Eun-Ju; Lee, Kyung-Sik; Kim, Hye-Ran; Na, Bo-Ra; Kwon, Min-Sung; Jeong, Gil-Saeng; Choi, Hyun Gyu; Choi, Eun Young; Jun, Chang-Duk

    2016-01-01

    Atopic dermatitis (AD) is a complex disease that is caused by various factors, including environmental change, genetic defects, and immune imbalance. We previously showed that p-hydroxycinnamic acid (HCA) isolated from the roots of Curcuma longa inhibits T-cell activation without inducing cell death. Here, we demonstrated that oral administration of HCA in a mouse model of ear AD attenuates the following local and systemic AD manifestations: ear thickening, immune-cell infiltration, production of AD-promoting immunoregulatory cytokines in ear tissues, increased spleen and draining lymph node size and weight, increased pro-inflammatory cytokine production by draining lymph nodes, and elevated serum immunoglobulin production. HCA treatment of CD4+ T cells in vitro suppressed their proliferation and differentiation into Th1 or Th2 and their Th1 and Th2 cytokine production. HCA treatment of keratinocytes lowered their production of the pro-inflammatory cytokines that drive either Th1 or Th2 responses in AD. Thus, HCA may be of therapeutic potential for AD as it acts by suppressing keratinocyte activation and downregulating T-cell differentiation and cytokine production. PMID:26959360

  2. Enhancement of ovalbumin-specific Th1, Th2, and Th17 immune responses by amorphous silica nanoparticles.

    PubMed

    Toda, Tsuguto; Yoshino, Shin

    2016-09-01

    Nanomaterials present in cosmetics and food additives are used for industrial applications. However, their safety profile is unclear. Amorphous silica nanoparticles (nSPs) are a widely used nanomaterial and have been shown to induce inflammatory cytokines following intratracheal administration in mice. The current study investigated the adjuvant effect of nSP30 (nSP with a diameter of 33 nm) on T helper (Th)1, Th2, and Th17 immune responses as well as immunoglobulin (Ig) levels in mice. BALB/c mice were intraperitoneally administered ovalbumin (OVA) with or without varying doses and varying sizes of nSPs. The adjuvant effect of nSPs was investigated by measuring OVA-specific IgG antibodies in sera, OVA-specific proliferative responses of splenocytes, and the production of Th1, Th2, and Th17 cytokines. Aluminum hydroxide was used as a positive adjuvant control. Anti-OVA IgG production, splenocyte proliferative responses, and secretion of IFN-γ, IL-2, IL-4, IL-5, and IL-17 were increased significantly in mice receiving a combined injection of nSP30 (30 or 300 µg) with OVA compared with OVA alone or a combined injection with nSP30 (3 µg). The responses were nSP30 dose-dependent. When different sized nSPs were used (with 30, 100, and 1000 nm diameters), the responses to OVA were enhanced and were size-dependent. The smaller sized nSP particles had a greater adjuvant effect. nSPs appear to exert a size-dependent adjuvant effect for Th1, Th2, and Th17 immune responses. Understanding the mechanisms of nSP adjuvanticity might lead to the development of novel vaccine adjuvants and therapies for allergic diseases caused by environmental factors. PMID:27343242

  3. Notch-ligand expression by NALT dendritic cells regulates mucosal Th1- and Th2-type responses

    SciTech Connect

    Fukuyama, Yoshiko; Tokuhara, Daisuke; Sekine, Shinichi; Kataoka, Kosuke; Markham, Jonathan D.; Irwin, Allyson R.; Moon, Grace H.; Tokuhara, Yuka; Fujihashi, Keiko; Davydova, Julia; Yamamoto, Masato; Gilbert, Rebekah S.; Fujihashi, Kohtaro

    2012-02-03

    Highlights: Black-Right-Pointing-Pointer Nasal Ad-FL effectively up-regulates APC function by CD11c{sup +} DCs in mucosal tissues. Black-Right-Pointing-Pointer Nasal Ad-FL induces Notch ligand (L)-expressing CD11c{sup +} DCs. Black-Right-Pointing-Pointer Notch L-expressing DCs support the induction of Th1- and Th2-type cytokine responses. -- Abstract: Our previous studies showed that an adenovirus (Ad) serotype 5 vector expressing Flt3 ligand (Ad-FL) as nasal adjuvant activates CD11c{sup +} dendritic cells (DCs) for the enhancement of antigen (Ag)-specific IgA antibody (Ab) responses. In this study, we examined the molecular mechanism for activation of CD11c{sup +} DCs and their roles in induction of Ag-specific Th1- and Th2-cell responses. Ad-FL activated CD11c{sup +} DCs expressed increased levels of the Notch ligand (L)-expression and specific mRNA. When CD11c{sup +} DCs from various mucosal and systemic lymphoid tissues of mice given nasal OVA plus Ad-FL were cultured with CD4{sup +} T cells isolated from non-immunized OVA TCR-transgenic (OT II) mice, significantly increased levels of T cell proliferative responses were noted. Furthermore, Ad-FL activated DCs induced IFN-{gamma}, IL-2 and IL-4 producing CD4{sup +} T cells. Of importance, these APC functions by Ad-FL activated DCs were down-regulated by blocking Notch-Notch-L pathway. These results show that Ad-FL induces CD11c{sup +} DCs to the express Notch-ligands and these activated DCs regulate the induction of Ag-specific Th1- and Th2-type cytokine responses.

  4. Sequential production of Th1 and Th2 cytokines in response to live bacillus Calmette-Guérin.

    PubMed Central

    Sander, B; Skansén-Saphir, U; Damm, O; Håkansson, L; Andersson, J; Andersson, U

    1995-01-01

    Causes of individual variation in susceptibility to mycobacterial diseases are only partly understood. An efficient cell-mediated immune response is crucial for resistance. Macrophages and T cells interact to eliminate the mycobacteria, partially through the effects of secreted cytokines. A vigorous anti-bacterial inflammatory response is sometimes accompanied by severe tissue damage, while immunosuppression leads to progressive infection. Here, live, attenuated Mycobacterium bovis, bacillus Calmette-Guérin (BCG), was used as a model antigen to study cytokine production at the single-cell level in response to mycobacteria. Peripheral blood mononuclear cells from healthy individuals were challenged in vitro and the kinetics and frequencies of cytokine-producing cells were studied by immunofluorescent visualization of intracellular cytokines. Fourteen cytokines were assayed; interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-1 receptor antagonist (IL-1ra), IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha), TNF-beta and granulocyte-macrophage colony-stimulating factor (GM-CSF). A sequential production of T helper-1 (Th1) and T helper-2 (Th2) cytokines was induced by BCG. Early, at days 1-2 after stimulation, the response was dominated by monokines and a low IFN-gamma and TNF-beta production. At days 4-5 there was a marked production of Th1 lymphokines, with approximately 6% IFN-gamma+ cells, 4% TNF-beta+ cells and 2% IL-2+ cells. Late in the reaction, at days 10-12, a Th2 response with IL-4, IL-5 and IL-10 was detected, while the synthesis of Th1 lymphokines and monokines declined. Overall, our results provide further evidence of IFN-gamma as the major cytokine induced by mycobacteria in healthy individuals, but also suggest that Th2 cytokines participate in the response. Images Figure 1 Figure 2 Figure 3 PMID:8567014

  5. Effect of murine exposure to gamma rays on the interplay between Th1 and Th2 lymphocytes.

    PubMed

    Ghazy, Amany A; Abu El-Nazar, Salma Y; Ghoneim, Hossam E; Taha, Abdul-Rahman M; Abouelella, Amira M

    2015-01-01

    Gamma radiation radiotherapy is one of the widely used treatments for cancer. There is an accumulating evidence that adaptive immunity is significantly contributes to the efficacy of radiotherapy. This study is carried out to investigate the effect of gamma rays on the interplay between Th1/Th2 response, splenocyte lymphoproliferative response to polyclonal mitogenic activators and lymphocytic capacity to produce IL-12 and IL-10 in mice. Results showed that exposure of intact spleens to different doses of γ-rays (5, 10, 20 Gy) caused spontaneous and dose-dependent immune stimulation manifested by enhanced cell proliferation and elevated IL-12 production with decreased IL-10 release (i.e., Th1 bias). While exposure of splenocytes suspension to different doses of γ-rays (5, 10, 20 Gy) showed activation in splenocytes stimulated by PWM at 5 Gy then a state of conventional immune suppression that is characterized by being dose-dependent and is manifested by decreased cell proliferation and IL-12 release accompanied by increase in IL-10 production (i.e., Th2 bias). In addition, we investigated the exposure of whole murine bodies to different doses of γ-rays and found that the exposure to low dose γ-rays (0.2 Gy) caused a state of immune stimulation terminated by a remarkable tendency for immune suppression. Exposure to 5 or 10 Gy of γ-rays resulted in a state of immune stimulation (Th1 bias), but exposure to 20 Gy showed a standard state of immune suppression (Th2 bias). The results indicated that apparently we can control the immune response by controlling the dose of γ-rays. PMID:25914644

  6. TH1 and TH2 responses are influenced by HLA antigens in healthy neonates vaccinated with recombinant hepatitis B vaccine.

    PubMed

    Jafarzadeh, Abdollah; Shokri, Fazel

    2012-12-01

    The immune response to hepatitis B surface antigen (HBsAg) is influenced by several factors, of which HLA antigens and balanced secretion of Th1/Th2 cytokines play important roles. The aim of this study was to evaluate the influence of HLA antigens on cytokine secretion by HBsAg-stimulated peripheral blood mononuclear cells (PBMC) from healthy neonates vaccinated with recombinant HBsAg. PBMCs were isolated from 48 Iranian neonates vaccinated with a recombinant HBV vaccine. The cells were stimulated in vitro with rHBsAg and the concentration of IL-4, IL-10, IL-12 and IFN-γ were quantitated in culture supernatant by sandwich ELISA. HLA typing was performed by microlymphocytotoxicity method. Significant diminished secretion of both Th1 (IFN-γ) and Th2 (IL-4, IL-10) cytokines was observed in HBsAg-stimulated PBMC from vaccinees expressing the HLA-DR7 compared to DR7 negative vaccinees. Similarly, lower production of these cytokines was also observed in vaccinees with DR7-DR53-DQ2, B7-DR7-DR53-DQ2 and A2-DR7-DR53-DQ2 haplotypes (p<0.05, p <0.005). While HBsAg-stimulated PBMC of DR13+ subjects produced lower levels of Th2-type cytokines (IL-4 and IL-10), those of HLA-B8+ or HLA-A9+ subjects produced higher levels of Th2-type cytokines. Cytokine secretion in response to PHA mitogen was not associated with a given HLA antigen or haplotype and was similarly represented in all groups of subjects irrespective of their HLA complex. These results indicate that HLA antigens may differentially influence cytokine secretion by HBsAg-specific T-cells of healthy neonates vaccinated with recombinant HB vaccine. This phenomenon may have an important implication for control of the immune response to HBsAg vaccine. PMID:23264407

  7. Th1/Th2 cytokines and their genotypes as predictors of hepatitis B virus related hepatocellular carcinoma

    PubMed Central

    Saxena, Roli; Kaur, Jyotdeep

    2015-01-01

    Hepatocellular carcinoma (HCC), the predominant type of primary liver cancer, is one of the most serious life-threatening malignancies, worldwide. In majority of the cases, HCC develops after prolonged and persistent chronic liver disease. hepatitis B virus (HBV) or HCV infection is prominent etiological factors, attributing to this condition. It has been well documented that HBV, being the inducer of chronic inflammation, is the main causative agent in causing HCC, particularly in Asian countries. The HBV infection leads to a wide range of clinical symptoms from carrier state to malignancy. Cytokines being immune-modulatory molecules, are the key mediators in the defense mechanism against viral infection. In this regard, this review will detail the substantial role of key Th1: interleukin 1 (IL-1), IL-2, IL-12, tumor necrosis factor-α, interferon-γ; Th2: IL-4, IL-10 and non Th1/Th2: IL-6, transforming growth factor-β1 cytokines genotypes in analyzing the variability in the clinical manifestations in an HBV-afflicted individual, which might finally, culminates into HCC. Since cytokine production is regulated genetically, the cytokine promoter region single-nucleotide polymorphisms induced changes, greatly affects the cytokine production, thus resulting into differential outcome of immune balance. PMID:26085916

  8. Myrrh and artesunate modulate some Th1 and Th2 cytokines secretion in Schistosoma mansoni infected mice

    PubMed Central

    Abdelaziz, Mohamed M.

    2016-01-01

    The effects of artesunate and myrrh on S. mansoni infection and the levels of some Th1 and Th2 cytokines were evaluated in the present study. Six weeks after infection, a group of mice was treated with 4 mg/kg of artesunate and other group was treated with 10 mg/kg of myrrh for 3 successive days. Worm burden was reduced with a percentage of 53.7% and 58.78% after treatment with myrrh and artesunate respectively as well as the levels of IgG antibodies were significantly reduced compared with infected group. No obvious changes were observed in the level of interferon γ after treatment. After treatment with artesunate, interleukin 2 (IL-2) level was significantly decreased, while no significant difference was observed in myrrh-treated group compared with the infected group. On the other hand, the level of IL-10 was not significantly decreased after treatment with artesunate, but it was significantly increased after treatment with myrrh. However, IL-12 levels were significantly decreased after treatment with artesunate. The results demonstrated that, artesunate or myrrh treatment could give a level of protection against S. mansoni infection and modulate the levels of some Th1 and Th2 cytokines in mice infected with S. mansoni. PMID:27536198

  9. UVB irradiation decreases the magnitude of the Th1 response to hapten but does not increase the Th2 response.

    PubMed

    Saijo, S; Kodari, E; Kripke, M L; Strickland, F M

    1996-08-01

    Exposure of murine skin to low doses of ultraviolet-B (UVB) radiation before sensitization with hapten reduces the ability of antigen presenting cells (APC) in the draining lymph nodes to initiate contact hypersensitivity responses in vivo and results in the induction of hapten-specific suppressor T cells. In the present study, we tested the hypothesis that exposure of skin to UVB radiation suppresses T cell responses to hapten in vivo by altering the functions of APC, resulting in decreased stimulation of Th1 lymphocytes, which mediate contact hypersensitivity responses, and preferential activation of Th2 cells. C3H/HeN mice were exposed to either a single 2 kJ/m2 dose of UVB or to 400 J/m2 of UVB daily from FS40 sunlamps for four consecutive days and sensitized with fluorescein isothiocyanate on UV-irradiated skin. Draining lymph node cells were collected 18 h after sensitization and co-cultured with nylon wool-purified T cells from naive or fluorescein-immunized mice. Unseparated lymph node cells or sorter-purified fluorescein-bearing APC from UV-irradiated mice induced less T cell proliferation than APC from non-UV-exposed mice. Lymph node cells produced less Th1 and Th2-associated cytokines, interferon-gamma and interleukin-4, respectively, in response to APC from UV-irradiated animals compared with APC from unirradiated, fluorescein-sensitized mice. Thus, low doses of UV radiation do not result in preferential stimulation of Th2 response in lymph nodes, and results from cloned cell lines may incompletely reflect T cell responses in vivo. PMID:9017790

  10. Zerumbone enhances the Th1 response and ameliorates ovalbumin-induced Th2 responses and airway inflammation in mice.

    PubMed

    Shieh, Ying-Hua; Huang, Huei-Mei; Wang, Ching-Chiung; Lee, Chen-Chen; Fan, Chia-Kwung; Lee, Yueh-Lun

    2015-02-01

    Zerumbone is a sesquiterpene compound isolated from the rhizome of wild ginger, Zingiber zerumbet Smith. The rhizomes of the plant are used as a spice and traditional medicine. Zerumbone was shown to possess anticarcinogenic, anti-inflammatory, and antioxidant properties. However, the antiallergic activity and the underlying mechanism of zerumbone have not been reported. Herein, we investigated the immunomodulatory effects of zerumbone on antigen-presenting dendritic cells (DCs) in vitro and its potential therapeutic effects against ovalbumin (OVA)-induced T helper 2 (Th2)-mediated asthma in mice. In the presence of zerumbone, lipopolysaccharide-activated bone marrow-derived DCs enhanced T cell proliferation and Th1 cell polarization in an allogeneic mixed lymphocyte reaction. In animal experiments, mice were sensitized and challenged with OVA, and were orally treated with different doses of zerumbone after sensitization. Circulating titers of OVA-specific antibodies, airway hyperresponsiveness to methacholine, histological changes in lung tissues, the cell composition and cytokine levels in bronchoalveolar lavage fluid, and cytokine profiles of spleen cells were assessed. Compared to OVA-induced hallmarks of asthma, oral administration of zerumbone induced lower OVA-specific immunoglobulin E (IgE) and higher IgG2a antibody production, attenuated airway hyperresponsiveness, prevented eosinophilic pulmonary infiltration, and ameliorated mucus hypersecretion. Zerumbone treatment also reduced the production of eotaxin, keratinocyte-derived chemokine (KC), interleukin (IL)-4, IL-5, IL-10, and IL-13, and promoted Th1 cytokine interferon (IFN)-γ production in asthmatic mice. Taken together, these results suggest that zerumbone exhibits an antiallergic effect via modulation of Th1/Th2 cytokines in an asthmatic mouse model. PMID:25573403

  11. Silencing c-Kit expression in human DCs suppresses Th2, Th17 response but enhances Th1 response

    PubMed Central

    Yang, Bin; Yang, Qin; Huang, Qianchuan; Yan, Hongbo; Sun, Ting; Tong, Hui

    2015-01-01

    Dendritic cells (DCs) are integral to the differentiation of T helper cells into T helper type 1 TH1, TH2 and TH17 subsets. RNA interference (RNAi), which causes the degradation of any RNA in a sequence specific manner, is a posttranscriptional gene silencing mechanism. Targeting the c-Kit in DCs has been used as an approach to enhance antitumor immunity. Here, we shwed that transfection of DCs with siRNA specific for c-Kit gene can significantly knock down c-Kit. When exposed to TNF-α, immature DCs transfected with c-Kit siRNA can differentiate into mature DCs without reducing viability or IL-12p70 production. The c-Kit siRNA-treated DCs exhibited an increased allostimulatory capacity in a lymphocyte proliferation assay. Furthermore, c-Kit siRNA-transfected DCs enhanced TH1 responses by increasing IFN-γ and decreasing IL-4 production, and much stronger cytotoxic activity was observed when DCs were co-transfected with c-Kit siRNA and an endogenous tumor antigen in vitro. Our findings indicate that silencing the c-Kit gene in DCs with siRNA may offer a potential approach to enhance antitumor immunotherapy. PMID:26550451

  12. RhIL-11 treatment normalized Th1/Th2 and T-bet/GATA-3 imbalance in in human immune thrombocytopenic purpura (ITP).

    PubMed

    Lin, Ying; Zhou, Xieming; Guo, Wenjian; Li, Qianqian; Pan, Xiahui; Bao, Yunhua; He, Muqing; Zhu, Baoling; Lin, Xiaoji; Jin, Limin; Yao, Rongxin

    2016-09-01

    Immune thrombocytopenia (ITP) is an autoimmune hemorrhagic disorder characterized by reduction in platelet counts. T helper 1 (Th1) cells polarization with an increased shift of Th1/Th2 ratio has been reported in ITP. This shift is associated with transcription factor T-box expressed in T cells (T-bet) upregulation and GATA-binding protein 3 (GATA-3) downregulation, leading to an increased T-bet/GATA-3 ratio. Our previous in vitro study showed that recombinant human interleukin-11 (rhIL-11) could normalize Th1/Th2 imbalance in the peripheral blood mononuclear cells (PBMCs) isolated from adult ITP patients, which co-occurred with T-bet/GATA-3 ratio restoration. In this report, we investigated whether rhIL-11 had therapeutic effect in clinical ITP patients and whether rhIL-11 treatment could normalize Th1/Th2 and T-bet/GATA-3 levels in vivo. We found rhIL-11 treatment had a response rate of 67.7% and significantly decreased Th1 and T-bet levels but increased Th2 and GATA-3 levels in ITP patients who showed good response, normalizing Th1/Th2 and T-bet/GATA-3 ratios similar to that in healthy controls. Thus our study suggested rhIL-11 was effective with tolerable adverse effects in ITP. The treatment strategy warrants further clinical investigation. PMID:27235596

  13. Long-chain polyunsaturated fatty acids are consumed during allergic inflammation and affect T helper type 1 (Th1)- and Th2-mediated hypersensitivity differently.

    PubMed

    Johansson, S; Lönnqvist, A; Ostman, S; Sandberg, A-S; Wold, A E

    2010-06-01

    Studies have shown that atopic individuals have decreased serum levels of n-3 fatty acids. Indicating these compounds may have a protective effect against allergic reaction and/or are consumed during inflammation. This study investigated whether fish (n-3) or sunflower (n-6) oil supplementation affected T helper type 1 (Th1)- and Th2-mediated hypersensitivity in the skin and airways, respectively, and whether the fatty acid serum profile changed during the inflammatory response. Mice were fed regular chow, chow + 10% fish oil or chow + 10% sunflower oil. Mice were immunized with ovalbumin (OVA) resolved in Th1 or Th2 adjuvant. For Th1 hypersensitivity, mice were challenged with OVA in the footpad. Footpad swelling, OVA-induced lymphocyte proliferation and cytokine production in the draining lymph node were evaluated. In the airway hypersensitivity model (Th2), mice were challenged intranasally with OVA and the resulting serum immunoglobulin (Ig)E and eosinophilic lung infiltration were measured. In the Th1 model, OVA-specific T cells proliferated less and produced less interferon (IFN)-gamma, tumour necrosis factor (TNF) and interleukin (IL)-6 in fish oil-fed mice versus controls. Footpad swelling was reduced marginally. In contrast, mice fed fish oil in the Th2 model produced more OVA-specific IgE and had slightly higher proportions of eosinophils in lung infiltrate. A significant fall in serum levels of long-chain n-3 fatty acids accompanied challenge and Th2-mediated inflammation in Th2 model. Fish oil supplementation affects Th1 and Th2 immune responses conversely; significant consumption of n-3 fatty acids occurs during Th2-driven inflammation. The latter observation may explain the association between Th2-mediated inflammation and low serum levels of n-3 fatty acids. PMID:20148912

  14. Correlation between the kinetics of Th1, Th2 cells and pathology in a murine model of experimental pulmonary tuberculosis.

    PubMed Central

    Hernández-Pando, R; Orozcoe, H; Sampieri, A; Pavón, L; Velasquillo, C; Larriva-Sahd, J; Alcocer, J M; Madrid, M V

    1996-01-01

    T-helper 1 (Th1) Th2 kinetics were studied by immunohistochemistry and molecular biology techniques (reverse transcriptase polymerase chain reaction. RT PCR, Southern-blot) during the course of pulmonary tuberculosis induced in BALB/c mice by the intratracheal instillation of the live and virulent strain H-37Rv. The histopathological study clearly showed two phases of the disease. The first one was an acute phase which was characterized by inflammatory infiltrate in the alveolar capillary interstitium, blood vessel and bronchial wall with formation of granulomas. In this acute phase which lasted from 1 to 28 days, a clear predominance of Th1 cells was observed, manifested by a high percentage of interleukin-2 (IL-2) positive cells in the inflammatory infiltrate and granulomas demonstrated by immunohistology, as well as a gradual increment of interferon-gamma (INF-gamma) m-RNA. This was followed by a chronic or advanced phase characterized by pneumonia, focal necrosis and fibrosis, with a Th0 balance due to an equivalent proportion of IL-2 and IL-4 positive cells in the lung lesions, that coincided with the highest level of INF-gamma and IL-4 mRNA. The cytofluorometric analysis of bronchial lavage cells, showed a predominance of CD4 T cells during the acute phase and CD8 T lymphocytes in the chronic phase, gamma-delta T lymphocytes showed two peaks, at the beginning (3 days) and at the end (4 months) of the infection. These results suggest that T-lymphocyte subset kinetics and the pattern of cytokines produced in the lung during tuberculosis infection changed over time and correlate with the type and magnitude of tissue injury. Images Figure 1 Figure 3 Figure 5 PMID:8911136

  15. Evaluation of Th1/Th2-Related Immune Response against Recombinant Proteins of Brucella abortus Infection in Mice.

    PubMed

    Im, Young Bin; Park, Woo Bin; Jung, Myunghwan; Kim, Suk; Yoo, Han Sang

    2016-06-28

    Brucellosis is a zoonotic disease caused by Brucella, a genus of gram-negative bacteria. Cytokines have key roles in the activation of innate and acquired immunities. Despite several research attempts to reveal the immune responses, the mechanism of Brucella infection remains unclear. Therefore, immune responses were analyzed in mice immunized with nine recombinant proteins. Cytokine production profiles were analyzed in the RAW 264.7 cells and naive splenocytes after stimulation with three recombinant proteins, metal-dependent hydrolase (r0628), bacterioferritin (rBfr), and thiamine transporter substrate-binding protein (rTbpA). Immune responses were analyzed by ELISA and ELISpot assay after immunization with proteins in mice. The production levels of NO, TNF-α, and IL-6 were time-dependently increased after having been stimulated with proteins in the RAW 264.7 cells. In naive splenocytes, the production of IFN-γ and IL-2 was increased after stimulation with the proteins. It was concluded that two recombinant proteins, r0628 and rTbpA, showed strong immunogenicity that was induced with Th1-related cytokines IFN-γ, IL-2, and TNF-α more than Th2-related cytokines IL-6, IL-4, and IL-5 in vitro. Conversely, a humoral immune response was activated by increasing the number of antigen-secreting cells specifically. Furthermore, these could be candidate diagnosis antigens for better understanding of brucellosis. PMID:27012238

  16. Anti-inflammatory effects of 27 selected terpenoid compounds tested through modulating Th1/Th2 cytokine secretion profiles using murine primary splenocytes.

    PubMed

    Ku, Chi-Mei; Lin, Jin-Yuarn

    2013-11-15

    This study investigated 27 selected terpenoid compounds, including 8 monoterpenoids, 7 sesqui-terpenoids, 3 di-terpenoids, 8 tri-terpenoids, and 1 tetra-terpenoid, for their Th1/Th2 immunomodulatory potential using mouse primary splenocytes. Changes in Th1 cytokines, including interleukin (IL)-2 and interferon (IFN)-γ, and Th2 cytokines, including IL-4, IL-5 and IL-10, secreted by terpenoid-treated splenocytes were measured using the ELISA method. The results showed that triptolide, a diterpenoid, was most cytotoxic, reflecting an IC50 value of 46nM. Eucalyptol, limonene, linalool, thymol, parthenolide, andrographolide, 18β-glycyrrhetinic acid, lupeol, ursolic acid and β-sitosterol showed a strong Th2-inclination and anti-inflammation potential in vitro. In addition, (-)-trans-caryophyllene, oridonin, triptolide, diosgenin, betulinic acid, escin, and β-sitosterol treatments significantly inhibited both IL-2 (Th1) and IL-10 (Th2) cytokine production at the same time, suggesting that these terpenoid compounds have an anti-inflammation potential through the inhibition of T-cell immune responses. Diosgenin treatments significantly increased IFN-γ secretion levels using mouse splenocytes, suggesting that diosgenin may be useful in treating a viral infection through the stimulation of IFN-γ production. Menthone, farnesol and oridonin treatments did not markedly increase IL-10/IL-2 (Th2/Th1) cytokine secretion ratios, suggesting that menthone, farnesol and oridonin may have a relative Th1-inclination property, compared to the other selected terpenoid compounds. The relative Th1-inclination property of menthone, farnesol and oridonin may be applied to improve Th2-skewed allergic diseases. PMID:23790892

  17. Multiparameter fluorescence imaging for quantification of TH-1 and TH-2 cytokines at the single-cell level

    NASA Astrophysics Data System (ADS)

    Fekkar, Hakim; Benbernou, N.; Esnault, S.; Shin, H. C.; Guenounou, Moncef

    1998-04-01

    Immune responses are strongly influenced by the cytokines following antigenic stimulation. Distinct cytokine-producing T cell subsets are well known to play a major role in immune responses and to be differentially regulated during immunological disorders, although the characterization and quantification of the TH-1/TH-2 cytokine pattern in T cells remained not clearly defined. Expression of cytokines by T lymphocytes is a highly balanced process, involving stimulatory and inhibitory intracellular signaling pathways. The aim of this study was (1) to quantify the cytokine expression in T cells at the single cell level using optical imaging, (2) and to analyze the influence of cyclic AMP- dependent signal transduction pathway in the balance between the TH-1 and TH-2 cytokine profile. We attempted to study several cytokines (IL-2, IFN-(gamma) , IL-4, IL-10 and IL-13) in peripheral blood mononuclear cells. Cells were prestimulated in vitro using phytohemagglutinin and phorbol ester for 36h, and then further cultured for 8h in the presence of monensin. Cells were permeabilized and then simple-, double- or triple-labeled with the corresponding specific fluorescent monoclonal antibodies. The cell phenotype was also determined by analyzing the expression of each of CD4, CD8, CD45RO and CD45RA with the cytokine expression. Conventional images of cells were recorded with a Peltier- cooled CCD camera (B/W C5985, Hamamatsu photonics) through an inverted microscope equipped with epi-fluorescence (Diaphot 300, Nikon). Images were digitalized using an acquisition video interface (Oculus TCX Coreco) in 762 by 570 pixels coded in 8 bits (256 gray levels), and analyzed thereafter in an IBM PC computer based on an intel pentium processor with an adequate software (Visilog 4, Noesis). The first image processing step is the extraction of cell areas using an edge detection and a binary thresholding method. In order to reduce the background noise of fluorescence, we performed an opening

  18. Cutaneous, Purpuric Painful Nodules Upon Addition of Ibrutinib to RCVP Therapy in a CLL Patient: A Distinctive Reaction Pattern Reflecting Iatrogenic Th2 to Th1 Milieu Reversal.

    PubMed

    Mulvey, Joseph Justin; Nuovo, Gerard J; Magro, Cynthia M

    2016-07-01

    A 70-year-old white man with stage C chronic lymphocytic leukemia who was being successfully treated with ibrutinib and rituximab developed bilateral, purpuric, painful cutaneous nodules. Biopsies of these nodules did not reveal the usual Th2 milieu of chronic lymphocytic leukemia but instead exhibited a Th1-rich lymphocytic infiltrate with resultant neutrophil and granulomatous inflammation. The eruption resolved with drug cessation emphasizing the potential importance of this drug in treating conditions associated with Th2 dysregulation. PMID:27043332

  19. IL-1 family members IL-18 and IL-33 upregulate the inflammatory potential of differentiated human Th1 and Th2 cultures.

    PubMed

    Blom, Lars; Poulsen, Lars K

    2012-11-01

    The IL-1 family members IL-1β, IL-18, and IL-33 are potent cytokines in relationship to amplifying the CD4(+) T cell cytokine production. To evaluate their impact on in vitro-differentiated human Th1 and Th2 cultures, such cultures were established from naive T cells, purified from healthy blood donors, and reactivated in the presence of IL-1β, IL-18, or IL-33. Interestingly, we observe modifying responses in Th1 and Th2 cultures induced by IL-18 or IL-33 but not by IL-1β, both contributing to amplify production of IL-5, IL-13, and IFN-γ. IL-18 or IL-33 stimulation of Th1 cultures resulted in increased IFN-γ and IL-13 production concurrent with reduced IL-10 gene transcription and secretion even though Th1 cultures, in contrast to IL-18Rα, had low ST2L expression. Furthermore, adding IL-18 to Th1 cultures promoted Tbet mRNA expression and production. Th2 cultures stimulated with IL-18 or IL-33 had an increased IL-5 secretion. Interestingly, E4BP4 gene expression and the percentage of E4BP4(+) cells of the recently shown IL-10 transcriptional regulator E4BP4 correlated with IL-10 gene expression and protein secretion in Th1 cultures. Taken together, we report that the IL-1 family "alarmins" IL-18 and IL-33 in addition to amplifying both Th1- and Th2-associated cytokines block production of the regulatory cytokine IL-10 in Th1 cultures. PMID:23028054

  20. Streptococcus pneumoniae fructose-1,6-bisphosphate aldolase, a protein vaccine candidate, elicits Th1/Th2/Th17-type cytokine responses in mice.

    PubMed

    Elhaik Goldman, Shirin; Dotan, Shahar; Talias, Amir; Lilo, Amit; Azriel, Shalhevet; Malka, Itay; Portnoi, Maxim; Ohayon, Ariel; Kafka, Daniel; Ellis, Ronald; Elkabets, Moshe; Porgador, Angel; Levin, Ditza; Azhari, Rosa; Swiatlo, Edwin; Ling, Eduard; Feldman, Galia; Tal, Michael; Dagan, Ron; Mizrachi Nebenzahl, Yaffa

    2016-04-01

    Streptococcus pneumoniae (S. pneumoniae) is a major pathogen worldwide. The currently available polysaccharide-based vaccines significantly reduce morbidity and mortality. However, the inherent disadvantages of the currently available polysaccharide-based vaccines have motivated the search for other bacterial immunogens capable of eliciting a protective immune response against S. pneumoniae. Fructose-1,6-bisphosphate aldolase (FBA) is a glycolytic enzyme, which was found to localize to the bacterial surface, where it functions as an adhesin. Previously, immunizing mice with recombinant FBA (rFBA) in the presence of alum elicited a protective immune response against a lethal challenge with S. pneumoniae. Thus, the aim of the present study was to determine the cytokine responses that are indicative of protective immunity following immunization with rFBA. The protective effects against pneumococcal challenge in mice immunized with rFBA with complete Freund's adjuvant (CFA) in the initial immunization and with incomplete Freund's adjuvant (IFA) in booster immunizations surpassed the protective effects observed following immunization with either rFBA + alum or pVACfba. CD4+ T-cells obtained from the rFBA/CFA/IFA/IFA-immunized mice co-cultured with rFBA-pulsed antigen-presenting cells (APCs), exhibited a significantly greater proliferative ability than CD4+ T-cells obtained from the adjuvant-immunized mice co-cultured with rFBA‑pulsed APCs. The levels of the Th1-type cytokines, interferon (IFN)-γ, interleukin (IL)-2, tumor necrosis factor (TNF)-α and IL-12, the Th2-type cytokines, IL-4, IL-5 and IL-10, and the Th17-type cytokine, IL-17A, significantly increased within 72 h of the initiation of co-culture with CD4+ T-cells obtained from the rFBA‑immunized mice, in comparison with the co-cultures with CD4+ T-cells obtained from the adjuvant-immunized mice. Immunizing mice with rFBA resulted in an IgG1/IgG2 ratio of 41, indicating a Th2 response with substantial Th1

  1. The Th1/Th2 cytokine balance changes with the progress of the immunopathological lesion of Sjogren’s syndrome

    PubMed Central

    MITSIAS, D I; TZIOUFAS, A G; VEIOPOULOU, C; ZINTZARAS, E; TASSIOS, I K; KOGOPOULOU, O; MOUTSOPOULOS, H M; THYPHRONITIS, G

    2002-01-01

    Expression of type-1 and type-2 cytokines at the mRNA level in labial salivary glands (LSG) of patients with Sjogren’s syndrome (SS), as reported by several groups, have generated conflicting results. In the present study we have directly examined the production of IL-4, IL-13 and IFN-γ by lymphocytes infiltrating the LSG of 44 consecutive patients referred for SS evaluation. Cytokines production was evaluated following in vitro culture of LSG in the presence of IL-2. IFN-γ and IL-13 were detected in the majority of SN (24/44 and 26/44, respectively) while IL-4 was present in 5/44 SN. The presence of IFN-γ was significantly higher in SS patients, as opposed to patients who did not fulfil the criteria for SS (P < 0·01). In addition, almost all cultured lymphocytes expressed mRNA for IFN-γ (17/19 cultures) and IL-13 (18/19) while IL-4 mRNA was also expressed at high frequency (14/19 cultures). Interestingly, the IFN-γ mRNA copies in cultured lymphocytes correlated significantly with the intensity of lymphocytic infiltration as evaluated by Chisholm’s score (P < 0·01). Furthermore, RT-PCR of RNA extracted from whole LSG from 14 SS patients also demonstrated the presence of all cytokines in the majority of the cases and the prevalence of IFN-γ in LSG with high-grade infiltration. Because IL-13 was produced by the majority of the cultured LSG, IgE production was also evaluated. Interestingly, IgE was detected in 21/44 LSG culture SN and mainly in those biopsies that had Chisholm’s score less than 0·5 (P < 0·05). We conclude that lymphocytes infiltrating the LSG are capable of producing both Th1 and Th2 cytokines and that the balance between them shifts in favour of Th1 in LSG with high infiltration score and in patients with SS. PMID:12067313

  2. Upregulation of Tim-3 on CD4+ T cells is associated with Th1/Th2 imbalance in patients with allergic asthma

    PubMed Central

    Tang, Fei; Wang, Fukun; An, Liyun; Wang, Xianling

    2015-01-01

    T cell Ig and mucin domain-containing molecule-3 (Tim-3) is a negative regulator preferentially expressed on Th1 cells. Allergic asthma is a clinical syndrome well characterized by Th1/Th2 imbalance. To investigate the role of Tim-3 in the pathogenesis of asthma and its relationship with Th1/Th2 imbalance, a total of 40 patients with allergic asthma and 40 healthy controls were enrolled. Expression of Tim-3 and Th1/Th2 imbalance as well as the relationship between them was analyzed by flow cytometry and real-time PCR. Peripheral blood mononuclear cells (PBMCs) were cultured in vitro and anti-Tim-3 was used to block Tim-3 signaling; Th1/Th2 cytokines in the culture supernatant were detected by enzyme linked immunosorbent assay (ELISA). CD4+ T cells and B cells were sorted and co-cultured in vitro, and anti-Tim-3 was used to block Tim-3 signaling; Total IgG/IgE in the culture supernatant was detected by ELISA. The mRNA level of T-bet and IFN-γ were significantly decreased in allergic asthma patients, while GATA-3 and IL-4 were significantly increased. Expression of Tim-3 on CD4+ T cells was much higher in allergic asthma patients and it was negatively correlated with T-bet/GATA-3 ratio or IFN-γ/IL-4 ratio. Blocking of Tim-3 significantly increased Th1 cytokines (TNF-α and IFN-γ) and decreased Th2 cytokines (IL-4, IL-5, IL-13) in the culture supernatant of PBMCs. Blocking of Tim-3 dramatically reduced the production of IgG and IgE in the co-culture supernatant of CD4+ T cells and B cells. In conclusion, Tim-3 was up-regulated in allergic asthma patients and related with the Th1/Th2 imbalance. Blocking of Tim-3 may be of therapeutic benefit by enhancing the Th1 cytokines response, down-regulating the Th2 cytokines response, and reducing IgG/IgE production. PMID:26064278

  3. TLR ligands of ryegrass pollen microbial contaminants enhance Th1 and Th2 responses and decrease induction of Foxp3(hi) regulatory T cells.

    PubMed

    Mittag, Diana; Varese, Nirupama; Scholzen, Anja; Mansell, Ashley; Barker, Gillian; Rice, Gregory; Rolland, Jennifer M; O'Hehir, Robyn E

    2013-03-01

    Microbial contamination of grass pollens could affect sensitization, subsequent allergic response, and efficacy of allergen-specific immunotherapy. We investigated whether bacterial immunomodulatory substances can direct PBMC responses of allergic and nonatopic subjects against ryegrass pollen (RGP) toward Th1, Th2, or regulatory T (Treg) cells. Aqueous extracts of RGP with high or low LPS were fractionated into large and small molecular weight (MW) components by diafiltration. CFSE-labeled PBMCs from allergic and nonatopic subjects were stimulated with RGP extracts (RGPEs) and analyzed for cytokine secretion and T-cell responses. High LPS RGPE increased IFN-γ(+) Th1 and IL-4(+) Th2 effector cell induction and consistently decreased CD4(+) Foxp3(hi) Treg-cell induction. IL-10-producing T-cell frequency was unaltered, but IL-10 secretion was increased by high LPS RGPE. RGPE-stimulation of TLR-transfected cell lines revealed that high LPS pollen also contained a TLR2-ligand, and both batches a TLR9-ligand. Beta-1,3-glucans were detected in large and small MW fractions and were also T-cell stimulatory. In conclusion, coexposure to allergen and proinflammatory microbial stimuli does not convert an established Th2- into a Th1-response. Instead, proinflammatory responses are exacerbated and Foxp3(hi) Treg-cell induction is decreased. These findings show that adjuvants for specific immunotherapy should enhance Treg cells rather than target immune deviation from Th2 to Th1. PMID:23238878

  4. Effects of Acute Low-Dose Exposure to the Chlorinated Flame Retardant Dechlorane 602 and Th1 and Th2 Immune Responses in Adult Male Mice

    PubMed Central

    Feng, Yu; Tian, Jijing; Xie, Heidi Qunhui; She, Jianwen; Xu, Sherry Li; Xu, Tuan; Tian, Wenjing; Fu, Hualing; Li, Shuaizhang; Tao, Wuqun; Wang, Lingyun; Chen, Yangsheng; Zhang, Songyan; Zhang, Wanglong; Guo, Tai L.; Zhao, Bin

    2016-01-01

    Background: Although the chlorinated flame retardant Dechlorane (Dec) 602 has been detected in food, human blood, and breast milk, there is limited information on potential health effects, including possible immunotoxicity. Objectives: We determined the immunotoxic potential of Dec 602 in mice by examining the expression of phenotypic markers on thymocyte and splenic lymphocyte subsets, Th1/Th2 transcription factors, and the production of cytokines and antibodies. Methods: Adult male C57BL/6 mice were orally exposed to environmentally relevant doses of Dec 602 (1 and 10 μg/kg body weight per day) for 7 consecutive days. Thymocyte and splenic CD4 and CD8 subsets and splenocyte apoptosis were examined by flow cytometric analysis. Cytokine expression was measured at both the mRNA and the protein levels. Levels of the transcription factors Th1 (T-bet and STAT1) and Th2 (GATA3) were determined using quantitative real-time polymerase chain reaction (qPCR). Serum levels of immunoglobulins IgG1, IgG2a, IgG2b and IgE were measured by enzyme-linked immunosorbent assay (ELISA). Results: Splenic CD4+ and CD8+ T cell subsets were decreased compared with vehicle controls, and apoptosis was significantly increased in splenic CD4+ T cells. Expression (mRNA and protein) of Th2 cytokines [interleukin (IL)-4, IL-10, and IL-13] increased, and that of Th1 cytokines [IL-2, interferon (IFN)-γ and tumor necrosis factor (TNF)-α] decreased. The Th2 transcriptional factor GATA3 increased, whereas the Th1 transcriptional factors T-bet and STAT1 decreased. As additional indicators of the Th2-Th1 imbalance, production of IgG1 was significantly increased, whereas IgG2a was reduced. Conclusions: To our knowledge, we are the first to report evidence of the effects of Dec 602 on immune function in mice, with findings indicating that Dec 602 exposure favored Th2 responses and reduced Th1 function. Citation: Feng Y, Tian J, Xie HQ, She J, Xu SL, Xu T, Tian W, Fu H, Li S, Tao W, Wang L, Chen Y

  5. Thymic irradiation inhibits the rapid recovery of TH1 but not TH2-like functions of CD4+ T cells after total lymphoid irradiation

    SciTech Connect

    Bass, H.; Adkins, B.; Strober, S. )

    1991-10-15

    Four to six weeks after total lymphoid irradiation (TLI), there is a selective deficit in the CD4+ T cells which secrete IL-2, proliferate in the MLR, and induce GVHD (Th1-like functions). A similar deficit in CD4+ T cells which secrete IL-4 and help antibody responses (Th2-like functions) is not observed. In the present study, shielding of the thymus with lead during TLI increased the Th1-like functions of CD4+ cells. Mice without thymus shields showed a marked selective reduction in the medullary stromal cells identified with the monoclonal antibody, MD1, and the severe reduction was prevented with thymus shields. Thus, shielding the thymus prevents the depletion of thymic medullary stromal cells and allows for a rapid recovery of Th1-like functions in the mouse spleen after TLI. Th2-like functions recover rapidly after TLI whether or not the thymus is irradiated.

  6. Effects of transcutaneous acupoint electrical stimulation on the imbalance of Th1, Th2, Th17 and Treg cells following thoracotomy of patients with lung cancer

    PubMed Central

    WU, HUAXING; WANG, KUN; LI, GUIXIAN; MENG, DEXIN; HAN, JIACHENG; WANG, GUONIAN; LI, YU

    2016-01-01

    An imbalance in the various T lymphocytes, including T-helper (Th)1, Th2 and Th17 cells, and regulatory T (Treg) cells, has been associated with immune dysfunction, and may occur following thoracotomy of patients with lung cancer. The use of transcutaneous acupoint electrical stimulation (TAES) has previously been demonstrated to exert immunoregulatory effects; therefore, the present study aimed to evaluate whether TAES was able to attenuate postoperative immune suppression in patients with lung cancer. Thoracic surgical patients with lung cancer (n=27) underwent TAES (frequency, 2/100 Hz; intensity, 4–12 mA) at the bilateral large intestine 4, pericardium 6, small intestine 3 and San Jiao 6 acupuncture points for 30 min, prior to incision, and at 20, 44, 68, 92 and 116 h following thoracotomy. The number of Th1, Th2, Th17 and Treg cells, and the protein and mRNA expression levels of related cytokines were measured by flow cytometry, ELISA and polymerase chain reaction, respectively. The balance of Th1, Th2, Th17 and Treg cells in the peripheral blood of patients with lung cancer was disrupted following thoracotomy. TAES administration increased the percentage of Th1 and Th17 cells, the protein expression levels of interleukin (IL)-2 and interferon-γ, the mRNA expression levels of T-bet and RAR-related orphan receptor-γt, and decreased the percentage of Th2 cells, IL-10 protein expression levels, and GATA binding protein 3 mRNA expression levels. The results of the present study demonstrated that TAES was able to partially attenuate the postoperative immune depression of patients with lung cancer, by regulating the balance of Th1, Th2, Th17 and Treg cells, and the expression levels of related cytokines and transcription factors; therefore, TAES may be considered to be a promising strategy for treating postoperative immune dysfunction in patients with lung cancer. PMID:26893636

  7. Balanced TH1 and TH2 immunopotentiating effects of silicates partly containing nanoparticles present in calcined serpentine.

    PubMed

    Elahi, Asif; Sharma, Yadhu; Bashir, Samina; Khan, Farah

    2016-05-01

    Calcined Serpentine (CS) is used in various formulations of alternative systems of medicine as a tonic to vital organs and as an anti-inflammatory agent. The process of calcination or incineration is believed to render non-toxic, gently absorbable, adaptable and digestible properties to the mineral compounds. The present study characterized CS and also evaluated its immunostimulatory potential. CS was characterized by using transmission electron microscopy (TEM), X-ray powder diffraction, atomic absorption spectroscopy and CHNS analysis. The characterized CS was further evaluated for its immunomodulatory potential in Swiss mice. X-Ray diffraction analysis revealed that the CS contained silicates of magnesium, calcium and iron as major minerals. Elemental composition and heavy metal analyses showed a presence of various inorganic elements/heavy metals, albeit at levels well below daily permissive intake values. TEM analysis of the test CS revealed a presence of nano particles with an average size of 10-20 nm (≈ 26% of total material). Oral administration of CS to mice at 50, 75, 100 or 200 μg/kg body weight for 10 days led to enhanced levels of total IgG, IgG1, IgG2a and IgG2b in ovalbumin-immunized mice as well as ex vivo lymphocyte proliferation and levels of TH1 (IL-2, IFNγ) and TH2 (IL-4, IL-10) cytokines produced by their cultured splenocytes. Similarly, CS treatment resulted in enhanced delayed-type hypersensitivity responses in GRBC-primed hosts. CS also activated host peritoneal macrophages, as indicated by increases in phagocytic activity and in TLR-2, CD80 and CD86 expression. The CS did not affect liver, kidney and spleen histology. Taken together, the results indicated that absorbed CS was stimulatory of host cell-mediated immune responses. It is hypothesized for now that the immunomodulatory effect of CS may have been due, in part, to a presence of nanoparticles on the CS; further study is required to validate this viewpoint. PMID:26484633

  8. Compound A, a Dissociated Glucocorticoid Receptor Modulator, Inhibits T-bet (Th1) and Induces GATA-3 (Th2) Activity in Immune Cells

    PubMed Central

    Ferraz-de-Paula, Viviane; Palermo-Neto, Joao; Castro, Carla N.; Druker, Jimena; Holsboer, Florian; Perone, Marcelo J.; Gerlo, Sarah; De Bosscher, Karolien; Haegeman, Guy; Arzt, Eduardo

    2012-01-01

    Background Compound A (CpdA) is a dissociating non-steroidal glucocorticoid receptor (GR) ligand which has anti-inflammatory properties exerted by down-modulating proinflammatory gene expression. By favouring GR monomer formation, CpdA does not enhance glucocorticoid (GC) response element-driven gene expression, resulting in a reduced side effect profile as compared to GCs. Considering the importance of Th1/Th2 balance in the final outcome of immune and inflammatory responses, we analyzed how selective GR modulation differentially regulates the activity of T-bet and GATA-3, master drivers of Th1 and Th2 differentiation, respectively. Results Using Western analysis and reporter gene assays, we show in murine T cells that, similar to GCs, CpdA inhibits T-bet activity via a transrepressive mechanism. Different from GCs, CpdA induces GATA-3 activity by p38 MAPK-induction of GATA-3 phosphorylation and nuclear translocation. CpdA effects are reversed by the GR antagonist RU38486, proving the involvement of GR in these actions. ELISA assays demonstrate that modulation of T-bet and GATA-3 impacts on cytokine production shown by a decrease in IFN-γ and an increase in IL-5 production, respectively. Conclusions Taken together, through their effect favoring Th2 over Th1 responses, particular dissociated GR ligands, for which CpdA represents a paradigm, hold potential for the application in Th1-mediated immune disorders. PMID:22496903

  9. Comparison of Th1- and Th2-associated immune reactivities stimulated by single versus multiple vaccination of mice with irradiated Schistosoma mansoni cercariae

    SciTech Connect

    Caulada-Benedetti, Z.; Al-Zamel, F.; Sher, A.; James, S. )

    1991-03-01

    Mice immunized against Schistosoma mansoni by a single percutaneous exposure to radiation-attenuated parasite larvae demonstrate partial resistance to challenge infection that has been shown to correlate with development of cell-mediated immunity, whereas mice hyperimmunized by multiple exposure to attenuated larvae produce antibodies capable of transferring partial protection to naive recipients. Measurement of Ag-specific lymphokine responses in these animals suggested that the difference in resistance mechanisms may be due to the differential induction of Th subset response by the two immunization protocols. Thus, upon Ag stimulation, singly immunized mice predominantly demonstrated responses associated with Th1 reactivity, including IL-2 and IFN-gamma production, whereas multiply immunized animals showed increased IL-5, IL-4, and IgG1 antibody production associated with enhanced Th2 response. These responses demonstrated some degree of organ compartmentalization, with splenocytes demonstrating higher Th1-related lymphokine production and cells from draining lymph nodes showing stronger proliferation and Th2 type reactivity. However, hyperimmunized mice also continued to demonstrate substantial Th1-associated immune reactivity. Moreover, in vivo Ag challenge elicited activated larvacidal macrophages in hyperimmunized animals. These observations indicate that protective cell-mediated mechanisms associated with induction of CD4+ Th1 cell reactivity predominate in singly vaccinated mice. Further vaccination stimulates Th2 responses, such as enhanced IgG1 production, that may also contribute to protective immunity.

  10. Lack of Th1 or Th2 polarization of CD4+ T cell response induced by particulate antigen targeted to phagocytic cells.

    PubMed

    Sedlik, C; Dériaud, E; Leclerc, C

    1997-01-01

    Several factors are involved in the selective activation of Th1 or Th2 subset of CD4+ T cells, such as the type of antigen-presenting cells, the dose of antigen, the route of immunization, etc. To analyze the influence of accessory cells on Th1/Th2 cell differentiation, we used a particulate antigen prepared by covalent linkage of hemocyanin (LH) to 1 microns synthetic microspheres. This particulate antigen was efficiently presented to T cells by macrophages but not by B lymphocytes. BALB/c mice immunized either with soluble LH in alum or with particulate LH without adjuvant produced both Th1 (IL-2 and IFN-gamma) and Th2 (IL-4 and IL-5) cytokines. Moreover, mice primed either with soluble or particulate LH secreted higher levels of IgG1- than of IgG2a-specific antibodies. The induction of this cytokine profile response was independent of the route of administration of the antigen, and was observed both in BALB/c and C57BL/6 mice. In contrast, immunization of mice with particulate LH in the presence of poly(I):(C) or of IL-12 induced a strong activation of Th1 cells, as shown by an up-regulated IFN-gamma production, and by decreased IL-4 and IL-5 levels associated to a greatly enhanced IgG2a antibody response. These results therefore demonstrate that targeting the antigen to phagocytic cells is not sufficient to stimulate a polarized Th response and that environmental cytokines play the major role in the selective activation of Th1 cells. This study provides important conclusions for the development of new vaccines and shows that particulate antigen associated with appropriate cofactor can selectively activate Th1 cells. PMID:9043951

  11. Coupling Peptide Antigens to Virus-Like Particles or to Protein Carriers Influences the Th1/Th2 Polarity of the Resulting Immune Response

    PubMed Central

    Pomwised, Rattanaruji; Intamaso, Uraiwan; Teintze, Martin; Young, Mark; Pincus, Seth H.

    2016-01-01

    We have conjugated the S9 peptide, a mimic of the group B streptococcal type III capsular polysaccharide, to different carriers in an effort to elicit an optimal immune response. As carriers, we utilized the soluble protein keyhole limpet hemocyanin and virus-like particles (VLPs) from two plant viruses, Cowpea Chlorotic Mottle Virus and Cowpea Mosaic Virus. We have found that coupling the peptide to the soluble protein elicits a Th2 immune response, as evidenced by the production of the peptide-specific IgG1 antibody and IL-4/IL-10 production in response to antigen stimulation, whereas the peptide conjugated to VLPs elicited a Th1 response (IgG2a, IFN-γ). Because the VLPs used as carriers package RNA during the assembly process, we hypothesize that this effect may result from the presence of nucleic acid in the immunogen, which affects the Th1/Th2 polarity of the response. PMID:27164150

  12. Coupling Peptide Antigens to Virus-Like Particles or to Protein Carriers Influences the Th1/Th2 Polarity of the Resulting Immune Response.

    PubMed

    Pomwised, Rattanaruji; Intamaso, Uraiwan; Teintze, Martin; Young, Mark; Pincus, Seth H

    2016-01-01

    We have conjugated the S9 peptide, a mimic of the group B streptococcal type III capsular polysaccharide, to different carriers in an effort to elicit an optimal immune response. As carriers, we utilized the soluble protein keyhole limpet hemocyanin and virus-like particles (VLPs) from two plant viruses, Cowpea Chlorotic Mottle Virus and Cowpea Mosaic Virus. We have found that coupling the peptide to the soluble protein elicits a Th2 immune response, as evidenced by the production of the peptide-specific IgG1 antibody and IL-4/IL-10 production in response to antigen stimulation, whereas the peptide conjugated to VLPs elicited a Th1 response (IgG2a, IFN-γ). Because the VLPs used as carriers package RNA during the assembly process, we hypothesize that this effect may result from the presence of nucleic acid in the immunogen, which affects the Th1/Th2 polarity of the response. PMID:27164150

  13. Cytokine responses during mycobacterial and schistosomal antigen-induced pulmonary granuloma formation. Production of Th1 and Th2 cytokines and relative contribution of tumor necrosis factor.

    PubMed Central

    Chensue, S. W.; Warmington, K.; Ruth, J.; Lincoln, P.; Kuo, M. C.; Kunkel, S. L.

    1994-01-01

    Synchronized pulmonary granulomas (GRs) were induced in presensitized mice by intravenous embolization of polymer beads bound with purified protein derivative (PPD) of Mycobacteria tuberculosis or soluble antigens derived from Schistosoma mansoni eggs (SEA). Uncoated beads served as a foreign body control (CON). Antigen-coated beads elicited GRs with characteristic epithelioid macrophages and multinucleate giant cells by 4 days after embolization. Unlike PPD GR, SEA bead lesions contained eosinophils, whereas CON beads elicited only a limited mononuclear infiltrate. GRs and draining lymph nodes (LN) were assessed on days 2, 4, and 8 for Th1-(interleukin-2 [IL-2], interferon-gamma[IFN] and Th2-type (IL-4, IL-5, and IL-10) cytokines. CON GR produced only a small amount of IFN-gamma on day 2 and failed to induce a significant response in draining LN. In contrast, both PPD and SEA antigen-coated beads induced reactive lymphoid hyperplasia but differed greatly in local and regional cytokine profiles. PPD GR produced IFN-gamma on day 2 and the draining LN produced predominantly Th1 cytokines on days 2 and 4. In contrast, SEA beads GRs were dominated by Th2 cytokines. The corresponding LN produced IL-2 and IL-4 on day 2; IL-2, IL-4, IFN-gamma, and IL-10 on day 4; then IL-2, IFN-gamma, and IL-4 on day 8, probably reflecting maturational changes of T cells. Macrophages (MP) from bead GR also showed different patterns of IL-6 and tumor necrosis factor (TNF) production. Compared with CON GR, MPs from PPD GR were weak sources of IL-6, whereas those of SEA GR showed enhanced and accelerated production. In contrast, MP of PPD GR had augmented TNF-producing capacity, whereas those of SEA GR showed delayed TNF production. In vivo depletion of TNF, respectively, caused 40 and 10% decreases in PPD GR and SEA GR but had no effect on CON GR area, indicating that TNF contributed to a greater degree to the PPD response. These data show that depending on the inciting agent, GR can be

  14. Phase 2 clinical trial of rapamycin-resistant donor CD4+ Th2/Th1 (T-Rapa) cells after low-intensity allogeneic hematopoietic cell transplantation

    PubMed Central

    Fowler, Daniel H.; Mossoba, Miriam E.; Steinberg, Seth M.; Halverson, David C.; Stroncek, David; Khuu, Hahn M.; Hakim, Frances T.; Castiello, Luciano; Sabatino, Marianna; Leitman, Susan F.; Mariotti, Jacopo; Gea-Banacloche, Juan C.; Sportes, Claude; Hardy, Nancy M.; Hickstein, Dennis D.; Pavletic, Steven Z.; Rowley, Scott; Goy, Andre; Donato, Michele; Korngold, Robert; Pecora, Andrew; Levine, Bruce L.; June, Carl H.; Gress, Ronald E.; Bishop, Michael R.

    2013-01-01

    In experimental models, ex vivo induced T-cell rapamycin resistance occurred independent of T helper 1 (Th1)/T helper 2 (Th2) differentiation and yielded allogeneic CD4+ T cells of increased in vivo efficacy that facilitated engraftment and permitted graft-versus-tumor effects while minimizing graft-versus-host disease (GVHD). To translate these findings, we performed a phase 2 multicenter clinical trial of rapamycin-resistant donor CD4+ Th2/Th1 (T-Rapa) cells after allogeneic-matched sibling donor hematopoietic cell transplantation (HCT) for therapy of refractory hematologic malignancy. T-Rapa cell products, which expressed a balanced Th2/Th1 phenotype, were administered as a preemptive donor lymphocyte infusion at day 14 post-HCT. After T-Rapa cell infusion, mixed donor/host chimerism rapidly converted, and there was preferential immune reconstitution with donor CD4+ Th2 and Th1 cells relative to regulatory T cells and CD8+ T cells. The cumulative incidence probability of acute GVHD was 20% and 40% at days 100 and 180 post-HCT, respectively. There was no transplant-related mortality. Eighteen of 40 patients (45%) remain in sustained complete remission (range of follow-up: 42-84 months). These results demonstrate the safety of this low-intensity transplant approach and the feasibility of subsequent randomized studies to compare T-Rapa cell-based therapy with standard transplantation regimens. This trial was registered at www.cancer.gov/clinicaltrials as #NCT 00077480. PMID:23426943

  15. CTLA4Ig inhibits airway eosinophilia and hyperresponsiveness by regulating the development of Th1/Th2 subsets in a murine model of asthma.

    PubMed

    Padrid, P A; Mathur, M; Li, X; Herrmann, K; Qin, Y; Cattamanchi, A; Weinstock, J; Elliott, D; Sperling, A I; Bluestone, J A

    1998-04-01

    Complete T-cell activation requires two distinct signals, one delivered via the T-cell receptor, and the second "co-stimulatory" signal through CD28/B7 ligation. Previous studies showed that the blockade of CD28/B7 ligation alters differentiation of Th1/Th2 lymphocyte subsets in vitro and in vivo. The present study was designed to determine the effect of a CD28/B7 antagonist (CTLA4Ig) on Th1/Th2 development in Schistosoma mansoni-sensitized and airway-challenged mice. Treatment of mice with CTLA4Ig beginning 1 wk after sensitization abolished airway responsiveness to intravenous methacholine determined 96 h following antigen challenge. We also found a significant reduction in bronchoalveolar lavage (BAL) eosinophilia, and reduced peribronchial eosinophilic infiltration and mucoid-cell hyperplasia. Furthermore, CTLA4Ig treatment significantly decreased interleukin (IL)-4 and IL-5 content in BAL fluid in vivo, and the production of IL-5 by lung lymphocytes stimulated with soluble egg antigen (SEA) in vitro. In contrast, the content of interferon-gamma in BAL fluid and supernatant from SEA-stimulated lung lymphocytes from CTLA4Ig-treated mice was increased significantly compared with untreated animals. Thus, CTLA4Ig inhibits eosinophilic airway inflammation and airway hyperresponsiveness in S. mansoni-sensitized and airway-challenged mice, most likely due to attenuated secretion of Th2-type cytokines and increased secretion of Th1-type cytokines. PMID:9533932

  16. Ferulic Acid Induces Th1 Responses by Modulating the Function of Dendritic Cells and Ameliorates Th2-Mediated Allergic Airway Inflammation in Mice

    PubMed Central

    Lee, Chen-Chen; Wang, Ching-Chiung; Huang, Huei-Mei; Lin, Chu-Lun; Leu, Sy-Jye; Lee, Yueh-Lun

    2015-01-01

    This study investigated the immunomodulatory effects of ferulic acid (FA) on antigen-presenting dendritic cells (DCs) in vitro and its antiallergic effects against ovalbumin- (OVA-) induced Th2-mediated allergic asthma in mice. The activation of FA-treated bone marrow-derived DCs by lipopolysaccharide (LPS) stimulation induced a high level of interleukin- (IL-) 12 but reduced the expression levels of the proinflammatory cytokines IL-1β, IL-6, and tumor necrosis factor- (TNF-) α. Compared to control-treated DCs, FA significantly enhanced the expressions of Notch ligand Delta-like 4 (Dll4), MHC class II, and CD40 molecules by these DCs. Furthermore, these FA-treated DCs enhanced T-cell proliferation and Th1 cell polarization. In animal experiments, oral administration of FA reduced the levels of OVA-specific immunoglobulin E (IgE) and IgG1 and enhanced IgG2a antibody production in serum. It also ameliorated airway hyperresponsiveness and attenuated eosinophilic pulmonary infiltration in dose-dependent manners. In addition, FA treatment inhibited the production of eotaxin, Th2 cytokines (IL-4, IL-5, and IL-13), and proinflammatory cytokines but promoted the Th1 cytokine interferon- (IFN-) γ production in bronchoalveolar lavage fluid (BALF) and the culture supernatant of spleen cells. These findings suggest that FA exhibits an antiallergic effect via restoring Th1/Th2 imbalance by modulating DCs function in an asthmatic mouse model. PMID:26495021

  17. Effect of Lactobacillus salivarius on Th1/Th2 cytokines and the number of spleen CD4+ CD25+ Foxp3+ Treg in asthma Balb/c mouse

    PubMed Central

    Yun, Xiang; Shang, Yunxiao; Li, Miao

    2015-01-01

    Background: Bronchial asthma is a chronic airway inflammatory disease that involves T lymphocytes. Methods: In order to explore the effect of Lactobacillus salivarius on Th1/Th2 cytokines and the number of spleen CD4+ CD25+ Foxp3+ Treg in asthma Balb/c mouse, we constructed acute asthma model with ovalbumin to observe the mouse behavior change in Balb/c mice. The expression of GATA-3 mRNA and T-bet mRNA was measured by real-time PCR. The proportion of CD4+ CD25+ Foxp3+ Treg/CD4+ was determined by flow cytometry. Results: The results demonstrated that oral gavage with Lactobacillus salivarius before sensitization could alleviate the clinical symptoms, airway hyper-reactivity and airway inflammation in asthma mouse to some extent; Lactobacillus salivarius may improve the imbalance of Th1/Th2 in asthma mouse through increasing the expression of T-bet mRNA at the transcriptional level and inhibiting the expression of GATA-3 mRNA simultaneously. Conclusion: CD4+ CD25+ Foxp3+ Treg cells may be involved in the pathogenesis of bronchial asthma, and may be the upstream regulatory mechanism of the improvement of Th1/Th2 imbalance by Lactobacillus salivarius. PMID:26339333

  18. Testosterone-Mediated Endocrine Function and TH1/TH2 Cytokine Balance after Prenatal Exposure to Perfluorooctane Sulfonate: By Sex Status.

    PubMed

    Zhong, Shou-Qiang; Chen, Zan-Xiong; Kong, Min-Li; Xie, Yan-Qi; Zhou, Yang; Qin, Xiao-Di; Paul, Gunther; Zeng, Xiao-Wen; Dong, Guang-Hui

    2016-01-01

    Little information exists about the evaluation of potential developmental immunotoxicity induced by perfluorooctane sulfonate (PFOS), a synthetic persistent and increasingly ubiquitous environmental contaminant. To assess potential sex-specific impacts of PFOS on immunological health in the offspring, using male and female C57BL/6 mice, pups were evaluated for developmental immunotoxic effects after maternal oral exposure to PFOS (0.1, 1.0 and 5.0 mg PFOS/kg/day) during Gestational Days 1-17. Spontaneous TH1/TH2-type cytokines, serum levels of testosterone and estradiol were evaluated in F1 pups at four and eight weeks of age. The study showed that male pups were more sensitive to the effects of PFOS than female pups. At eight weeks of age, an imbalance in TH1/TH2-type cytokines with excess TH2 cytokines (IL-4) was found only in male pups. As for hormone levels, PFOS treatment in utero significantly decreased serum testosterone levels and increased estradiol levels only in male pups, and a significant interaction between sex and PFOS was observed for serum testosterone at both four weeks of age (pinteraction = 0.0049) and eight weeks of age (pinteraction = 0.0227) and for estradiol alternation at four weeks of age (pinteraction = 0.0351). In conclusion, testosterone-mediated endocrine function may be partially involved in the TH1/TH2 imbalance induced by PFOS, and these deficits are detectable among both young and adult mice and may affect males more than females. PMID:27626407

  19. Th1 and Th2 cytokine profiles induced by hepatitis C virus F protein in peripheral blood mononuclear cells from chronic hepatitis C patients.

    PubMed

    Yue, Ming; Deng, Xiaozhao; Zhai, Xiangjun; Xu, Ke; Kong, Jing; Zhang, Jinhai; Zhou, Zhenxian; Yu, Xiaojie; Xu, Xiaodong; Liu, Yunxi; Zhu, Danyan; Zhang, Yun

    2013-05-01

    Th1 and Th2 cytokine response has been confirmed to be correlated with the pathogenesis of HCV infection. The aim of the study is to investigate the Th1 and Th2 cytokine profiles induced by HCV alternate reading frame protein (F protein) in chronic hepatitis C patients. We assessed the immune responses specific to HCV F protein in 55 chronic HCV patients. IFN-γ, IL-2, IL-4 and IL-5 secretion by peripheral blood mononuclear cells (PBMC) post F protein stimulation were compared among HCV patients and healthy donors. Finally, the associations between HCV F protein and HLA class II alleles were explored. We found that the seroprevalence of anti-F antibodies in HCV-related hepatocellular carcinoma (HCC) patients was significantly higher than that of patients without HCC, but such a significant difference in humoral immune responses to F protein was not observed in HCV 1b-infected- and non-HCV 1b-infected-patients. Additionally, the PBMC proliferation of HCC patients was significantly lower than that of patients without HCC. Furthermore, F protein stimulation of PBMCs from F-seropositive patients resulted in Th2 biased cytokine responses (significantly decreased IFN-γ and/or IL-2 and significantly increased IL-4 and/or IL-5 levels) that reportedly may contribute to HCC progression and pathogenesis. However, no significant difference in the association between HCV F protein and HLA-DRB1*0201, 0301, 0405, 1001 and HLA-DQB1*0201, 0401, 0502, 0602 was observed in this study. These findings suggest that F protein may contribute to the HCV-associated bias in Th1/Th2 responses of chronic hepatitis C patients including the progress of HCC pathogenesis. PMID:23680070

  20. Altered interleukin-12 responsiveness in Th1 and Th2 cells is associated with the differential activation of STAT5 and STAT1.

    PubMed

    Gollob, J A; Murphy, E A; Mahajan, S; Schnipper, C P; Ritz, J; Frank, D A

    1998-02-15

    T-cell activation in response to interleukin-12 (IL-12) is mediated through signaling events that include the tyrosine phosphorylation of STAT4. IL-12 responsiveness and the ability of IL-12 to activate STAT4 is different in T cells induced to differentiate into a Th1 or Th2 phenotype. In this report, we show that STAT5, STAT1alpha, and STAT1beta, in addition to STAT4, are tyrosine phosphorylated in response to IL-12 in phytohemagglutinin (PHA)-activated human T cells. To understand how the activation of these STATs contributes to T-cell IL-12 responsiveness, we analyzed the IL-12-induced activation of STAT5 and STAT1 in T cells stimulated to undergo Th1 or Th2 differentiation. The IL-12-induced tyrosine phosphorylation of STAT5 and STAT1, but not STAT4, is augmented in T cells activated into Th1 cells with PHA + interferon-gamma (IFN-gamma) compared with T cells activated with PHA alone. STAT5 DNA binding induced by IL-12 is also augmented in T cells activated with PHA + IFN-gamma compared with T cells activated with PHA alone, whereas STAT4 DNA binding is not increased. In contrast, the IL-12-induced activation of these STATs is inhibited in T cells activated into Th2 cells with PHA + IL-4. The enhancement of IL-12 signaling by IFN-gamma is not a direct effect of IFN-gamma on T cells, but rather is mediated by IL-12 that is produced by antigen-presenting cells in response to IFN-gamma. This positive autoregulatory effect of IL-12 on the activation of select STATs correlates with an increase in T-cell IFN-gamma production in response to IL-12. These findings suggest that the activation of STAT5 and STAT1 may augment select STAT4-dependent functional responses to IL-12 in Th1 cells. PMID:9454765

  1. Characterization and Clinical Implication of Th1/Th2/Th17 Cytokines Produced from Three-Dimensionally Cultured Tumor Tissues Resected from Breast Cancer Patients

    PubMed Central

    Kiyomi, Anna; Makita, Masujiro; Ozeki, Tomoko; Li, Na; Satomura, Aiko; Tanaka, Sachiko; Onda, Kenji; Sugiyama, Kentaro; Iwase, Takuji; Hirano, Toshihiko

    2015-01-01

    OBJECTIVES: Several cytokines secreted from breast cancer tissues are suggested to be related to disease prognosis. We examined Th1/Th2/Th17 cytokines produced from three-dimensionally cultured breast cancer tissues and related them with patient clinical profiles. METHODS: 21 tumor tissues and 9 normal tissues surgically resected from breast cancer patients were cultured in thermoreversible gelatin polymer–containing medium. Tissue growth and Th1/Th2/Th17 cytokine concentrations in the culture medium were analyzed and were related with hormone receptor expressions and patient clinical profiles. RESULTS: IL-6 and IL-10 were expressed highly in culture medium of both cancer and normal tissues. However, IFN-γ, TNF-α, IL-2, and IL-17A were not detected in the supernatant of the three-dimensionally cultured normal mammary gland and are seemed to be specific to breast cancer tissues. The growth abilities of hormone receptor–negative cancer tissues were significantly higher than those of receptor-positive tissues (P = 0.0383). Cancer tissues of stage ≥ IIB patients expressed significantly higher TNF-α levels as compared with those of patients with stage < IIB (P = 0.0096). CONCLUSIONS: The tumor tissues resected from breast cancer patients can grow in the three-dimensional thermoreversible gelatin polymer culture system and produce Th1/Th2/Th17 cytokines. Hormone receptor–positive cancer tissues showed less growth ability. TNF-α is suggested to be a biomarker for the cancer stage. PMID:26310378

  2. Matrix MTM adjuvanted virosomal H5N1 vaccine induces balanced Th1/Th2 CD4+ T cell responses in man

    PubMed Central

    Pedersen, Gabriel K; Sjursen, Haakon; Nøstbakken, Jane K; Jul-Larsen, Åsne; Hoschler, Katja; Cox, Rebecca J

    2014-01-01

    T cellular responses play a significant role in mediating protective immune responses against influenza in humans. In the current study, we evaluated the ability of a candidate virosomal H5N1 vaccine adjuvanted with Matrix MTM to induce CD4+ and CD8+ T cell responses in a phase 1 clinical trial. We vaccinated 60 healthy adult volunteers (at days 0 and 21) with 30 μg haemagglutinin (HA) alone or 1.5, 7.5, or 30 μg HA formulated with Matrix MTM. To evaluate the T cellular responses, lymphocytes were stimulated in vitro with homologous (A/Vietnam/1194/2004 [H5N1]) and heterologous H5N1 (A/Anhui/1/05 or A/Bar-headed Goose/Qinghai/1A/05) antigens. The antigen-specific cytokine responses were measured by intracellular cytokine staining and by multiplex (Luminex) assays. An increase in CD4+ Th1 and Th2 cytokines was detected 21 days after the first vaccine dose. No increase in Th cytokine responses was observed after the second dose, although it is possible that the cytokine levels peaked earlier than sampling point at day 42. Formulation with the Matrix MTM adjuvant augmented both the homologous and cross-reactive cytokine response. Antigen-specific CD8+ T cell responses were detected only in a few vaccinated individuals. The concentrations of Th1 and to a lesser extent, Th2 cytokines at 21 days post-vaccination correlated moderately with subsequent days 35 and 180 serological responses as measured by the microneutralisation, haemagglutination inhibition, and single radial hemolysis assays. Results presented here show that the virosomal H5N1 vaccine induced balanced Th1/Th2 cytokine responses and that Matrix MTM is a promising adjuvant for future development of candidate pandemic influenza vaccines. PMID:25424948

  3. Suppression of Th1- and Th2-type immune responses in infant mouse spleen after prenatal and postnatal exposure to low-level toluene and peptidoglycan.

    PubMed

    Yamamoto, Shoji; Win-Shwe, Tin-Tin; Tin-Tin-Win-Shwe; Yoshida, Yasuhiro; Kunugita, Naoki; Arashidani, Keiichi; Fujimaki, Hidekazu

    2009-08-01

    The aim of the present study was to investigate the effect of low-level concentrations, under the occupational acceptable limits, of toluene exposure and peptidoglycan (PGN) stimulation on Th1/Th2 immunity in infant mice. Pregnant BALB/c mice and their offspring were exposed to low-level toluene inhalation (0, 5, and 50 ppm) for 4 wk (from the late prenatal stage to early postnatal stage) in a whole-body exposure chamber. Some of the pregnant mice and their offspring were stimulated with PGN during toluene exposure. We measured total immunoglobulins of different subclasses in plasma, and production and expression level of cytokines in the lung and spleen, and transcription factors related to Th1/Th2 immunity in the spleen of infant (3 wk old) mice. Exposure of mice to 5 or 50 ppm toluene resulted in increased immunoglobulin (Ig) G1 and decreased IgG2a and IgE antibodies in the plasma; significantly decreased T-bet, GATA-3, and Foxp3 mRNA in the spleen; and a tendency toward decreased interferon (IFN)-gamma mRNA in spleen. Exposure of mice to low-level toluene together with PGN stimulation resulted in decreased IgG1 as well as IgG2a antibodies in the plasma and Foxp3 mRNA in spleen as compared with control or PGN-treated mice. These findings suggest that low-level toluene exposure and PGN stimulation from the late prenatal to early postnatal stage suppressed the splenic parameter related to Th1/Th2 immunity in infant mice. PMID:19645570

  4. Relationship between NADPH and Th1/Th2 ratio in patients with non-Hodgkin lymphoma who have been exposed to pesticides

    PubMed Central

    Zahzeh, Meriem Rabia; Loukidi, Bouchra; Meziane, Warda; Haddouche, Mustapha; Mesli, Naima; Zouaoui, Zahia; Aribi, Mourad

    2015-01-01

    The effect of pesticides on nicotinamide adenine dinucleotide phosphate hydrogen (NADPH), including its level and relationship with the T helper 1 (Th1)/Th2 ratio, in patients suffering from non-Hodgkin lymphoma (NHL) was investigated. One hundred newly diagnosed patients with aggressive NHL (53 men, 47 women) and 40 healthy age-, sex-, and body mass index-matched controls (23 men, 17 women), exposed or not to pesticides, were recruited for a cross-sectional study conducted at the Clinical Hematology Departments of Tlemcen and Sidi Bel-Abbès University Medical Centers in the northwest of Algeria. NADPH levels were significantly increased in patients compared with controls; and in exposed patients compared with those not exposed, and controls (one-way analysis of variance; P=0.000). Albumin, glutathione peroxidase, superoxide dismutase, catalase activity, and oxygen radical absorbance capacity levels were significantly decreased in patients compared with in the control group. Oxygen radical absorbance capacity levels were significantly decreased in exposed patients compared with in unexposed patients; however, malondialdehyde levels were significantly increased in exposed patients when compared with controls and unexposed patients. Protein carbonyl and xanthine oxidase levels were significantly increased in exposed patients compared with controls; meanwhile, there were no significant differences between the two patient groups or between unexposed patients and controls. The Th1/Th2 ratio was significantly decreased in patients when compared with controls; the neutrophil-to-lymphocyte ratio was significantly increased (for both comparisons, P<0.001). In addition, NADPH was strongly associated with NHL (Mantel–Haenszel common odds ratio estimate =5.55; 95% confidence interval, 2.22–13.88; P=0.000). Moreover, NADPH levels were significantly negatively related to the Th1/Th2 ratio, either in exposed patients or in unexposed patients (respectively, r=−0.498 [P=0

  5. Relationship between NADPH and Th1/Th2 ratio in patients with non-Hodgkin lymphoma who have been exposed to pesticides.

    PubMed

    Zahzeh, Meriem Rabia; Loukidi, Bouchra; Meziane, Warda; Haddouche, Mustapha; Mesli, Naima; Zouaoui, Zahia; Aribi, Mourad

    2015-01-01

    The effect of pesticides on nicotinamide adenine dinucleotide phosphate hydrogen (NADPH), including its level and relationship with the T helper 1 (Th1)/Th2 ratio, in patients suffering from non-Hodgkin lymphoma (NHL) was investigated. One hundred newly diagnosed patients with aggressive NHL (53 men, 47 women) and 40 healthy age-, sex-, and body mass index-matched controls (23 men, 17 women), exposed or not to pesticides, were recruited for a cross-sectional study conducted at the Clinical Hematology Departments of Tlemcen and Sidi Bel-Abbès University Medical Centers in the northwest of Algeria. NADPH levels were significantly increased in patients compared with controls; and in exposed patients compared with those not exposed, and controls (one-way analysis of variance; P=0.000). Albumin, glutathione peroxidase, superoxide dismutase, catalase activity, and oxygen radical absorbance capacity levels were significantly decreased in patients compared with in the control group. Oxygen radical absorbance capacity levels were significantly decreased in exposed patients compared with in unexposed patients; however, malondialdehyde levels were significantly increased in exposed patients when compared with controls and unexposed patients. Protein carbonyl and xanthine oxidase levels were significantly increased in exposed patients compared with controls; meanwhile, there were no significant differences between the two patient groups or between unexposed patients and controls. The Th1/Th2 ratio was significantly decreased in patients when compared with controls; the neutrophil-to-lymphocyte ratio was significantly increased (for both comparisons, P<0.001). In addition, NADPH was strongly associated with NHL (Mantel-Haenszel common odds ratio estimate =5.55; 95% confidence interval, 2.22-13.88; P=0.000). Moreover, NADPH levels were significantly negatively related to the Th1/Th2 ratio, either in exposed patients or in unexposed patients (respectively, r=-0.498 [P=0.004] and

  6. Differential induction of Th2- and Th1-associated responses by filarial antigens and endosymbiotic Wolbachia in a murine model of river blindness.

    PubMed

    Gentil, K; Hoerauf, A; Pearlman, E

    2012-06-01

    Immune responses to filarial parasites like the river blindness inducing Onchocerca volvulus are obscured by combined reactions to the filarial nematodes themselves and their endosymbiont bacteria Wolbachia. Overall, infection with filarial nematodes induces a strong Th2 response characterized by IL-5 production and to a lesser degree a Th1 response and IFNγ production. Neutrophil and eosinophil infiltration into the corneal stroma are hallmark features of Onchocerca volvulus stimulation in a mouse model of river blindness. To determine the splenic and corneal response to filarial antigens in the absence of Wolbachia, C57BL/6 mice were immunized subcutaneously with either endosymbiotic Wolbachia alone, a soluble extract from the filaria Acanthocheilonema viteae that does not contain Wolbachia, or both, and injected into the corneal stroma. Neutrophil and eosinophil infiltration into the cornea was assessed by immunohistochemistry. In addition, Th1- and Th2-associated responses to filaria or Wolbachia were investigated by determining IL-5 and IFN-γ production by splenocytes. We found that A. viteae in the absence of Wolbachia induced IL-5 production and eosinophil infiltration, but not IFN-γ. Conversely, Wolbachia induced IFN-γ production and no migration of eosinophils. There was no difference in neutrophil infiltration. Together, these findings demonstrate a distinct Th-associated phenotype induced by filaria and Wolbachia. PMID:24672682

  7. PIF direct immune regulation: Blocks mitogen-activated PBMCs proliferation, promotes TH2/TH1 bias, independent of Ca(2+).

    PubMed

    Barnea, Eytan R; Kirk, David; Todorova, Krassimira; McElhinney, James; Hayrabedyan, Soren; Fernández, Nelson

    2015-07-01

    PreImplantation Factor (PIF(9&15)) secreted by viable embryos exerts an essential transplant acceptance and immune regulatory role in pregnancy. Synthetic PIF replicates endogenous PIF's effect in pregnant and non-pregnant immune disorder models. PIF binds macrophages to regulate CD3/CD28-induced T-cell response. We present evidence that PIF regulates the co-stimulatory T-cell receptor, CD2, which binds to and is activated by phytohemagglutinin (PHA), a potent mitogen, confirming PIF's ability to systemically respond to diverse immune stimulants. PIF's effect on PHA-activated PBMC (male and non-pregnant females) proliferation and cytokine secretion was tested, showing that both PIF(9&15) block PHA-induced PBMC proliferation and promote anti-inflammatory IL10 secretion, while reducing pro-inflammatory IFNγ secretion. Thus favoring a T(H)2 cytokine bias. Surface plasmon resonance spectroscopy, immunocytochemistry and Flex station experiments reveal that PIF effect is direct. PIF targets intracellular targets but does not affect early Ca(2+) mobilization. By promoting the CD2 receptor in activated T-cells and through inhibition of co-ligand CD58 expression, PIF regulates antigen-presenting cell (APC)-T-cell interactions required for PHA action. Structure-based design demonstrated that PIF15 offers improved target specificity as compared to PIF9. Collectively, PIF directly regulates mitogen-induced PBMC activation. Results support PIF translation for therapy of immune disorders. PMID:25766203

  8. Th2 but Not Th1 Immune Bias Results in Altered Lung Functions in a Murine Model of Pulmonary Cryptococcus neoformans Infection▿

    PubMed Central

    Jain, Aditya V.; Zhang, Yanmei; Fields, W. Bradley; McNamara, David A.; Choe, Mun Y.; Chen, Gwo-hsiao; Erb-Downward, John; Osterholzer, John J.; Toews, Galen B.; Huffnagle, Gary B.; Olszewski, Michal A.

    2009-01-01

    Changes in airway dynamics have been reported in the rat model of pulmonary cryptococcosis. However, it is not known if Cryptococcus neoformans-induced changes in lung functions are related to the immunophenotype that develops in response to cryptococcal infection in the lungs. In this study we performed a parallel analysis of the immunophenotype and airway resistance (standard resistance of the airways [SRAW]) in BALB/c mice infected with highly virulent C. neoformans strain H99 and moderately virulent strain 52D. H99 infection evoked a Th2 response and was associated with increased SRAW, while the SRAW for 52D infection, which resulted in a predominantly Th1-skewed response, did not differ from the SRAW for uninfected mice. We found that an altered SRAW in mice did not positively or negatively correlate with the pulmonary fungal burden, the magnitude of inflammatory response, the numbers of T cells, eosinophils or eosinophil subsets, neutrophils, or monocytes/macrophages, or the levels of cytokines (interleukin-4 [IL-4], IL-10, gamma interferon, or IL-13) produced by lung leukocytes. However, the level of a systemic Th2 marker, serum immunoglobulin E (IgE), correlated significantly with SRAW, indicating that the changes in lung functions were proportional to the level of Th2 skewing in this model. These data also imply that IgE may contribute to the altered SRAW observed in H99-infected mice. Lung histological analysis revealed severe allergic bronchopulmonary mycosis pathology in H99-infected mice and evidence of protective responses in 52D-infected mice with well-marginalized lesions. Taken together, the data show that C. neoformans can significantly affect airflow physiology, particularly in the context of a Th2 immune response with possible involvement of IgE as an important factor. PMID:19752036

  9. Effectiveness of an immunocastration vaccine formulation to reduce the gonadal function in female and male mice by Th1/Th2 immune response.

    PubMed

    Siel, Daniela; Vidal, Sonia; Sevilla, Rafael; Paredes, Rodolfo; Carvallo, Francisco; Lapierre, Lisette; Maino, Mario; Pérez, Oliver; Sáenz, Leonardo

    2016-10-01

    Immunocastration has emerged as an alternative to surgical castration in different animal species. This study examined the effectiveness of a new vaccine formulation for immunocastration using the biopolymer chitosan as adjuvant. First, female and male mice (n = 4), in three subsequent experiments were vaccinated at Days 1 and 30 of the study, to determine the immune response profile and gonadal alterations due to immunization. The results demonstrated that the vaccine was able to elicit strong antibody responses against native GnRH hormone (P < 0.01), with a T helper (Th) 1/Th2 immune response profile. Along with this, a suppression of gonadal activity with a decrease of luteal bodies (1.08 ± 0.22 and 4.08 ± 0.39) and antral follicles (1.17 ± 0.32 and 4.5 ± 0.38) in the ovaries of immunized females and control, respectively, and a reduction of seminiferous tubules size (142.3 ± 5.58 mm and 198.0 ± 6.11 mm) and germinal cellular layers (3.58 ± 0.26 and 5.08 ± 0.29) of immunized males and control animals, respectively, were observed (P < 0.01). Then, in a study of long-term immune response due to vaccination in female and male mice (n = 4) from two subsequent experiments, a suppression of gonadal function and an induction of a Th1/Th2 immune response was also observed, determined by both, immunoglobulin and cytokine profiles, which lasted until the end of the study (7 months; P < 0.01). The findings of this study have demonstrated that vaccination with a new immunocastration vaccine inducing a Th1/Th2 immune response against GnRH (P < 0.01) elicit a decrease of gonadal function in male and female mice (P < 0.01). Owing to long-term duration of the antibody levels generated, this vaccine formulation appears as a promising alternative for immunocastration of several animal species where long-lasting reproductive block is needed. PMID:27344434

  10. Methods for the in vitro determination of an individual disposition towards TH1- or TH2-reactivity by the application of appropriate stimulatory antigens

    PubMed Central

    BARTH, H; BERG, P A; KLEIN, R

    2003-01-01

    In this study we performed several methods for the determination of cytokines (RT-PCR for the demonstration of cytokine mRNA and flow cytometry for the analysis of intracellular cytokines) and compared them with a recently established test system stimulating peripheral blood mononuclear cells (PBMC) with TH1- and TH2-relevant recall antigens and analysing type 1 and type 2 cytokines by ELISA. Aim of the study was therefore to evaluate the reliability of TH1/TH2 cytokine profiles in two individuals with different types of an allergic/atopic disposition: one of them showed a strong TH1/type 1-mediated tuberculin-reaction (subject A), the other (subject B) revealed elevated IgE-levels and eosinophil counts (TH2/type 2-mediated). PBMC were incubated with the type 1-antigen purified protein derivative (PPD) and the type 2-antigen tetanus-toxoid (TT) for seven days. From the comparison of ELISA with RT-PCR and flow cytometry-analysis it became evident that all three methods allowed the definition of subject A as a ‘type 1-responder’. Subject B showed a pure type 2-response in the ELISA method; PCR and flow cytometry analysis revealed the simultaneous production of type 1- and type 2-cytokines resulting in a mixed type 1/type 2-profile. Active immunization of subject A with TT at the end of the observation period of 12 months resulted in a transient shift from type 1- to a mixed type 1/type 2-profile (simultaneous PPD-induced IFN-γ- and TT-induced IL-5 production). From this pilot study based on clear cut clinical criteria concerning either a humoral or cellular immunological reactivity towards allergens/antigens it is suggested that the determination of type 1/type 2-cytokines by ELISA in supernatants of PBMC stimulated with type 1/type 2-relevant antigens is a useful approach for a better classification of ‘type1-’ or ‘type 2-responder’. PMID:12974758

  11. CD45-mediated signaling pathway is involved in Rhizoctonia bataticola lectin (RBL)-induced proliferation and Th1/Th2 cytokine secretion in human PBMC

    SciTech Connect

    Pujari, Radha; Eligar, Sachin M.; Kumar, Natesh; Nagre, Nagaraja N.; Inamdar, Shashikala R.; Swamy, Bale M.; Shastry, Padma

    2012-03-23

    Highlights: Black-Right-Pointing-Pointer RBL, a potent mitogenic and complex N-glycan specific lectin binds to CD45 on PBMC. Black-Right-Pointing-Pointer RBL triggers CD45-mediated signaling involved in activation of p38MAPK and STAT-5. Black-Right-Pointing-Pointer Inhibition of CD45 PTPase signaling blocks RBL-induced ZAP70 phosphorylation. Black-Right-Pointing-Pointer RBL-CD45 mediated signaling is crucial for RBL-induced immunodulatory activities. -- Abstract: We earlier reported the mitogenic and immunostimulatory activities of Rhizoctonia bataticola lectin (RBL), purified from phytopathogenic fungus R. bataticola in human PBMC. The lectin demonstrates specificity towards glycoproteins containing complex N-glycans. Since CD45-protein tyrosine phosphatase that abundantly expresses N-glycans is important in T-cell signaling, the study aimed to investigate the involvement of CD45 in the immunomodulatory activities of RBL. Flowcytometry and confocal microscopy studies revealed that RBL exhibited binding to PBMC and colocalized with CD45. The binding was comparable in cells expressing different CD45 isoforms-RA, -RB and -RO. CD45 blocking antibody reduced the binding and proliferation of PBMC induced by RBL. CD45-PTPase inhibitor dephostatin inhibited RBL-induced proliferation, expression of CD25 and pZAP-70. RBL-induced secretion of Th1/Th2 cytokines were significantly inhibited in presence of dephostatin. Also, dephostatin blocked phosphorylation of p38MAPK and STAT-5 that was crucial for the biological functions of RBL. The study demonstrates the involvement of CD45-mediated signaling in RBL-induced PBMC proliferation and Th1/Th2 cytokine secretion through activation of p38MAPK and STAT-5.

  12. Genetically engineered Newcastle disease virus expressing human interferon-λ1 induces apoptosis in gastric adenocarcinoma cells and modulates the Th1/Th2 immune response.

    PubMed

    Bu, Xuefeng; Li, Mi; Zhao, Yinghai; Liu, Sha; Wang, Mubin; Ge, Jinying; Bu, Zhigao; Yan, Yulan

    2016-09-01

    Interferon-λ1 (IFN-λ1), a recently discovered cytokine of the type III IFN family, was found to be a therapeutic alternative to type I IFN in terms of tumors. Using reverse genetics technique, we generated a recombinant Newcastle disease virus (NDV) LaSota strains named as human IFN‑λ1 recombinant adenovirus (rL-hIFN-λ1) containing human IFN-λ1 gene and further evaluated the expressing of IFN-λ1 in human gastric adenocarcinoma cell line SGC-7901 after infected with rL-hIFN-λ1 by using western blot analysis, RT-PCR and immunofluorescence analyses. IFN-λl specific receptor IFNLR1 was detected on several gastric tumor cell lines including SGC-7901 and AGS and on PBMCs.The expression of the IFN-λ1 proteins reached a high level detected in the supernatant harvested 24 h after the infection of tumor cells. The proliferation changes of SGC infected with rL-hIFN-λ1 was significantly inhibited compared with NDV-infected group. Apoptosis was significantly induced by rL-hIFN-λ1 in gastric cancer cells compared with NDV virus tested by TUNEL assay, western blot analysis and Annexin V flow cytometry. Due to the high dose of IFN-λ1 expressed by the rL-hIFN-λ1-infected tumor cells, the immune study showed that rL-hIFN-λ1 increased IFN-γ production [the T helper cell subtype 1 (Th1) response] and inhibited interleukin (IL)-13 production [the T helper cell subtype 2 (Th2) response] to change the Th1/Th2 response of tumor microenvironment which inhibited tumor growth. This study aims at building recombinant NDV rL-hIFN-λ1 as an efficient antitumor agent. PMID:27430534

  13. Mutants of Escherichia coli Heat-Labile Toxin Act as Effective Mucosal Adjuvants for Nasal Delivery of an Acellular Pertussis Vaccine: Differential Effects of the Nontoxic AB Complex and Enzyme Activity on Th1 and Th2 Cells

    PubMed Central

    Ryan, Elizabeth J.; McNeela, Edel; Murphy, Geraldine A.; Stewart, Helen; O'hagan, Derek; Pizza, Mariagrazia; Rappuoli, Rino; Mills, Kingston H. G.

    1999-01-01

    Mucosal delivery of vaccines is dependent on the identification of safe and effective adjuvants that can enhance the immunogenicity of protein antigens administered by nasal or oral routes. In this study we demonstrate that two mutants of Escherichia coli heat-labile toxin (LT), LTK63, which lacks ADP-ribosylating activity, and LTR72, which has partial enzyme activity, act as potent mucosal adjuvants for the nasal delivery of an acellular pertussis (Pa) vaccine. Both LTK63 and LTR72 enhanced antigen-specific serum immunoglobulin G (IgG), secretory IgA, and local and systemic T-cell responses. Furthermore, using the murine respiratory challenge model for infection with Bordetella pertussis, we demonstrated that a nasally delivered diphtheria, tetanus, and acellular pertussis (DTPa) combination vaccine formulated with LTK63 as an adjuvant conferred a high level of protection, equivalent to that generated with a parenterally delivered DTPa vaccine formulated with alum. This study also provides significant new information on the roles of the binding and enzyme components of LT in the modulation of Th1 and Th2 responses. LTK63, which lacks enzyme activity, promoted T-cell responses with a mixed Th1Th2 profile, but LTR72, which retains partial enzyme activity, and the wild-type toxin, especially at low dose, induced a more polarized Th2-type response and very high IgA and IgG antibody titers. Our findings suggest that the nontoxic AB complex has broad adjuvant activity for T-cell responses and that the ADP-ribosyltransferase activity of the A subunit also appears to modulate cytokine production, but its effect on T-cell subtypes, as well as enhancing, may be selectively suppressive. PMID:10569737

  14. Mutants of Escherichia coli heat-labile toxin act as effective mucosal adjuvants for nasal delivery of an acellular pertussis vaccine: differential effects of the nontoxic AB complex and enzyme activity on Th1 and Th2 cells.

    PubMed

    Ryan, E J; McNeela, E; Murphy, G A; Stewart, H; O'hagan, D; Pizza, M; Rappuoli, R; Mills, K H

    1999-12-01

    Mucosal delivery of vaccines is dependent on the identification of safe and effective adjuvants that can enhance the immunogenicity of protein antigens administered by nasal or oral routes. In this study we demonstrate that two mutants of Escherichia coli heat-labile toxin (LT), LTK63, which lacks ADP-ribosylating activity, and LTR72, which has partial enzyme activity, act as potent mucosal adjuvants for the nasal delivery of an acellular pertussis (Pa) vaccine. Both LTK63 and LTR72 enhanced antigen-specific serum immunoglobulin G (IgG), secretory IgA, and local and systemic T-cell responses. Furthermore, using the murine respiratory challenge model for infection with Bordetella pertussis, we demonstrated that a nasally delivered diphtheria, tetanus, and acellular pertussis (DTPa) combination vaccine formulated with LTK63 as an adjuvant conferred a high level of protection, equivalent to that generated with a parenterally delivered DTPa vaccine formulated with alum. This study also provides significant new information on the roles of the binding and enzyme components of LT in the modulation of Th1 and Th2 responses. LTK63, which lacks enzyme activity, promoted T-cell responses with a mixed Th1-Th2 profile, but LTR72, which retains partial enzyme activity, and the wild-type toxin, especially at low dose, induced a more polarized Th2-type response and very high IgA and IgG antibody titers. Our findings suggest that the nontoxic AB complex has broad adjuvant activity for T-cell responses and that the ADP-ribosyltransferase activity of the A subunit also appears to modulate cytokine production, but its effect on T-cell subtypes, as well as enhancing, may be selectively suppressive. PMID:10569737

  15. Pre-Existing Adenovirus Immunity Modifies a Complex Mixed Th1 and Th2 Cytokine Response to an Ad5/HIV-1 Vaccine Candidate in Humans

    PubMed Central

    Pine, Samuel O.; Kublin, James G.; Hammer, Scott M.; Borgerding, Joleen; Huang, Yunda; Casimiro, Danilo R.; McElrath, M. Juliana

    2011-01-01

    The results of the recent Step Study highlight a need to clarify the effects of pre-existing natural immunity to a vaccine vector on vaccine-induced T-cell responses. To investigate this interaction, we examined the relationship between pre-existing Ad5 immunity and T-cell cytokine response profiles in healthy, HIV-uninfected recipients of MRKAd5 HIV-1 gag vaccine (HVTN 050, ClinicalTrials.gov #NCT00849732). Participants were grouped by baseline Ad5 neutralizing antibody titer as either Ad5-seronegative (titer ≤18; n = 36) or Ad5-seropositive (titer >200; n = 34). Samples from vaccine recipients were analyzed for immune responses to either HIV-1 Gag peptide pools or Ad5 empty vector using an ex vivo assay that measures thirty cytokines in the absence of long-term culture. The overall profiles of cytokine responses to Gag and Ad5 had similar combinations of induced Th1- and Th2-type cytokines, including IFN-γ, IL-2, TNF-α, IP-10, IL-13, and IL-10, although the Ad5-specific responses were uniformly higher than the Gag-specific responses (p<0.0001 for 9 out of 11 significantly expressed analytes). At the peak response time point, PBMC from Ad5-seronegative vaccinees secreted significantly more IP-10 in response to Gag (p = 0.008), and significantly more IP-10 (p = 0.0009), IL-2 (p = 0.006) and IL-10 (p = 0.05) in response to Ad5 empty vector than PBMC from Ad5-seropositive vaccinees. Additionally, similar responses to the Ad5 vector prior to vaccination were observed in almost all subjects, regardless of Ad5 neutralizing antibody status, and the levels of secreted IFN-γ, IL-10, IL-1Ra and GM-CSF were blunted following vaccination. The cytokine response profile of Gag-specific T cells mirrored the Ad5-specific response present in all subjects before vaccination, and included a number of Th1- and Th2-associated cytokines not routinely assessed in current vaccine trials, such as IP-10, IL-10, IL-13, and GM-CSF. Together, these results suggest

  16. Whole recombinant Hansenula polymorpha expressing hepatitis B virus surface antigen (yeast-HBsAg) induces potent HBsAg-specific Th1 and Th2 immune responses.

    PubMed

    Bian, Guanglin; Cheng, Yuming; Wang, Zekun; Hu, Yunwen; Zhang, Xiaonan; Wu, Min; Chen, Zhiao; Shi, Bisheng; Sun, Shuhui; Shen, Yan; Chen, Er Jia; Yao, Xin; Wen, Yumei; Yuan, Zhenghong

    2009-12-10

    Recent studies have suggested that yeast cell wall components possess adjuvant activities. In the present study, heat-killed whole recombinant Hansenula polymorpha yeast expressing hepatitis B surface antigen (yeast-HBsAg) was generated, and the immune responses elicited by yeast-HBsAg were investigated in mice. The studies showed that yeast-HBsAg as well as yeast greatly promotes the accumulation of immune cells in mouse spleen and contributes to the maturation of dendritic cells (DCs). Yeast-HBsAg not only induces significantly higher antibody responses (including IgG, IgG1 and IgG2a), but also increases the IgG2a/IgG1 ratio, while alum combined with HBsAg (HBsAg+alum) only enhances antibody responses, but not the IgG2a/IgG1 ratio compared to HBsAg alone. Analysis of HBsAg-specific cytokines revealed that yeast-HBsAg is associated with production of both IFN-gamma and IL-4, but neither IFN-gamma nor IL-4 was detected in the HBsAg+alum-immunized group. Moreover, yeast-HBsAg induces potent HBsAg-specific lymphocyte proliferation and Cytotoxic T lymphocyte (CTL) responses. In conclusion, yeast-HBsAg enhances both HBsAg-specific Th1 and Th2 immune responses, while alum only enhances Th2 immune responses, suggesting that yeast-HBsAg may be an ideal candidate for an effective vaccine for the control of chronic hepatitis B virus (HBV) infection. PMID:19789093

  17. A Novel Role of IGFBP7 in Mouse Uterus: Regulating Uterine Receptivity through Th1/Th2 Lymphocyte Balance and Decidualization

    PubMed Central

    Liu, Zhen-Kun; Wang, Rong-Chun; Han, Bing-Chen; Yang, Ying; Peng, Jing-Pian

    2012-01-01

    Previously we have screened out Insulin-like Growth Factor Binding Protein 7 (IGFBP7) as a differentially expressed gene in post-implantation uterus versus pre-implantation uterus by suppressive subtractive hybridation. However its function in uterus was not clearly identified. In this research, the expression and function of IGFBP7 during post-implantation were studied. We found that IGFBP7 was mainly located in the glandular epithelium and the stroma, and was upregulated after embryo implantation. The vector pCR3.1-IGFBP7-t expressing partial IGFBP7 was constructed. Inhibition of IGFBP7 by specific DNA immunization induced significant reduction of implanted embryos and pregnancy rate. The number of implanted embryos (5.68±0.46) was significantly reduced after immunization with pCR3.1-IGFBP7-t, as compared with that of the mice immunized with the control vector (12.29±0.36) or saline (14.58±0.40) (p<0.01). After specific inhibition of IGFBP7, the T helper type 1 (Th1) cytokine IFNγ, was significantly elevated (p<0.05) and the Th2 cytokines IL-4 and IL-10, were reduced in uteri (p<0.05). The increase of Tbet and the decrease of Gata3 were found in mice peripheral lymphocytes by flow cytometry. The expression of decidualization marker IGFBP1 and angiogenesis regulator VEGF were declined in uteri (p<0.05). The expression of apoptosis-associated proteins, caspase3 and Bcl-2, were also declined (p<0.05). These results showed that inhibition of IGFBP7 induced pregnancy failure by shifting uterine cytokines to Th1 type dominance and repressing uterine decidualization. PMID:23028860

  18. As2 O3 combined with leflunomide prolongs heart xenograft survival via suppressing the response of Th1, Th2, and B cells in a rat model.

    PubMed

    Jiao, Zhi-Xing; Leng, Yun; Xia, Jun-Jie; Wu, Hai-Qiao; Jin, Ning; Fu, Jia-Zhao; Cheng, Lian-Na; Wang, Jin-Hua; Ni, Shao-Bin; Qi, Zhong-Quan

    2016-05-01

    Xenotransplantation remits the severe shortage of human organs and tissues for transplantation, which is a problem that severely limits the application of transplantation to the treatment of human disease. However, severe immune rejection significantly limits the efficacy of xenotransplantation. In this study, we systematically investigated the immunosuppressive effect and mechanism of action of As2 O3 and leflunomide using a hamster-to-rat heart xenotransplantation model. We initially examined heart xenograft survival following As2 O3 and leflunomide treatment alone or combined treatment. We found that treatment with As2 O3 combined with leflunomide can significantly prolong the survival of heart xenograft by inhibiting Th1 and Th2 differentiation and reducing the production of IgG and IgM. Interestingly, As2 O3 and leflunomide showed low toxicity to the organs of the recipient. Taken together, these observations indicate that treatment with As2 O3 combined with leflunomide may be a promising immunosuppressive schedule for xenotransplantation. PMID:27188662

  19. Reciprocal Regulation of Th1- and Th2-Cytokine-Producing T Cells during Clearance of Parasitemia in Plasmodium falciparum Malaria

    PubMed Central

    Winkler, Stefan; Willheim, Martin; Baier, Karin; Schmid, Daniela; Aichelburg, Alexander; Graninger, Wolfgang; Kremsner, Peter G.

    1998-01-01

    Flow cytometry for the intracellular detection of T-cell cytokines was performed for 15 Gabonese patients during acute uncomplicated Plasmodium falciparum malaria. A striking expansion of CD4+ and CD8+ T cells producing gamma interferon (IFN-γ) was found during drug-induced clearance of parasitemia, paralleled by a decrease of interleukin-2 (IL-2) production. The frequency of IL-4- and IL-13-producing CD4+ cells gradually decreased, whereas the frequency of T cells producing IL-2+–IFN-γ+, IL-4−–IL-5+, and IL-4+–IL-5+ cytokines as well as IL-4+–IFN-γ+ and IL-13+–IFN-γ+ cytokines was not significantly altered. The capacity for IL-10 production within the CD4+ subset increased due to an expansion of both IL-10+–IFN-γ− and IL-10+–IFN-γ+ cytokine-expressing cells. Thus, a more pronounced Th2-driven immune response during acute untreated P. falciparum infection with a shift towards Th1 responsiveness induced by parasite clearance is suggested. PMID:9826394

  20. Rapeseed Oil and Ginseng Saponins Work Synergistically To Enhance Th1 and Th2 Immune Responses Induced by the Foot-and-Mouth Disease Vaccine

    PubMed Central

    Zhang, Cenrong; Wang, Yuemin; Wang, Meng; Su, Xiaoyan; Lu, Yisong; Su, Fei

    2014-01-01

    Previous investigations demonstrated that saponins isolated from the root of Panax ginseng C. A. Meyer (i.e., ginseng root saponin [GS-R]) had adjuvant activity. In the present study, the combined effects of rapeseed oil (RO) and GS-R on the immune responses elicited by foot-and-mouth disease (FMD) vaccine were investigated by measuring FMD virus (FMDV)-specific antibody levels, cytokine levels, lymphocyte proliferation, and long-lived IgG-secreting plasma cells from bone marrow in a mouse model. The results indicated that RO in combination with GS-R significantly enhanced serum IgG and isotype concentrations, gamma interferon (IFN-γ) and interleukin 5 (IL-5) levels, splenocyte proliferative responses to stimulations with concanavalin A (ConA), lipopolysaccharide (LPS), and FMDV antigen, and the numbers of IgG-secreting plasma cells in the bone marrow, suggesting that RO/GS-R enhanced both Th1 and Th2 immune responses. In addition, no significant difference was found between RO/GS-R and the commercial adjuvant oil ISA 206 in the promotion of FMD vaccine-induced immune responses. Considering the vegetable origin of RO and GS-R and the potent adjuvant activity, RO/GS-R should be studied further for the development of veterinary vaccines, especially for use in food animals in order to promote food safety. PMID:24920601

  1. [EFFECT OF 4-METHYLPYRAZOLE ON IMMUNE RESPONSE, FUNCTION OF Th1 AND Th2 LYMPHOCYTES, AND CYTOKINE CONCENTRATION IN RAT BLOOD AFTER ACUTE METHANOL POISONING].

    PubMed

    Zabrodskii, P F; Maslyakov, V V; Gromov, M S

    2016-01-01

    It was established in experiments on noninbred albino rats that the acute intoxication with methanol (1.0 LD50) decreased cellular and humoral immune responses, Th2-lymphocyte activity (to a greater extent as compared to the function of Th1 cells), reduced the blood concentration of immunoregulatory (IFN-g, IL-2, IL-4) and proinflammatory (TNF, IL-1b, IL-6) cytokines on the average by 36.5% (p < 0.05), and did not affect the content of anti-inflammatory cytokines (IL-10, IL-13). Methanol antidote 4-methylpyrazole (non-competitive inhibitor of alcohol dehydrogenase) administered upon acute intoxication with methanol at a dose of 1.0 DL50 partially reduces the intoxication-induced suppression of humoral and cellular immune response, activity of T-helper cells, and production of IL-4 and restores blood levels of TNF, IL-1b, IFN-γ, IL-4, IL-2, IL-6 to the control values. PMID:27455577

  2. Immunization with Wuchereria bancrofti Glutathione-S-transferase Elicits a Mixed Th1/Th2 Type of Protective Immune Response Against Filarial Infection in Mastomys.

    PubMed

    Andure, Dhananjay; Pote, Kiran; Khatri, Vishal; Amdare, Nitin; Padalkar, Ramchandra; Reddy, Maryada Venkata Rami

    2016-10-01

    Lymphatic filariasis is a mosquito borne parasitic infection and can severely affect the normal working ability of an individual. Currently there is no vaccine available to prevent this infection and the development of a potential vaccine could effectively support the on-going mass drug administration program by World Health Organization (WHO). Filarial parasites have complex mechanisms to modulate the host immune responses against them. The glutathione-S-transferases (GST) are the important enzymes effectively involved to counteract the oxidative free radicals produced by the host. In the present study, we have shown that the mastomys which are fully permissible rodents for Brugia malayi when immunized with Wuchereria bancrofti recombinant GST (rWbGST) could induce 65.5 % in situ cytotoxicity against B. malayi infective (L3) larvae. There was a balanced Th1/Th2 immune response in the vaccinated animals, characterized by higher levels of WbGST-specific IgG1 and IgG2a antibodies and pronounced IFN-γ, IL-10 and IL-4 cytokines production by the spleen cells. PMID:27605739

  3. The comparison of Th1, Th2, Th9, Th17 and Th22 cytokine profiles in acute and chronic HIV-1 infection.

    PubMed

    Gorenec, Lana; Zidovec Lepej, Snjezana; Grgic, Ivana; Planinic, Ana; Iscic Bes, Janja; Vince, Adriana; Begovac, Josip

    2016-08-01

    The aim of this study was to compare cytokine expression on both gene and protein levels in acute and chronic phase of HIV type 1 (HIV-1) infection. Thirty four patients were enrolled for cytokine expression analysis on protein level in acute and chronic stage of HIV-1 infection. Using PCR array technology, expression of 84 cytokine genes was measured in 3 patients in acute and 3 patients in chronic stage of HIV-1 infection. Bead-based cytometry was used to quantify levels of Th1/Th2/Th9/Th17/Th22 cytokines. The results showed statistically significant increase of 13 cytokine gene expression (cd40lg, csf2, ifna5, il12b, il1b, il20, lta, osm, spp1, tgfa, tnfsf 11, 14 and 8) and downregulation of the il12a expression in chronic HIV type 1 infection. Concentrations of IL-10, IL-4 and TNF-α were increased in the acute HIV type 1 infection when compared to control group. During chronic HIV type 1 infection there was an increase of IL-10, TNF-α, IL-2, IL-6, IL-13 and IL-22 levels when compared to control group. Comparison of cytokine expression between two stages of infection showed a significant decrease in IL-9 concentration. This study showed changes in cytokine profiles on both gene and protein levels in different stages of HIV-infection. PMID:27268396

  4. Effect of iodine excess on Th1, Th2, Th17, and Treg cell subpopulations in the thyroid of NOD.H-2h4 mice.

    PubMed

    Yang, Xiao; Gao, Tianshu; Shi, Rui; Zhou, Xiyu; Qu, Jinqiao; Xu, Jia; Shan, Zhongyan; Teng, Weiping

    2014-06-01

    Iodine is an indispensable micronutrient for thyroid hormone synthesis and metabolism. Iodine excess may trigger and exacerbate autoimmune thyroiditis (AIT). The pathogenetic mechanism of iodine excess-induced AIT is partly regarded as T helper type 1 (Th1) cell and/or T helper type 17 (Th17) cell dominant autoimmune disease. It is still unknown whether other cluster of differentiation 4+ T (CD4+T) cell subpopulations are involved. Therefore, we studied the profile of all the CD4+T cell subpopulations of the thyroid in iodine excess-induced nonobese diabetic-H2h4 (NOD.H-2h4) mice to explore the potential immunologic mechanism of iodine excess-induced AIT. A total of 40 healthy 8-week-old NOD.H-2h4 mice were randomly allocated into the normal group (NG, n=20) and the test group (TG, n=20), which were fed with double-distilled water and 0.05% sodium iodine (NaI) for 8 weeks, respectively. Compared to the NG, in the TG, the incidence of AIT was significantly higher, the expressions of interleukin-17 (IL-17), interleukin-23 (IL-23), interleukin-6 (IL-6), and transforming growth factor-β (TGF-β) remarkably increased by immunohistochemistry, which were further verified by reverse transcription polymerase chain reaction (RT-PCR), while the protein and mRNA expressions of interleukin-4 (IL-4) and interferon-γ (INF-γ) decreased markedly. In the AIT mice, the expressions of retinoic acid-related orphan receptor gamma t (RORγt), retinoic acid-related orphan receptor alpha (RORα), and signal transducer and activator of transcription 3 (STAT3) were much higher, the expression of forkhead/winged helix transcription factor p3 (Foxp3) significantly lower by western blot, and the proportion of Th17 cells by flow cytometry method (FCM) much larger compared to those of the NG group. In conclusion, Th17 cells may promote an inflammatory reaction in the development of iodine-excess-induced AIT, which is negatively regulated by Th1, T helper type 2 (Th2), and regulatory T (Treg

  5. Stimulation of the histamine 4 receptor with 4-methylhistamine modulates the effects of chronic stress on the Th1/Th2 cytokine balance.

    PubMed

    Ahmad, Sheikh Fayaz; Zoheir, Khairy M A; Ansari, Mushtaq Ahmad; Korashy, Hesham M; Bakheet, Saleh A; Ashour, Abdelkader E; Attia, Sabry M

    2015-03-01

    Alterations to the immune system caused by stress have been considered to markedly increase the risk for immune-related diseases such as cancer and autoimmune disorders. We investigated the potential anti-stress effects of the histamine 4 receptor (H4R) agonist, 4-methylhistamine (4-MeH), in a murine stress model. Mice were placed in 50ml conical centrifuge tubes for 12h followed by a 12h rest. The effects of treatment with 4-MeH (30mg/kg, i.p., twice daily) for 2 days were assessed. At 2 days after physical restraint, mice were sacrificed and tissues harvested. We evaluated the effects of 4-MeH treatment on CD4(+) T cell production, and intracellular IFN-γ and IL-4 expression in these cells. We also assessed IL-1β, IFN-γ, TNF-α, and IL-4 mRNA expression as well as IFN-γ, TNF-α, GITR, Ox40 and IL-4 protein expression in the spleen. The results showed that 4-MeH treatment of stressed mice results in a substantial increase in the CD4(+) T cells as well as in IFN-γ production by these cells. Compared to both untreated and stressed controls. In contrast, IL-4 expression decreased significantly following 4-MeH treatment of mice. Moreover, stimulation of the H4R resulted in up-regulated expression of IL-1β, IFN-γ and TNF-α mRNAs and decreased the expression of IL-4. Western blot analysis confirmed decreased protein expression of IFN-γ, TNF-α, GITR, Ox40 and increased IL-4 in the SC group and treatment of mice with 4-MeH reversed these effects. Our results confirm the significant impact of chronic stress on T cell function and production of Th1/Th2 mediators H4R. PMID:25457414

  6. Does Genetic Regulation of IgE Begin In-Utero? Evidence from TH1/TH2 Gene Polymorphisms and Cord Blood Total IgE

    PubMed Central

    Hong, Xiumei; Tsai, Hui-Ju; Liu, Xin; Arguelles, Lester; Kumar, Rajesh; Wang, Guoying; Kuptsova-Clarkson, Nataliya; Pearson, Colleen; Ortiz, Kathryn; Bonzagni, Anthony; Apollon, Stephanie; Fu, Lingling; Pongracic, Jacqueline A; Schleimer, Robert; Holt, Patrick G.; Bauchner, Howard; Wang, Xiaobin

    2010-01-01

    Background Elucidation of early life factors is critical to understand the development of allergic diseases, especially those manifesting in early life such as food allergies and atopic dermatitis. Cord blood IgE (CBIgE) is a recognized risk factor for the subsequent development of allergic diseases. In contrast to numerous genetic studies of total serum IgE in children and adults, limited genetic studies on CBIgE have been conducted. Objective To test the associations between functional or tagging single nucleotide polymorphisms (SNPs) in genes involved in the TH1/TH2 pathway and CBIgE in a large U.S. inner-city birth cohort. Methods CBIgE, measured by Phadia ImmnunoCAP, was analyzed as a continuous and a binary variable. The association of each SNP with the two outcomes was tested using tobit and logistic regression models, respectively, with adjustment for pertinent covariates, ancestral proportion, and multiple testing. Ethnic heterogeneity and gene-gene interactions were also explored. Results Three SNPs (rs1800925, rs2069743 and rs1295686) in the IL13 gene were significantly associated with CBIgE concentration (p≤6×10-4, pFDR<0.05). These SNPs jointly influenced CBIgE in a dose-response manner (ptrend=9×10-8). Significant associations also were observed for SNPs in the IL13RA1 (rs5956080) and STAT6 (rs11172106) genes. Ethnicity-specific genetic effects were observed for SNPs in the IL5 and GATA3 genes. Several gene-gene interactions (including IL13-IL4R and IL13-STAT6 interactions) were detected in relation to CBIgE. Conclusion Our data demonstrated that multiple SNPs were individually and jointly associated with CBIgE, with evidence of gene-gene interactions and ethnic heterogeneity. These findings suggest that genetic regulation of IgE may begin in-utero. PMID:21050946

  7. Peroxisome proliferator-activated receptor {alpha} agonists modulate Th1 and Th2 chemokine secretion in normal thyrocytes and Graves' disease

    SciTech Connect

    Antonelli, Alessandro; Ferrari, Silvia Martina; Frascerra, Silvia; Corrado, Alda; Pupilli, Cinzia; Bernini, Giampaolo; Benvenga, Salvatore; Ferrannini, Ele; Fallahi, Poupak

    2011-07-01

    Until now, no data are present about the effect of peroxisome proliferator-activated receptor (PPAR){alpha} activation on the prototype Th1 [chemokine (C-X-C motif) ligand (CXCL)10] (CXCL10) and Th2 [chemokine (C-C motif) ligand 2] (CCL2) chemokines secretion in thyroid cells. The role of PPAR{alpha} and PPAR{gamma} activation on CXCL10 and CCL2 secretion was tested in Graves' disease (GD) and control primary thyrocytes stimulated with interferon (IFN){gamma} and tumor necrosis factor (TNF){alpha}. IFN{gamma} stimulated both CXCL10 and CCL2 secretion in primary GD and control thyrocytes. TNF{alpha} alone stimulated CCL2 secretion, while had no effect on CXCL10. The combination of IFN{gamma} and TNF{alpha} had a synergistic effect both on CXCL10 and CCL2 chemokines in GD thyrocytes at levels comparable to those of controls. PPAR{alpha} activators inhibited the secretion of both chemokines (stimulated with IFN{gamma} and TNF{alpha}) at a level higher (for CXCL10, about 60-72%) than PPAR{gamma} agonists (about 25-35%), which were confirmed to inhibit CXCL10, but not CCL2. Our data show that CCL2 is modulated by IFN{gamma} and TNF{alpha} in GD and normal thyrocytes. Furthermore we first show that PPAR{alpha} activators inhibit the secretion of CXCL10 and CCL2 in thyrocytes, suggesting that PPAR{alpha} may be involved in the modulation of the immune response in the thyroid.

  8. TH1/TH2 cytokine profile, metalloprotease-9 activity and hormonal status in pregnant rheumatoid arthritis and systemic lupus erythematosus patients

    PubMed Central

    MUÑOZ-VALLE, J F; VÁZQUEZ-DEL MERCADO, M; GARCÍA-IGLESIAS, T; OROZCO-BAROCIO, G; BERNARD-MEDINA, G; MARTÍNEZ-BONILLA, G; BASTIDAS-RAMÍREZ, B E; NAVARRO, A D; BUENO, M; MARTÍNEZ-LÓPEZ, E; BEST-AGUILERA, C R; KAMACHI, M; ARMENDÁRIZ-BORUNDA, J

    2003-01-01

    During the course of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), several immune and neuroendocrine changes associated with pregnancy may exert positive (amelioration) or negative (exacerbation) effects on the clinical outcome. In order to shed light on the mechanisms underlying these responses, we performed a prospective longitudinal study in RA and SLE pregnant women, including healthy pregnant women as a control group. Cytokine messenger RNA (mRNA) expression assessed by quantitative competitive polymerase chain reaction (PCR) in peripheral blood mononuclear cells (PBMC), cytokine levels and lymphocyte proliferation responses (LPR) following phytohaemagglutinin (PHA) stimulation of PBMC, plasma metalloprotease-9 activity (MMP-9) and hormonal status during pregnancy were determined. TNFa was the most abundant cytokine mRNA expressed in PBMC in all groups studied (healthy pregnant women, RA and SLE pregnant patients). However, a general TH2 response reflected by high IL-10 levels was found in RA, as well as SLE, patients. A significant change in IFN-γ was observed in RA patients but only during the first trimester of pregnancy. This compared with a major TH1 response in healthy pregnant women. Interestingly, our study showed a homogeneous hormonal pattern in RA and SLE patients. Although decreased cortisol levels were observed in all patients studied, this is possibly related to the remission of disease activity status brought about by steroid treatment before and during pregnancy. In summary, we suggest that complex immune and hormonal networks are involved in pregnancy and that rheumatic diseases are very dynamic immune processes that cannot be described with a clear-cut cytokine profile. Furthermore, the observations in this study may reflect treatment-related immune effects more than those associated with disease. PMID:12562402

  9. L-Theanine Improves Immunity by Altering TH2/TH1 Cytokine Balance, Brain Neurotransmitters, and Expression of Phospholipase C in Rat Hearts.

    PubMed

    Li, Chengjian; Tong, Haiou; Yan, Qiongxian; Tang, Shaoxun; Han, Xuefeng; Xiao, Wenjun; Tan, Zhiliang

    2016-01-01

    BACKGROUND This study aimed to investigate the regulatory effects of L-theanine on secretion of immune cytokines, hormones, and neurotransmitters, and mRNA expression of phospholipase C (PLC) in rats, and to explore its regulatory mechanism in immune function. MATERIAL AND METHODS Sixty-four Sprague-Dawley rats received daily intragastric infusion of different doses of L-theanine solution [0, 50 (LT), 200 (MT), and 400 (HT) mg/kg BW]. Cytokines, immunoglobulins, and hormones in the serum, neurotransmitters, and mRNA expression of PLC in the relevant tissues were assayed. RESULTS L-theanine administration increased the splenic organ index and decreased the contents of ILs-4/6/10 and the ratio of IL-4/IFN-γ in the serum. High-dose L-theanine administration increased the levels of dopamine and 5-hydroxytryptamine in the pituitary and hippocampus, resulting in decrease in corticosterone level in the serum. L-theanine administration decreased the mRNA expressions of PLC isomers in the liver and PLC-γ1 and PLC-δ1 in the spleen. Interestingly, mRNA expressions of PLC-β1 in the spleen and PLC isomers mRNA in the heart were up-regulated by L-theanine administration. CONCLUSIONS Administration of 400 mg/kg BWL-theanine improved immune function of the rats by increasing the splenic weight, altering the Th2/Th1 cytokine balance, decreasing the corticosterone level in the serum, elevating dopamine and 5-hydroxytryptamine in the brain, and regulating the mRNA expression of PLC isomers in the heart. PMID:26922362

  10. L-Theanine Improves Immunity by Altering TH2/TH1 Cytokine Balance, Brain Neurotransmitters, and Expression of Phospholipase C in Rat Hearts

    PubMed Central

    Li, Chengjian; Tong, Haiou; Yan, Qiongxian; Tang, Shaoxun; Han, Xuefeng; Xiao, Wenjun; Tan, Zhiliang

    2016-01-01

    Background This study aimed to investigate the regulatory effects of L-theanine on secretion of immune cytokines, hormones, and neurotransmitters, and mRNA expression of phospholipase C (PLC) in rats, and to explore its regulatory mechanism in immune function. Material/Methods Sixty-four Sprague-Dawley rats received daily intragastric infusion of different doses of L-theanine solution [0, 50 (LT), 200 (MT), and 400 (HT) mg/kg BW]. Cytokines, immunoglobulins, and hormones in the serum, neurotransmitters, and mRNA expression of PLC in the relevant tissues were assayed. Results L-theanine administration increased the splenic organ index and decreased the contents of ILs-4/6/10 and the ratio of IL-4/IFN-γ in the serum. High-dose L-theanine administration increased the levels of dopamine and 5-hydroxytryptamine in the pituitary and hippocampus, resulting in decrease in corticosterone level in the serum. L-theanine administration decreased the mRNA expressions of PLC isomers in the liver and PLC-γ1 and PLC-δ1 in the spleen. Interestingly, mRNA expressions of PLC-βf1 in the spleen and PLC isomers mRNA in the heart were up-regulated by L-theanine administration. Conclusions Administration of 400 mg/kg BWL-theanine improved immune function of the rats by increasing the splenic weight, altering the Th2/Th1 cytokine balance, decreasing the corticosterone level in the serum, elevating dopamine and 5-hydroxytryptamine in the brain, and regulating the mRNA expression of PLC isomers in the heart. PMID:26922362

  11. Expression Pattern of Transcription Factors and Intracellular Cytokines Reveals That Clinically Cured Tuberculosis Is Accompanied by an Increase in Mycobacterium-Specific Th1, Th2, and Th17 Cells

    PubMed Central

    da Silva, Marcos V.; Massaro Junior, Vladimir J.; Machado, Juliana R.; Silva, Djalma A. A.; Castellano, Lúcio R.; Alexandre, Patricia B. D.; Rodrigues, Denise B. R.; Rodrigues, Virmondes

    2015-01-01

    Tuberculosis (TB) remains a major global health problem and is the second biggest cause of death by infectious disease worldwide. Here, we investigate in vitro the Th1, Th2, Th17, and Treg cytokines and transcriptional factors produced after Mycobacterium-specific antigen stimulation in patients with active pulmonary tuberculosis, clinically cured pulmonary tuberculosis, and healthy donors with a positive tuberculin skin test (TST+). Together, our data indicate that clinical cure after treatment increases the percentages of Mycobacterium-specific Th1, Th2, and Th17 cells compared with those found in active-TB and TST+ healthy donors. These results show that the host-parasite equilibrium in latent TB breaks in favor of the microorganism and that the subsequent clinical recovery posttreatment does not return the percentage levels of such cells to those observed in latent tuberculosis. Additionally, our results indicate that rather than showing an increase in the percentage of Mycobacterium-specific Tregs, active-TB patients display lower Th1 : Treg and Th17 : Treg ratios. These data, together with lower Th1 : Th2 and Th17 : Th2 ratios, may indicate a mechanism by which the breakdown of the host-parasite equilibrium leads to active-TB and changes in the repertoire of Mycobacterium-specific Th cells that are associated with clinical cure after treatment of pulmonary tuberculosis. PMID:26000298

  12. The effect of combined IL10 siRNA and CpG ODN as pathogen-mimicking microparticles on Th1/Th2 cytokine balance in dendritic cells and protective immunity against B cell lymphoma

    PubMed Central

    Pradhan, Pallab; Qin, Hong; Leleux, Jardin; Gwak, Dongho; Sakamaki, Ippei; Kwak, Larry W.; Roy, Krishnendu

    2014-01-01

    Success of an immunotherapy for cancer often depends on the critical balance of T helper 1 (Th1) and T helper 2 (Th2) responses driven by antigen presenting cells, specifically dendritic cells (DCs). Th1-driven cytotoxic T cell (CTL) responses are key to eliminating tumor cells. It is well established that CpG oligonucleotides (ODN), a widely studied Toll-like receptor 9 (TLR9) agonist, used to enhance Th1 response, also induces high levels of the anti-inflammatory, Th2-promoting cytokine IL10, which could dampen the resulting Th1 response. Biomaterials-based immunomodulatory strategies that can reduce IL10 production while maintaining IL12 levels during CpG delivery could further enhance the Th1/Th2 cytokine balance and improve anti-tumor immune response. Here we report that dual-delivery of IL10-silencing siRNA along with CpG ODN to the same DCs using pathogen-mimicking microparticles (PMPs), significantly enhances their Th1/Th2 cytokine ratio through concurrent inhibition of CpG-induced IL10 production. Co-delivery of poly(I:C), a TLR3 agonist had only minor effects on IL10 levels. Further, simultaneous immunotherapy with CpG ODN and IL10 siRNA enhanced immune protection of an idiotype DNA vaccine in a prophylactic murine model of B cell lymphoma whereas co-delivery of poly(I:C) and CpG did not enhance protection. These results suggest that PMPs can be used to precisely modulate TLR ligand-mediated immune-stimulation in DCs, through co-delivery of cytokine-silencing siRNAs and thereby boost antitumor immunity. PMID:24720881

  13. Relationships between Th1 or Th2 iNKT Cell Activity and Structures of CD1d-Antigen Complexes: Meta-analysis of CD1d-Glycolipids Dynamics Simulations

    PubMed Central

    Laurent, Xavier; Renault, Nicolas; Farce, Amaury; Chavatte, Philippe; Hénon, Eric

    2014-01-01

    A number of potentially bioactive molecules can be found in nature. In particular, marine organisms are a valuable source of bioactive compounds. The activity of an α-galactosylceramide was first discovered in 1993 via screening of a Japanese marine sponge (Agelas mauritanius). Very rapidly, a synthetic glycololipid analogue of this natural molecule was discovered, called KRN7000. Associated with the CD1d protein, this α-galactosylceramide 1 (KRN7000) interacts with the T-cell antigen receptor to form a ternary complex that yields T helper (Th) 1 and Th2 responses with opposing effects. In our work, we carried out molecular dynamics simulations (11.5 µs in total) involving eight different ligands (conducted in triplicate) in an effort to find out correlation at the molecular level, if any, between chemical modulation of 1 and the orientation of the known biological response, Th1 or Th2. Comparative investigations of human versus mouse and Th1 versus Th2 data have been carried out. A large set of analysis tools was employed including free energy landscapes. One major result is the identification of a specific conformational state of the sugar polar head, which could be correlated, in the present study, to the biological Th2 biased response. These theoretical tools provide a structural basis for predicting the very different dynamical behaviors of α-glycosphingolipids in CD1d and might aid in the future design of new analogues of 1. PMID:25376021

  14. Differential effects of Th1, monocyte/macrophage and Th2 cytokine mixtures on early gene expression for glial and neural-related molecules in central nervous system mixed glial cell cultures: neurotrophins, growth factors and structural proteins

    PubMed Central

    Lisak, Robert P; Benjamins, Joyce A; Bealmear, Beverly; Nedelkoska, Liljana; Yao, Bin; Land, Susan; Studzinski, Diane

    2007-01-01

    Background In multiple sclerosis, inflammatory cells are found in both active and chronic lesions, and it is increasingly clear that cytokines are involved directly and indirectly in both formation and inhibition of lesions. We propose that cytokine mixtures typical of Th1 or Th2 lymphocytes, or monocyte/macrophages each induce unique molecular changes in glial cells. Methods To examine changes in gene expression that might occur in glial cells exposed to the secreted products of immune cells, we have used gene array analysis to assess the early effects of different cytokine mixtures on mixed CNS glia in culture. We compared the effects of cytokines typical of Th1 and Th2 lymphocytes and monocyte/macrophages (M/M) on CNS glia after 6 hours of treatment. Results In this paper we focus on changes with potential relevance for neuroprotection and axon/glial interactions. Each mixture of cytokines induced a unique pattern of changes in genes for neurotrophins, growth and maturation factors and related receptors; most notably an alternatively spliced form of trkC was markedly downregulated by Th1 and M/M cytokines, while Th2 cytokines upregulated BDNF. Genes for molecules of potential importance in axon/glial interactions, including cell adhesion molecules, connexins, and some molecules traditionally associated with neurons showed significant changes, while no genes for myelin-associated genes were regulated at this early time point. Unexpectedly, changes occurred in several genes for proteins initially associated with retina, cancer or bone development, and not previously reported in glial cells. Conclusion Each of the three cytokine mixtures induced specific changes in gene expression that could be altered by pharmacologic strategies to promote protection of the central nervous system. PMID:18088439

  15. Clinical association of baseline levels of conjugated dienes in low-density lipoprotein and nitric oxide with aggressive B-cell non-Hodgkin lymphoma and their relationship with immunoglobulins and Th1-to-Th2 ratio

    PubMed Central

    Haddouche, Mustapha; Meziane, Warda; Hadjidj, Zeyneb; Mesli, Naima; Aribi, Mourad

    2016-01-01

    Objective The aim of this study was to highlight the clinical association of baseline levels of conjugated dienes in low-density lipoprotein (LDL-BCD) and nitric oxide (NO) with immunoglobulins (Igs) and T helper (Th)1/Th2 ratio in patients with newly diagnosed B-cell non-Hodgkin lymphoma (NHL). Patients and methods Thirty-two newly diagnosed patients with aggressive B-cell NHL and 25 age-, sex-, and body-mass-index-matched healthy controls were randomly selected for a cross-sectional case–control study conducted at the Hematology Department of Tlemcen Medical Centre University (northwest of Algeria). Results Circulating levels of LDL-BCD and NO and those of IgA and IgM were significantly higher in patients than in controls. The levels of Th1/Th2 ratio and plasma total antioxidant capacity were significantly lower in patients compared with controls, while malondialdehyde and protein carbonyl levels were significantly higher in patients. B-cell NHL was significantly associated with high levels of LDL-BCD from 25th to 75th percentile (25th percentile: relative risk [RR] =2.26, 95% confidence interval [CI] 1.42–3.59, P=0.014; 50th percentile: RR =2.84, 95% CI 1.72–4.68, P<0.001; 75th percentile: RR =5.43, 95% CI 2.58–11.42, P<0.001). Similarly, the disease was significantly associated with high levels of NO production from 25th to 75th percentile (25th percentile: RR =2.07, 95% CI 1.25–3.44, P=0.024; 50th percentile: RR =2.78, 95% CI 1.63–4.72, P<0.001; 75th percentile: RR =4.68, 95% CI 2.21–9.91, P<0.001). Moreover, LDL-BCD levels were positively and significantly correlated with interferon (IFN)-γ, whereas NO levels were inversely and significantly correlated with IFN-γ and Th1/Th2 ratio. Conclusion LDL-BCD and NO production seem to be associated with aggressive B-cell NHL and alteration of Th1/Th2 ratio. Our results have to be examined using ex vivo mechanistic studies leading to further investigations of these parameters, with an interest in the

  16. Combined Effects of Circulating Levels of 25-Hydroxyvitamin D and Th1 and Th2 Cytokines on Breast Cancer Estrogen Receptor Status

    PubMed Central

    Yao, Song; Hong, Chi-Chen; McCann, Susan E.; Zirpoli, Gary; Quan, Lei; Gong, Zhihong; Johnson, Candace S.; Trump, Donald L.; Ambrosone, Christine B.

    2014-01-01

    Vitamin D has been recognized for its immune-modulating properties. We have previously found that levels of 25OHD, and cytokines including IL5, IFNα2, and TNFα, are also associated with estrogen receptor (ER) negative breast cancer in younger women. Thus, we hypothesized that there may be interactions between vitamin D and the immune system in influencing breast cancer ER status, which was tested in 490 women with incident breast cancer. There was no correlation of the levels of 25OHD with any cytokine, and their associations with tumor ER negative status were independent of each other. However, premenopausal women with low 25OHD and high TNFα levels had the highest likelihood of having ER negative cancer (odds ratio [OR] = 7.32, 95% confidence interval [CI] = 2.44−21.98), with evidence of synergy between the two (relative excess risk due to interaction [RERI] = 5.46, p for additive interaction = 0.14, and p for multiplicative interaction = 0.09). There were similar synergistic associations between 25OHD and IL5, and several IFNα2 to Th2 cytokine ratios. This is the first study to provide evidence of interactions between vitamin D and the immune system in relation to breast cancer ER status, which may inform combinational use of vitamin D and anti-inflammatory drugs for cancer prevention and therapy. PMID:24473087

  17. Combined effects of circulating levels of 25-hydroxyvitamin d and Th1 and th2 cytokines on breast cancer estrogen receptor status.

    PubMed

    Yao, Song; Hong, Chi-Chen; McCann, Susan E; Zirpoli, Gary; Quan, Lei; Gong, Zhihong; Johnson, Candace S; Trump, Donald L; Ambrosone, Christine B

    2014-01-01

    Vitamin D has been recognized for its immune-modulating properties. We have previously found that levels of 25OHD, and cytokines including IL5, IFNα2, and TNFα, are also associated with estrogen receptor (ER) negative breast cancer in younger women. Thus, we hypothesized that there may be interactions between vitamin D and the immune system in influencing breast cancer ER status, which was tested in 490 women with incident breast cancer. There was no correlation of the levels of 25OHD with any cytokine, and their associations with tumor ER negative status were independent of each other. However, premenopausal women with low 25OHD and high TNFα levels had the highest likelihood of having ER negative cancer (odds ratio [OR] = 7.32, 95% confidence interval [CI] = 2.44-21.98), with evidence of synergy between the two (relative excess risk due to interaction [RERI] = 5.46, p for additive interaction = 0.14, and p for multiplicative interaction = 0.09). There were similar synergistic associations between 25OHD and IL5, and several IFNα2 to Th2 cytokine ratios. This is the first study to provide evidence of interactions between vitamin D and the immune system in relation to breast cancer ER status, which may inform combinational use of vitamin D and anti-inflammatory drugs for cancer prevention and therapy. PMID:24473087

  18. CD4+CD25+Foxp3+ T regulatory cells, Th1 (CCR5, IL-2, IFN-γ) and Th2 (CCR4, IL-4, Il-13) type chemokine receptors and intracellular cytokines in children with common variable immunodeficiency.

    PubMed

    Kutukculer, Necil; Azarsiz, Elif; Aksu, Guzide; Karaca, Neslihan Edeer

    2016-06-01

    Common variable immunodeficiency (CVID) is a heterogeneous group of primary antibody deficiencies characterized by decreased serum immunoglobulin G along with a decrease in serum IgA and/or IgM, defective specific antibody production, and recurrent bacterial infections. Abnormal lymphocyte trafficking, dysregulated cellular responses to chemokines, and uncontrolled T cell polarization may be involved in the pathogenesis and may help to understand the clinical complications. We evaluated T helper cell subsets (chemokine receptors CCR4, CCR5, and CCR7), expressions on T lymphocytes, intracellular cytokines - IL-2, IL-4, IL-13, IFN- γ-on CD4(+) T cells, and expression of CD4(+)CD25(+)Foxp3(+) regulatory T cells of 20 CVID patients and 26 healthy controls. Autoimmune clinical findings and other complications were also determined. Percentages and absolute numbers of CD4(+)CD25(+) Foxp3(+) cells did not show any significant difference between CVID cases and healthy controls nor between severe and moderate disease patients. The only significant difference regarding Th1 and Th2 type intracellular cytokines was the decreased absolute numbers of CD3(+)CD4(+)IL4(+) cells in CVID cases. There were some findings about T helper cell type dominance in CVID patients such as positive correlation between hepatomegaly and high IL-2 and IFN-γ in CD3(+)CD4(+) cells and very high expression of CCR5 (Th1) on CD3(+)CD4(+) cells in patients with granuloma. Th1 (CCR5) and Th2 (CCR4) type chemokine receptors did not show any dominance in CVID cases. However, frequencies of CCR7 expressing CD3(+) T cells, CD3(+)CD4(+) T helper cells and CD3(+)CD8(+) T cytotoxic cells were significantly lower in severe CVID patients. In addition, presence of autoimmune clinical findings was negatively correlated with CCR7(+) cells. As CCR7 is a key mediator balancing immunity and tolerance in the immune system, the abnormality of this mediator may contribute to the profound immune dysregulation seen in CVID

  19. Crucial Role of Gamma Interferon-Producing CD4+ Th1 Cells but Dispensable Function of CD8+ T Cell, B Cell, Th2, and Th17 Responses in the Control of Brucella melitensis Infection in Mice

    PubMed Central

    Vitry, Marie-Alice; De Trez, Carl; Goriely, Stanislas; Dumoutier, Laure; Akira, Shizuo; Ryffel, Bernhard; Carlier, Yves

    2012-01-01

    Brucella spp. are facultative intracellular bacterial pathogens responsible for brucellosis, a worldwide zoonosis that causes abortion in domestic animals and chronic febrile disease associated with serious complications in humans. There is currently no approved vaccine against human brucellosis, and antibiotic therapy is long and costly. Development of a safe protective vaccine requires a better understanding of the roles played by components of adaptive immunity in the control of Brucella infection. The importance of lymphocyte subsets in the control of Brucella growth has been investigated separately by various research groups and remains unclear or controversial. Here, we used a large panel of genetically deficient mice to compare the importance of B cells, transporter associated with antigen processing (TAP-1), and major histocompatibility complex class II-dependent pathways of antigen presentation as well as T helper 1 (Th1), Th2, and Th17-mediated responses on the immune control of Brucella melitensis 16 M infection. We clearly confirmed the key function played by gamma interferon (IFN-γ)-producing Th1 CD4+ T cells in the control of B. melitensis infection, whereas IFN-γ-producing CD8+ T cells or B cell-mediated humoral immunity plays only a modest role in the clearance of bacteria during primary infection. In the presence of a Th1 response, Th2 or Th17 responses do not really develop or play a positive or negative role during the course of B. melitensis infection. On the whole, these results could improve our ability to develop protective vaccines or therapeutic treatments against brucellosis. PMID:23006848

  20. p(⁷⁰S⁶K¹) in the TORC1 pathway is essential for the differentiation of Th17 Cells, but not Th1, Th2, or Treg cells in mice.

    PubMed

    Sasaki, Carl Y; Chen, Gang; Munk, Rachel; Eitan, Erez; Martindale, Jennifer; Longo, Dan L; Ghosh, Paritosh

    2016-01-01

    The TORC1 pathway is necessary for ribosomal biogenesis and initiation of protein translation. Furthermore, the differentiation of Th1 and Th17 cells requires TORC1 activity. To investigate the role of the TORC1 pathway in the differentiation of Th1 and/or Th17 cells in more detail, we compared the differentiation capacity of naïve T cells from wild type and p70(S6K1) knockout mice. Expression of many of the genes associated with Th17-cell differentiation, such as IL17a, IL17f, and IL-23R, were reduced in p70(S6K1) knockout mice. In contrast, the development of Th1, Th2, and Treg cells was unaffected in the absence of p70(S6K1) . Furthermore, expression of the major transcription factor in Th17-cell differentiation, retinoic acid receptor-related orphan receptor gamma T, remained unchanged. However, the acetylation of histone 3 at the promoters of IL17a and IL17f was reduced in the absence of p70(S6K1) . In accordance with the in vitro data, the kinetics, but not the development, of EAE was affected with the loss of p70(S6K1) expression. Collectively, our findings suggested that both in vitro and in vivo differentiation of Th17 cells were positively regulated by p70(S6K1) . PMID:26514620

  1. Unlipidated Outer Membrane Protein Omp16 (U-Omp16) from Brucella spp. as Nasal Adjuvant Induces a Th1 Immune Response and Modulates the Th2 Allergic Response to Cow’s Milk Proteins

    PubMed Central

    Ibañez, Andrés E.; Smaldini, Paola; Coria, Lorena M.; Delpino, María V.; Pacífico, Lucila G. G.; Oliveira, Sergio C.; Risso, Gabriela S.; Pasquevich, Karina A.; Fossati, Carlos Alberto; Giambartolomei, Guillermo H.; Docena, Guillermo H.; Cassataro, Juliana

    2013-01-01

    The discovery of novel mucosal adjuvants will help to develop new formulations to control infectious and allergic diseases. In this work we demonstrate that U-Omp16 from Brucella spp. delivered by the nasal route (i.n.) induced an inflammatory immune response in bronchoalveolar lavage (BAL) and lung tissues. Nasal co-administration of U-Omp16 with the model antigen (Ag) ovalbumin (OVA) increased the amount of Ag in lung tissues and induced OVA-specific systemic IgG and T helper (Th) 1 immune responses. The usefulness of U-Omp16 was also assessed in a mouse model of food allergy. U-Omp16 i.n. administration during sensitization ameliorated the hypersensitivity responses of sensitized mice upon oral exposure to Cow’s Milk Protein (CMP), decreased clinical signs, reduced anti-CMP IgE serum antibodies and modulated the Th2 response in favor of Th1 immunity. Thus, U-Omp16 could be used as a broad Th1 mucosal adjuvant for different Ag formulations. PMID:23861971

  2. The Mushroom Agaricus blazei Murill Elicits Medicinal Effects on Tumor, Infection, Allergy, and Inflammation through Its Modulation of Innate Immunity and Amelioration of Th1/Th2 Imbalance and Inflammation

    PubMed Central

    Hetland, Geir; Johnson, Egil; Lyberg, Torstein; Kvalheim, Gunnar

    2011-01-01

    The medicinal mushroom Agaricus blazei Murill from the Brazilian rain forest has been used in traditional medicine and as health food for the prevention of a range of diseases, including infection, allergy, and cancer. Other scientists and we have examined whether there is scientific evidence behind such postulations. Agaricus blazei M is rich in the immunomodulating polysaccharides, β-glucans, and has been shown to have antitumor, anti-infection, and antiallergic/-asthmatic properties in mouse models, in addition to anti-inflammatory effects in inflammatory bowel disease patients. These effects are mediated through the mushroom's stimulation of innate immune cells, such as monocytes, NK cells, and dendritic cells, and the amelioration of a skewed Th1/Th2 balance and inflammation. PMID:21912538

  3. Immune modulatory treatment of trinitrobenzene sulfonic acid colitis with calcitriol is associated with a change of a T helper (Th) 1/Th17 to a Th2 and regulatory T cell profile.

    PubMed

    Daniel, Carolin; Sartory, Nico A; Zahn, Nadine; Radeke, Heinfried H; Stein, Jürgen M

    2008-01-01

    A number of recent studies testify that calcitriol alone or in combination with corticosteroids exerts strong immune modulatory activity. As a new approach, we evaluated the protolerogenic potential of calcitriol and dexamethasone in acute T helper (Th)1-mediated colitis in mice. A rectal enema of trinitrobenzene sulfonic acid (TNBS) (100 mg/kg) was applied to BALB/c mice. Calcitriol and/or dexamethasone were administered i.p. from days 0 to 3 or 3 to 5 following the instillation of the haptenating agent. Assessment of colitis severity was performed daily. Colon tissue was analyzed macroscopically and microscopically, and myeloperoxidase activity, as well as cytokine levels [tumor necrosis factor-alpha, interferon-gamma, interleukin (IL)-12p70, IL-1beta, IL-10, IL-4] were determined by enzyme-linked immunosorbent assay, T-bet, GATA family of transcription factors 3, a Th2 master regulator (GATA3), Foxp3, cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), IL-23p19 and IL-17 expression by immunoblot analysis. The combination of the steroids most effectively reduced the clinical and histopathologic severity of TNBS colitis. Th1-related parameters were down-regulated, whereas Th2 markers like IL-4 and GATA3 were up-regulated. Apart from known steroid effects, calcitriol in particular promoted regulatory T cell profiles as indicated by a marked increase of IL-10, TGFbeta, FoxP3, and CTLA4. Furthermore, analysis of dendritic cell mediators responsible for a proinflammatory differentiation of T cells revealed a significant reduction of IL-12p70 and IL23p19 as well as IL-6 and IL-17. Thus, our data support a rationale for a steroid-sparing, clinical application of calcitriol derivatives in inflammatory bowel disease. Furthermore they suggest that early markers of inflammatory dendritic cell and Th17 differentiation qualify as new target molecules for both calcitriol and highly selective immune-modulating vitamin D analogs. PMID:17911375

  4. A Fusion Protein Consisting of the Vaccine Adjuvant Monophosphoryl Lipid A and the Allergen Ovalbumin Boosts Allergen-Specific Th1, Th2, and Th17 Responses In Vitro

    PubMed Central

    Vogel, Lothar; Hanschmann, Kay-Martin; Vieths, Stefan

    2016-01-01

    Background. The detoxified TLR4-ligand Monophosphoryl Lipid A (MPLA) is the first approved TLR-agonist used as adjuvant in licensed vaccines but has not yet been explored as part of conjugated vaccines. Objective. To investigate the immune-modulating properties of a fusion protein consisting of MPLA and Ovalbumin (MPLA : Ova). Results. MPLA and Ova were chemically coupled by stable carbamate linkage. MPLA : Ova was highly pure without detectable product-related impurities by either noncoupled MPLA or Ova. Light scattering analysis revealed MPLA : Ova to be aggregated. Stimulation of mDC and mDC : DO11.10 CD4+ TC cocultures showed a stronger activation of both mDC and Ova-specific DO11.10 CD4+ TC by MPLA : Ova compared to the mixture of both components. MPLA : Ova induced both strong proinflammatory (IL-1β, IL-6, and TNF-α) and anti-inflammatory (IL-10) cytokine responses from mDCs while also boosting allergen-specific Th1, Th2, and Th17 cytokine secretion. Conclusion. Conjugation of MPLA and antigen enhanced the immune response compared to the mixture of both components. Due to the nonbiased boost of Ova-specific Th2 and Th17 responses while also inducing Th1 responses, this fusion protein may not be a suitable vaccine candidate for allergy treatment but may hold potential for the treatment of other diseases that require a strong stimulation of the host's immune system (e.g., cancer). PMID:27340679

  5. Molecular cloning of a Poria cocos protein that activates Th1 immune response and allays Th2 cytokine and IgE production in a murine atopic dermatitis model.

    PubMed

    Lu, Ya-Ting; Kuan, Yen-Chou; Chang, Hui-Hsin; Sheu, Fuu

    2014-04-01

    Edible fungus Poria cocos (Schw.) Wolf is a cooking material that has myriad health benefits. However, its active constituents have not been well-defined. We previously purified an immunomodulatory protein, PCP, from P. cocos and described its biochemical features and its ability to activate primary macrophage via TLR4. In this study, we cloned the gene of PCP and demonstrated its ability to activate Th1 response in cell cultures and in mice. The complete cDNA sequence of PCP consisted of 807 bp, which included a 579 bp coding sequence that encoded 194 amino acids. With the addition of co-stimulatory CD3/CD28 signals, PCP significantly increased the surface expression of CD44 and CD69 on effector T cells. PCP could also up-regulate T-bet and STAT4 expressions and IFN-γ and IL-2 secretions. Oral administration of PCP suppressed the production of both total and OVA-specific IgG1 in serum and enhanced the amounts of serum and OVA-specific IgG2a and Th1-related cytokine production in BALB/c splenocytes. In addition, oral administration of PCP significantly reduced IL-4 and IgE expressions in a murine model of atopic dermatitis. In conclusion, these results provide evidence that PCP could regulate mammalian immune cells and reveal their pharmaceutical potential in developing therapeutic strategies against Th2-mediated immune disorders. PMID:24625278

  6. Efficient Immuno-Modulation of TH1/TH2 Biomarkers in 2,4-Dinitrofluorobenzene-Induced Atopic Dermatitis: Nanocarrier-Mediated Transcutaneous Co-Delivery of Anti-Inflammatory and Antioxidant Drugs

    PubMed Central

    Hussain, Zahid; Katas, Haliza; Mohd Amin, Mohd Cairul Iqbal; Kumolosasi, Endang

    2014-01-01

    The present study was conducted with the aim to investigate the immuno-modulatory and histological stabilization effects of nanocarrier–based transcutaneous co-delivery of hydrocortisone (HC) and hydroxytyrosol (HT). In this investigation, the clinical and pharmacological efficacies of nanoparticle (NP)-based formulation to alleviate 2,4-dinitrofluorobenzene (DNFB)-induced atopic dermatitis (AD) was explored by using an NC/Nga mouse model. Ex vivo visual examination of AD induction in experimental mice indicated remarkable control of NP-based formulations in reducing pathological severity of AD-like skin lesions. Therapeutic effectiveness of NP-based formulations was also evaluated by comparing skin thickness of AD-induced NP-treated mice (456±27 µm) with that of atopic mice (916±37 µm). Analysis of the immuno-spectrum of AD also revealed the dominance of NP-based formulations in restraining immunoglobulin-E (IgE), histamine, prostaglandin-E2 (PGE2), vascular endothelial growth factor-α (VEGF-α), and T-helper cells (TH1/TH2) producing cytokines in serum and skin biopsies of tested mice. These anti-AD data were further supported by histological findings that revealed alleviated pathological features, including collagen fiber deposition, fibroblasts infiltration, and fragmentation of elastic fibers in experimental mice. Thus, NP-mediated transcutaneous co-delivery of HC and HT can be considered as a promising therapy for managing immunological and histological spectra associated with AD. PMID:25396426

  7. Role of HLA-G in tumor escape through expansion of myeloid-derived suppressor cells and cytokinic balance in favor of Th2 versus Th1/Th17.

    PubMed

    Agaugué, Sophie; Carosella, Edgardo D; Rouas-Freiss, Nathalie

    2011-06-30

    The expression of HLA-G by malignant cells has been proposed as a tumor escape mechanism from immunosurveillance. However, although the inhibitory effect of HLA-G on antitumoral immune effectors has been documented in vitro, it remains to be resolved in vivo. In this context, the development of an animal model is now a priority to establish the proof of concept that an HLA-G(+) tumor cell develops and tolerizes the host antitumor immune response in vivo. In the present study, we provide the first in vivo evidence of such a role by a xenotumor model in mice based on the interactions between human HLA-G and the murine paired immunoglobulin-like receptor-B (PIR-B). We demonstrate that human tumor cells expressing HLA-G grow in an immunocompetent host by affecting both innate and adaptive immunity. Expansion of blood myeloid-derived CD11b(+)Gr1(+)PIR-B(+) suppressor cells, loss of peripheral T cells, and cytokinic balance in favor of Th2 versus Th1/Th17 constitute the main mechanisms by which HLA-G promotes tumor expansion. These data demonstrate for the first time that HLA-G plays a crucial role in in vivo tumor evasion. Finally, blocking HLA-G function by a specific Ab inhibits the in vivo development of the tumor, offering a new innovative therapeutic strategy in cancer. PMID:21482709

  8. Batf3-dependent CD103+ dendritic cells are major producers of IL-12 that drive local Th1 immunity against Leishmania major infection in mice

    PubMed Central

    Martínez-López, María; Iborra, Salvador; Conde-Garrosa, Ruth; Sancho, David

    2015-01-01

    The role of different DC subsets in priming and maintenance of immunity against Leishmania major (L. major) infection is debated. The transcription factor basic leucine zipper transcription factor, ATF-like 3 (Batf3) is essential for the development of mouse CD103+ DCs and some functions of CD8α+ DCs. We found that CD103+ DCs were significantly reduced in the dermis of Batf3-deficient C57BL/6 mice. Batf3−/− mice developed exacerbated and unresolved cutaneous pathology following a low dose of intradermal L. major infection in the ear pinnae. Parasite load was increased 1000-fold locally and expanded systemically. Batf3 deficiency did not affect L. major antigen presentation to T cells, which was directly exerted by CD8α− conventional DCs (cDCs) in the skin draining LN. However, CD4+ T-cell differentiation in the LN and skin was skewed to nonprotective Treg- and Th2-cell subtypes. CD103+ DCs are major IL-12 producers during L. major infection. Local Th1 immunity was severely hindered, correlating with impaired IL-12 production and reduction in CD103+ DC numbers. Adoptive transfer of WT but not IL-12p40−/− Batf3-dependent DCs significantly improved anti-L. major response in infected Batf3−/− mice. Our results suggest that IL-12 production by Batf3-dependent CD103+ DCs is crucial for maintenance of local Th1 immunity against L. major infection. PMID:25312824

  9. Reduction of IL-17A might suppress the Th1 response and promote the Th2 response by boosting the function of Treg cells during silica-induced inflammatory response in vitro.

    PubMed

    Tang, Wen; Liu, Fangwei; Chen, Ying; Song, Laiyu; Dai, Wujing; Li, Chao; Weng, Dong; Chen, Jie

    2014-01-01

    Silica inhalation can induce chronic lung inflammation and fibrosis. Upon silica stimulation, activated macrophages trigger the T-lymphocyte which can differentiate into many different types of Th cells, including the recently discovered Th17 cells. IL-17A, the typical Th17 cytokine, is reported in some inflammatory diseases. However, the role of IL-17A in silica-induced inflammatory response is still not clear. The regulatory mechanism of silica-induced Th17 response also needs to be investigated. So we established a mice primary cell coculture system (macrophage and lymphocyte) to investigate the role of IL-17A in silica-induced inflammatory response in vitro, by using anti-IL-17A mAb and IL-1Ra. Both anti-IL-17A mAb and IL-1Ra decreased the level of IL-17A and increased the function of Treg cells. The Th1 response was suppressed and the Th2 response was promoted by the addition of anti-IL-17A mAb or IL-1Ra. IL-1Ra treatment decreased the level of IL-6, whereas the levels of IL-23 and ROR- γ t were increased. Our study demonstrated that IL-17A reduction altered the pattern of silica-induced Th responses by boosting the function of Treg cells in vitro. Blocking the function of IL-1 signal pathway could suppress the level of IL-17A, which played the major role in modulating silica-induced Th responses in vitro. PMID:24692850

  10. Differential regulation of IL-13 and IL-4 production by human CD8+ and CD4+ Th0, Th1 and Th2 T cell clones and EBV-transformed B cells.

    PubMed

    de Waal Malefyt, R; Abrams, J S; Zurawski, S M; Lecron, J C; Mohan-Peterson, S; Sanjanwala, B; Bennett, B; Silver, J; de Vries, J E; Yssel, H

    1995-09-01

    In the present study, the requirements and characteristics for the production of IL-13 by human T cells, T cell clones and B cells were determined and compared with those of IL-4. IL-13 was produced by human CD4+ and CD8+ T lymphocyte subsets isolated from peripheral blood mononuclear cells and by CD4+ and CD8+ T cell clones. CD4+ T cell clones belonging to Th0, Th1-like and Th2-like subsets produced IL-13 following antigen-specific or polyclonal activation. In addition, EBV-transformed B cell lines expressed IL-13 mRNA and produced small amounts of IL-13 protein. Expression of IL-13 mRNA and production of IL-13 protein by peripheral blood T cells and T cell clones was induced rapidly and was relatively long lasting, whereas IL-4 production by these cells was transient. In addition, IL-13 mRNA expression was induced by modes of activation that failed to induce IL-4 mRNA expression. IL-13 shares many biological activities with IL-4 which is compatible with the notion that the IL-13 and IL-4 receptors share a common component required for signal transduction. However, IL-13 lacks the T cell-activating properties of IL-4. Here we have shown that this is related to the fact that T cells fail to bind radiolabeled IL-13 and do not express the IL-13-specific receptor component. Taken together, these results indicate that the differences in expression and biological activities of IL-4 and IL-13 on T cells may have consequences for the relative roles of these cytokines in the immune response. PMID:7495748

  11. Modulation of Th1/Th2 Immune Responses by Killed Propionibacterium acnes and Its Soluble Polysaccharide Fraction in a Type I Hypersensitivity Murine Model: Induction of Different Activation Status of Antigen-Presenting Cells

    PubMed Central

    Mussalem, Juliana Sekeres; Ishimura, Mayari Eika; Longo-Maugéri, Ieda Maria

    2015-01-01

    Propionibacterium acnes (P. acnes) is a gram-positive anaerobic bacillus present in normal human skin microbiota, which exerts important immunomodulatory effects, when used as heat- or phenol-killed suspensions. We previously demonstrated that heat-killed P. acnes or its soluble polysaccharide (PS), extracted from the bacterium cell wall, suppressed or potentiated the Th2 response to ovalbumin (OVA) in an immediate hypersensitivity model, depending on the treatment protocol. Herein, we investigated the mechanisms responsible for these effects, using the same model and focusing on the activation status of antigen-presenting cells (APCs). We verified that higher numbers of APCs expressing costimulatory molecules and higher expression levels of these molecules are probably related to potentiation of the Th2 response to OVA induced by P. acnes or PS, while higher expression of toll-like receptors (TLRs) seems to be related to Th2 suppression. In vitro cytokines production in cocultures of dendritic cells and T lymphocytes indicated that P. acnes and PS seem to perform their effects by acting directly on APCs. Our data suggest that P. acnes and PS directly act on APCs, modulating the expression of costimulatory molecules and TLRs, and these differently activated APCs drive distinct T helper patterns to OVA in our model. PMID:25973430

  12. Modulation of Th1/Th2 immune responses by killed Propionibacterium acnes and its soluble polysaccharide fraction in a type I hypersensitivity murine model: induction of different activation status of antigen-presenting cells.

    PubMed

    Squaiella-Baptistão, Carla Cristina; Teixeira, Daniela; Mussalem, Juliana Sekeres; Ishimura, Mayari Eika; Longo-Maugéri, Ieda Maria

    2015-01-01

    Propionibacterium acnes (P. acnes) is a gram-positive anaerobic bacillus present in normal human skin microbiota, which exerts important immunomodulatory effects, when used as heat- or phenol-killed suspensions. We previously demonstrated that heat-killed P. acnes or its soluble polysaccharide (PS), extracted from the bacterium cell wall, suppressed or potentiated the Th2 response to ovalbumin (OVA) in an immediate hypersensitivity model, depending on the treatment protocol. Herein, we investigated the mechanisms responsible for these effects, using the same model and focusing on the activation status of antigen-presenting cells (APCs). We verified that higher numbers of APCs expressing costimulatory molecules and higher expression levels of these molecules are probably related to potentiation of the Th2 response to OVA induced by P. acnes or PS, while higher expression of toll-like receptors (TLRs) seems to be related to Th2 suppression. In vitro cytokines production in cocultures of dendritic cells and T lymphocytes indicated that P. acnes and PS seem to perform their effects by acting directly on APCs. Our data suggest that P. acnes and PS directly act on APCs, modulating the expression of costimulatory molecules and TLRs, and these differently activated APCs drive distinct T helper patterns to OVA in our model. PMID:25973430

  13. Downregulation of Hlx Closely Related to the Decreased Expressions of T-bet and Runx3 in Patients with Gastric Cancer May Be Associated with a Pathological Event Leading to the Imbalance of Th1/Th2

    PubMed Central

    Xu, Yan; Gao, Jingjing; Su, Zhaoliang; Dai, Xiaoli; Li, Yazhen; Liu, Yingzhao; Chen, Jianguo; Tong, Jia; Zhang, Yun; Wu, Chaoyang; Zheng, Dong; Wang, Shengjun; Xu, Huaxi

    2012-01-01

    T-bet plays an important role in immunoregulation; it induces the differentiation of Th1 together with the homeobox transcription factor gene Hlx. Recent studies show that T-bet and Th1-associated factors are critical in regulating tumor development. However, the contributions of Hlx in the occurrence and development of cancer remain unknown. In this study, the Hlx, T-bet, Runx3, and IFN-γ were measured in PBMC from patients with gastric cancer and the correlation between Hlx and T-bet or IFN-γ was assessed. The expression levels of Hlx, T-bet, and IFN-γwere significantly decreased, and there was a positive correlation between Hlx and T-bet or IFN-γ. In addition, the Runx3 expression was also downregulated with the lower T-bet mRNA level. These results suggested that the decreased Hlx expression was closely associated with T-bet and Runx3 downregulations and may contribute to the development of gastric cancer. PMID:23243425

  14. Mycobacterial antigen-induced T helper type 1 (Th1) and Th2 reactivity of peripheral blood mononuclear cells from diabetic and non-diabetic tuberculosis patients and Mycobacterium bovis bacilli Calmette–Guérin (BCG)-vaccinated healthy subjects

    PubMed Central

    Al-Attiyah, R J; Mustafa, A S

    2009-01-01

    Patients with diabetes mellitus are more susceptible to tuberculosis (TB), and the clinical conditions of diabetic TB patients deteriorate faster than non-diabetic TB patients, but the immunological basis for this phenomenon is not understood clearly. Given the role of cell-mediated immunity (CMI) in providing protection against TB, we investigated whether CMI responses in diabetic TB patients are compromised. Peripheral blood mononuclear cells (PBMC) obtained from diabetic TB patients, non-diabetic TB patients and Mycobacterium bovis bacilli Calmette–Guérin (BCG)-vaccinated healthy subjects were cultured in the presence of complex mycobacterial antigens and pools of M. tuberculosis regions of difference (RD)1, RD4, RD6 and RD10 peptides. The PBMC were assessed for antigen-induced cell proliferation and secretion of T helper 1 (Th1) [interferon (IFN)-γ, interleukin (IL)-2, tumour necrosis factor (TNF)-β], and Th2 (IL-4, IL-5, IL-10) cytokines as CMI parameters. All the complex mycobacterial antigens and RD1pool stimulated strong proliferation of PBMC of all groups, except moderate responses to RD1pool in healthy subjects. In response to complex mycobacterial antigens, both IFN-γ and TNF-β were secreted by PBMC of all groups whereas diabetic TB patients secreted IL-10 with concentrations higher than the other two groups. Furthermore, in response to RD peptides, IFN-γ and IL-10 were secreted by PBMC of diabetic TB patients only. The analyses of data in relation to relative cytokine concentrations showed that diabetic TB patients had lower Th1 : Th2 cytokines ratios, and a higher Th2 bias. The results demonstrate a shift towards Th2 bias in diabetic TB patients which may explain, at least in part, a faster deterioration in their clinical conditions. PMID:19737232

  15. Solanum tuberosum L. cv Jayoung Epidermis Extract Inhibits Mite Antigen-Induced Atopic Dermatitis in NC/Nga Mice by Regulating the Th1/Th2 Balance and Expression of Filaggrin.

    PubMed

    Yang, Gabsik; Cheon, Se-Yun; Chung, Kyung-Sook; Lee, Sung-Jin; Hong, Chul-Hee; Lee, Kyung-Tae; Jang, Dae-Sik; Jeong, Jin-Cheol; Kwon, Oh-Keun; Nam, Jung-Hwan; An, Hyo-Jin

    2015-09-01

    Solanum tuberosum L. cv Jayoung (JY) is a potato with dark purple flesh and contains substantial amounts of polyphenols. In this study, we evaluated the therapeutic effects of S. tuberosum L. cv JY in a mouse model of Dermatophagoides farinae body (Dfb)-induced atopic dermatitis (AD). The ethanol extract of the peel of JY (EPJ) ameliorated Dfb-induced dermatitis severity, serum levels of immunoglobulin E (IgE) and thymus and activation-regulated chemokine. Histological analysis of the skin also revealed that EPJ treatment significantly decreased mast cell infiltration. The suppression of dermatitis by EPJ treatment was accompanied by a decrease in the skin levels of type 2 helper T-cell cytokines such as interleukin (IL)-4, IL-5, and IL-13. The induction of thymic stromal lymphopoietin, which leads to a systemic Th2 response, was also decreased in the skin by EPJ. Nuclear translocation of nuclear factor-κB p65 was decreased by EPJ in Dfb-induced NC/Nga mice. The protein expression of filaggrin in the AD-like skin lesions was restored by EPJ treatment. These results suggested that EPJ may be a potential therapeutic tool for the treatment of AD. PMID:26102094

  16. Localized Th1-, Th2-,and inflamation-associated hepatic and pulmonary immune responses in Ascaris-infected swine are increased by retinoic acid.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Pigs infected with Ascaris suum were treated with all-trans retinoic acid (ATRA) on d–1, d+1, d+3 of infection. Control or infected pigs were given 100 (LD-ATRA) or 1,000 (HD-ATRA) µg/kg ATRA in corn oil, or corn oil alone, and sacrificed at 7 and 14 days after inoculation (DAI) with infective eggs...

  17. FIBROTIC DISEASE AND THE TH1/TH2 PARADIGM

    PubMed Central

    Wynn, Thomas A.

    2009-01-01

    Tissue fibrosis (scarring) is a leading cause of morbidity and mortality. Current treatments for fibrotic disorders, such as idiopathic pulmonary fibrosis, hepatic fibrosis and systemic sclerosis, target the inflammatory cascade, but they have been widely unsuccessful, largely because the mechanisms that are involved in fibrogenesis are now known to be distinct from those involved in inflammation. Several experimental models have recently been developed to dissect the molecular mechanisms of wound healing and fibrosis. It is hoped that by better understanding the immunological mechanisms that initiate, sustain and suppress the fibrotic process, we will achieve the elusive goal of targeted and effective therapeutics for fibroproliferative diseases. PMID:15286725

  18. Allergen challenge induces Ifng dependent GTPases in the lungs as part of a Th1 transcriptome response in a murine model of allergic asthma.

    PubMed

    Dharajiya, Nilesh; Vaidya, Swapnil; Sinha, Mala; Luxon, Bruce; Boldogh, Istvan; Sur, Sanjiv

    2009-01-01

    According to the current paradigm, allergic airway inflammation is mediated by Th2 cytokines and pro-inflammatory chemokines. Since allergic inflammation is self-limited, we hypothesized that allergen challenge simultaneously induces anti-inflammatory genes to counter-balance the effects of Th2 cytokines and chemokines. To identify these putative anti-inflammatory genes, we compared the gene expression profile in the lungs of ragweed-sensitized mice four hours after challenge with either PBS or ragweed extract (RWE) using a micro-array platform. Consistent with our hypothesis, RWE challenge concurrently upregulated Th1-associated early target genes of the Il12/Stat4 pathway, such as p47 and p65 GTPases (Iigp, Tgtp and Gbp1), Socs1, Cxcl9, Cxcl10 and Gadd45g with the Th2 genes Il4, Il5, Ccl2 and Ccl7. These Th1-associated genes remain upregulated longer than the Th2 genes. Augmentation of the local Th1 milieu by administration of Il12 or CpG prior to RWE challenge further upregulated these Th1 genes. Abolition of the Th1 response by disrupting the Ifng gene increased allergic airway inflammation and abrogated RWE challenge-induced upregulation of GTPases, Cxcl9, Cxcl10 and Socs1, but not Gadd45g. Our data demonstrate that allergen challenge induces two sets of Th1-associated genes in the lungs: 1) Ifng-dependent genes such as p47 and p65 GTPases, Socs1, Cxcl9 and Cxcl10 and 2) Ifng-independent Th1-inducing genes like Gadd45g. We propose that allergen-induced airway inflammation is regulated by simultaneous upregulation of Th1 and Th2 genes, and that persistent unopposed upregulation of Th1 genes resolves allergic inflammation. PMID:20027288

  19. Developmental control of integrin expression regulates Th2 effector homing

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Integrin CD18, a component of the LFA-1 complex that also includes CD11a, is essential for Th2, but not Th1, cell homing, but the explanation for this phenomenon remains obscure. In this study, we investigate the mechanism by which Th2 effector responses require the LFA-1 complex. CD11a-deficient T ...

  20. Nasal delivery of chitosan-coated poly(lactide-co-glycolide)-encapsulated honeybee (Apis mellifera) venom promotes Th 1-specific systemic and local intestinal immune responses in weaned pigs.

    PubMed

    Lee, Jin-A; Kim, Yun-Mi; Kim, Tae-Hoon; Lee, Sang-Ho; Lee, Cho-A; Cho, Cheong-Weon; Jeon, Jong-Woon; Park, Jin-Kyu; Kim, Sang-Ki; Jung, Bock-Gie; Lee, Bong-Joo

    2016-10-01

    Nasal delivery is a convenient and acceptable route for drug administration, and has been shown to elicit a much more potent local and systemic response compared with other drug delivery routes. We previously demonstrated that rectal administration of poly(lactide-co-glycolide)-encapsulated honeybee venom (P-HBV) could enhance systemic Th 1-specific immune responses. We therefore synthesized chitosan-coated P-HBV (CP-HBV) and then evaluated the immune-boosting efficacy of nasally administered CP-HBV on systemic and local intestinal immunity compared with non-chitosan-coated P-HBV. The nasally delivered CP-HBV effectively enhanced Th 1-specific responses, eliciting a significant increase in the CD3(+)CD4(+)CD8(-) Th cell population, lymphocyte proliferation capacity, and expression of Th 1 cytokines (IFN-γ, IL-12, and IL-2) in peripheral blood mononuclear cells. Furthermore, these immune-boosting effects persisted up to 21days post CP-HBV administration. Nasal administration of CP-HBV also led to an increase of not only the CD4(+) Th 1 and IFN-γ secreting CD4(+) Th 1 cell population but also Th 1-specific cytokines and transcription factors, including IL-12, IFN-γ, STAT4, and T-bet, in isolated mononuclear cells from the spleen and ileum. PMID:27496748

  1. Regulation of Th2 Cell Immunity by Dendritic Cells

    PubMed Central

    Na, Hyeongjin

    2016-01-01

    Th2 cell immunity is required for host defense against helminths, but it is detrimental in allergic diseases in humans. Unlike Th1 cell and Th17 cell subsets, the mechanism by which dendritic cells modulate Th2 cell responses has been obscure, in part because of the inability of dendritic cells to provide IL-4, which is indispensable for Th2 cell lineage commitment. In this regard, immune cells other than dendritic cells, such as basophils and innate lymphoid cells, have been suggested as Th2 cell inducers. More recently, multiple independent researchers have shown that specialized subsets of dendritic cells mediate Th2 cell responses. This review will discuss the current understanding related to the regulation of Th2 cell responses by dendritic cells and other immune cells. PMID:26937227

  2. Immunomodulation of TH2 biased immunity with mucosal administration of nanoemulsion adjuvant.

    PubMed

    Bielinska, Anna U; O'Konek, Jessica J; Janczak, Katarzyna W; Baker, James R

    2016-07-25

    TH2-biased immune responses are associated with inadequate protection against some pathogens and with cancer, colitis, asthma and allergy. Since most currently used vaccine adjuvants induce a TH2-biased response, this has led to interest in developing adjuvants capable of activating TH1 immunity and modulating existing TH2 responses. Immunotherapies to shift immune responses from TH2 to TH1 have generally required prolonged immunization protocols and have not induced effective TH1 responses. We have demonstrated that nanoscale emulsions (NE), a novel mucosal adjuvant, induce robust IgA and IgG antibody responses and TH1/TH17 cellular immunity resulting in protection against a variety of respiratory and mucosal infections. Because intranasal (i.n.) delivery of NE adjuvant consistently induces TH1/TH17 biased responses, we hypothesized that NE could be used as a therapeutic vaccine to redirect existing TH2 polarized immunity towards a more balanced TH1/TH2 profile. To test this, a TH2 immune response was established by intramuscular immunization of mice with alum-adjuvanted hepatitis B surface antigen (HBs), followed by a single subsequent i.n. immunization with NE-HBs. These animals exhibited increased TH1 associated immune responses and IL-17, and decreased TH2 cytokines (IL-4 and IL-5) and IgG1. NE immunization induced regulatory T cells and IL-10, and IL-10 was required for the suppression of TH2 immunity. These data demonstrate that NE-based vaccines can modulate existing TH2 immune responses to promote TH1/TH17 immunity and suggest the potential therapeutic use of NE vaccines for diseases associated with TH2 immunity. PMID:27317451

  3. The Adenylate Cyclase Toxins of Bacillus anthracis and Bordetella pertussis Promote Th2 Cell Development by Shaping T Cell Antigen Receptor Signaling

    PubMed Central

    Rossi Paccani, Silvia; Benagiano, Marisa; Capitani, Nagaja; Zornetta, Irene; Ladant, Daniel; Montecucco, Cesare; D'Elios, Mario M.; Baldari, Cosima T.

    2009-01-01

    The adjuvanticity of bacterial adenylate cyclase toxins has been ascribed to their capacity, largely mediated by cAMP, to modulate APC activation, resulting in the expression of Th2–driving cytokines. On the other hand, cAMP has been demonstrated to induce a Th2 bias when present during T cell priming, suggesting that bacterial cAMP elevating toxins may directly affect the Th1/Th2 balance. Here we have investigated the effects on human CD4+ T cell differentiation of two adenylate cyclase toxins, Bacillus anthracis edema toxin (ET) and Bordetella pertussis CyaA, which differ in structure, mode of cell entry, and subcellular localization. We show that low concentrations of ET and CyaA, but not of their genetically detoxified adenylate cyclase defective counterparts, potently promote Th2 cell differentiation by inducing expression of the master Th2 transcription factors, c-maf and GATA-3. We also present evidence that the Th2–polarizing concentrations of ET and CyaA selectively inhibit TCR–dependent activation of Akt1, which is required for Th1 cell differentiation, while enhancing the activation of two TCR–signaling mediators, Vav1 and p38, implicated in Th2 cell differentiation. This is at variance from the immunosuppressive toxin concentrations, which interfere with the earliest step in TCR signaling, activation of the tyrosine kinase Lck, resulting in impaired CD3ζ phosphorylation and inhibition of TCR coupling to ZAP-70 and Erk activation. These results demonstrate that, notwithstanding their differences in their intracellular localization, which result in focalized cAMP production, both toxins directly affect the Th1/Th2 balance by interfering with the same steps in TCR signaling, and suggest that their adjuvanticity is likely to result from their combined effects on APC and CD4+ T cells. Furthermore, our results strongly support the key role of cAMP in the adjuvanticity of these toxins. PMID:19266022

  4. Intestinal Irradiation and Fibrosis in a Th1-Deficient Environment

    SciTech Connect

    Linard, Christine; Billiard, Fabienne; Benderitter, Marc

    2012-09-01

    Purpose: Changes in the Th1/Th2 immune balance may play a role in increasing the incidence of radiation-induced toxicity. This study evaluates the consequences of Th1 deficiency on intestinal response (fibrosis and T cell trafficking) to abdominal irradiation and examines in mucosa and mesenteric lymph nodes (MLN) the differential involvement of the two Th1 pathways, T-bet/STAT1 and IL-12/STAT4, in controlling this balance in mice. Methods and Materials: Using T-bet-deficient mice (T-bet{sup -/-}), we evaluated the mRNA and protein expression of the Th1 pathways (IFN-{gamma}, T-bet/STAT1, and IL-12/STAT4) and the CD4{sup +} and CD8{sup +} populations in ileal mucosa and MLN during the first 3 months after 10 Gy abdominal irradiation. Results: The T-bet-deficient mice showed an increased fibrotic response to radiation, characterized by higher TGF-{beta}1, col3a1 expression, and collagen deposition in mucosa compared with wild-type mice. This response was associated with drastically lower expression of IFN-{gamma}, the hallmark Th1 cytokine. Analysis of the Th1 expression pathways, T-bet/STAT1 and IL-12/STAT4, showed their equal involvement in the failure of Th1 polarization. A minimal IFN-{gamma} level depended on the IL-23-p19/STAT4 level. In addition, the radiation-induced deficiency in the priming of Th1 by IFN-{gamma} was related to the defective homing capacity of CD8{sup +} cells in the mucosa. Conclusion: Irradiation induces Th2 polarization, and the Th2 immune response may play a role in potentiating irradiation-induced intestinal collagen deposition.

  5. Hydroxypropyl-β-cyclodextrin spikes local inflammation that induces Th2 cell and T follicular helper cell responses to the coadministered antigen.

    PubMed

    Onishi, Motoyasu; Ozasa, Koji; Kobiyama, Kouji; Ohata, Keiichi; Kitano, Mitsutaka; Taniguchi, Keiichi; Homma, Tomoyuki; Kobayashi, Masanori; Sato, Akihiko; Katakai, Yuko; Yasutomi, Yasuhiro; Wijaya, Edward; Igarashi, Yoshinobu; Nakatsu, Noriyuki; Ise, Wataru; Inoue, Takeshi; Yamada, Hiroshi; Vandenbon, Alexis; Standley, Daron M; Kurosaki, Tomohiro; Coban, Cevayir; Aoshi, Taiki; Kuroda, Etsushi; Ishii, Ken J

    2015-03-15

    Cyclodextrins are commonly used as a safe excipient to enhance the solubility and bioavailability of hydrophobic pharmaceutical agents. Their efficacies and mechanisms as drug-delivery systems have been investigated for decades, but their immunological properties have not been examined. In this study, we reprofiled hydroxypropyl-β-cyclodextrin (HP-β-CD) as a vaccine adjuvant and found that it acts as a potent and unique adjuvant. HP-β-CD triggered the innate immune response at the injection site, was trapped by MARCO(+) macrophages, increased Ag uptake by dendritic cells, and facilitated the generation of T follicular helper cells in the draining lymph nodes. It significantly enhanced Ag-specific Th2 and IgG Ab responses as potently as did the conventional adjuvant, aluminum salt (alum), whereas its ability to induce Ag-specific IgE was less than that of alum. At the injection site, HP-β-CD induced the temporary release of host dsDNA, a damage-associated molecular pattern. DNase-treated mice, MyD88-deficient mice, and TBK1-deficient mice showed significantly reduced Ab responses after immunization with this adjuvant. Finally, we demonstrated that HP-β-CD-adjuvanted influenza hemagglutinin split vaccine protected against a lethal challenge with a clinically isolated pandemic H1N1 influenza virus, and the adjuvant effect of HP-β-CD was demonstrated in cynomolgus macaques. Our results suggest that HP-β-CD acts as a potent MyD88- and TBK1-dependent T follicular helper cell adjuvant and is readily applicable to various vaccines. PMID:25681338

  6. Hydroxypropyl-β-Cyclodextrin Spikes Local Inflammation That Induces Th2 Cell and T Follicular Helper Cell Responses to the Coadministered Antigen

    PubMed Central

    Onishi, Motoyasu; Ozasa, Koji; Kobiyama, Kouji; Ohata, Keiichi; Kitano, Mitsutaka; Taniguchi, Keiichi; Homma, Tomoyuki; Kobayashi, Masanori; Sato, Akihiko; Katakai, Yuko; Yasutomi, Yasuhiro; Wijaya, Edward; Igarashi, Yoshinobu; Nakatsu, Noriyuki; Ise, Wataru; Inoue, Takeshi; Yamada, Hiroshi; Vandenbon, Alexis; Standley, Daron M.; Kurosaki, Tomohiro; Coban, Cevayir; Aoshi, Taiki; Kuroda, Etsushi

    2015-01-01

    Cyclodextrins are commonly used as a safe excipient to enhance the solubility and bioavailability of hydrophobic pharmaceutical agents. Their efficacies and mechanisms as drug-delivery systems have been investigated for decades, but their immunological properties have not been examined. In this study, we reprofiled hydroxypropyl-β-cyclodextrin (HP-β-CD) as a vaccine adjuvant and found that it acts as a potent and unique adjuvant. HP-β-CD triggered the innate immune response at the injection site, was trapped by MARCO+ macrophages, increased Ag uptake by dendritic cells, and facilitated the generation of T follicular helper cells in the draining lymph nodes. It significantly enhanced Ag-specific Th2 and IgG Ab responses as potently as did the conventional adjuvant, aluminum salt (alum), whereas its ability to induce Ag-specific IgE was less than that of alum. At the injection site, HP-β-CD induced the temporary release of host dsDNA, a damage-associated molecular pattern. DNase-treated mice, MyD88-deficient mice, and TBK1-deficient mice showed significantly reduced Ab responses after immunization with this adjuvant. Finally, we demonstrated that HP-β-CD–adjuvanted influenza hemagglutinin split vaccine protected against a lethal challenge with a clinically isolated pandemic H1N1 influenza virus, and the adjuvant effect of HP-β-CD was demonstrated in cynomolgus macaques. Our results suggest that HP-β-CD acts as a potent MyD88- and TBK1-dependent T follicular helper cell adjuvant and is readily applicable to various vaccines. PMID:25681338

  7. Th1/Th2 Cytokines: An Easy Model to Study Gene Expression in Immune Cells

    ERIC Educational Resources Information Center

    Moran, Jose M.; Gonzalez-Polo, Rosa A.; Soler, German; Fuentes, Jose M.

    2006-01-01

    This report describes a laboratory exercise that was incorporated into a Cell Biology and Molecular Biology advanced course. The exercise was made for a class size with eight students and was designed to reinforce the understanding of basic molecular biology techniques. Students used the techniques of reverse transcription and arginase activity…

  8. Th1/Th2 Cytokines: An Easy Model to Study Gene Expression in Immune Cells

    PubMed Central

    González-Polo, Rosa A.; Soler, Germán; Fuentes, José M.

    2006-01-01

    This report describes a laboratory exercise that was incorporated into a Cell Biology and Molecular Biology advanced course. The exercise was made for a class size with eight students and was designed to reinforce the understanding of basic molecular biology techniques. Students used the techniques of reverse transcription and arginase activity measurement as well as nitric oxide determination to discover whether two specific genes were expressed by cytokine-stimulated dendritic cells. The experiment served as the basis for discussing the importance of differential gene expression inside the eukaryotic cell and the importance of cytokines in the immune system. PMID:17012221

  9. Th1/Th2 cytokine pattern in Arab children with severe asthma

    PubMed Central

    Al-Daghri, Nasser M; Alokail, Majed S; Draz, Hossam M; Abd-Alrahman, Sherif H; Yakout, Sobhy M; Clerici, Mario

    2014-01-01

    Background: Bronchial Asthma has recently emerged as one of the most prevalent diseases in Arab countries. Environmental and geographical influences were shown to be the reasons of the variations in the rates of prevalence; no analyses have nevertheless yet been performed on the immunologic background associated with this condition in Arabic children. Objectives: To examine the cytokine production from T cells in children with and without asthma, and to determine the role of the most related cytokine patterns in childhood asthma. Methods: A total of 195 Saudis children (98 asthma pediatric patients and 97 healthy controls) were randomly selected from the Riyadh Cohort Study for inclusion. Asthma was based on established pediatric diagnosis and medications taken. Results: Significant differences were observed between the two groups, thus, GMCSF, INF-γ, IL-5, IL-6, IL-8 and IgG-3 were reduced in patients compared to controls; in these same patients IgE, resistin, IL-4 and IgG-4 were significantly increased. In contrast with these results no differences between patients and controls were seen in CRP, TNF-α, IL-1, IL-2, IL-7, IL-10, IL-13, IgG-1, IgG-2, IgG-A and IgG-M. Result of a principal component analysis suggested that IL4. INF-γ and IgE are major players in the pathogenesis of asthma in Arabic children. Conclusion: These are the first data obtained in asthmatic children in Saudi; data herein confirm that this disease is associated with a profound degree of immune impairment independently of the peculiar genetic of the analyzed individuals, and of the environmental conditions that are present in this part of the world. PMID:25232422

  10. Cell-mediated immunity to Toxoplasma gondii develops primarily by local Th-1 host immune responses in the absence of parasite replication1

    PubMed Central

    Gigley, Jason P.; Fox, Barbara A.; Bzik, David J.

    2008-01-01

    A single inoculation of mice with the live attenuated Toxoplasma gondii uracil auxotroph strain cps1-1 induces long-lasting immunity against lethal challenge with hyper-virulent strain RH. The mechanism for this robust immunity in the absence of parasite replication has not been addressed. The mechanism of long-lasting immunity, the importance of route of immunization, cellular recruitment to the site of infection, and local and systemic inflammation were evaluated. Our results show that infection with cps1-1 elicits long-lasting CD8+ T cell mediated immunity. We show that immunization with cps1-1 infected DCs elicits long-lasting immunity. Intraperitoneal infection with cps1-1 induced a rapid influx of GR1+ neutrophils and 2 stages of GR1+ CD68+ inflammatory monocyte infiltration into the site of inoculation. CD19+ B cells and CD3+ T cells steadily increase for 8 days after infection. CD8+ T cells were rapidly recruited to the site of infection and increased faster than CD4+ T cells. Surprisingly, cps1-1 infection induced high systemic levels of bioactive IL-12p70 and very low level and transient systemic Ifn-γ. Furthermore, we show significant levels of these inflammatory cytokines were locally produced at the site of cps1-1 inoculation. These findings offer new insight into immunological mechanisms and local host responses to a non-replicating Type I parasite infection associated with development of long-lasting immunity to Toxoplasma gondii. PMID:19124750

  11. Cell-mediated immunity to Toxoplasma gondii develops primarily by local Th1 host immune responses in the absence of parasite replication.

    PubMed

    Gigley, Jason P; Fox, Barbara A; Bzik, David J

    2009-01-15

    A single inoculation of mice with the live, attenuated Toxoplasma gondii uracil auxotroph strain cps1-1 induces long-lasting immunity against lethal challenge with hypervirulent strain RH. The mechanism for this robust immunity in the absence of parasite replication has not been addressed. The mechanism of long-lasting immunity, the importance of route of immunization, cellular recruitment to the site of infection, and local and systemic inflammation were evaluated. Our results show that infection with cps1-1 elicits long-lasting CD8+ T cell- mediated immunity. We show that immunization with cps1-1-infected dendritic cells elicits long-lasting immunity. Intraperitoneal infection with cps1-1 induced a rapid influx of GR1+ neutrophils and two stages of GR1+CD68+ inflammatory monocyte infiltration into the site of inoculation. CD19+ B cells and CD3+ T cells steadily increase for 8 days after infection. CD8+ T cells were rapidly recruited to the site of infection and increased faster than CD4+ T cells. Surprisingly, cps1-1 infection induced high systemic levels of bioactive IL-12p70 and a very low level and transient systemic IFN-gamma. Furthermore, we show significant levels of these inflammatory cytokines were locally produced at the site of cps1-1 inoculation. These findings offer new insight into immunological mechanisms and local host responses to a non-replicating type I parasite infection associated with development of long-lasting immunity to Toxoplasma gondii. PMID:19124750

  12. Morphine Suppresses T helper Lymphocyte Differentiation to Th1 Type Through PI3K/AKT Pathway.

    PubMed

    Mao, Mao; Qian, Yanning; Sun, Jie

    2016-04-01

    To investigate the effect of morphine on T helper lymphocyte differentiation and PI3K/AKT pathway mechanism, CD4+ lymphocytes were treated by phorbol-myristate-acetate (25 ng/ml) (PMA) plus ionomycin (1 μg/ml) in the presence of various concentrations of morphine (25, 50, 100, 200 ng/ml) for 4 h. Th1 and Th2 subsets, supernatant cytokines, and PI3K, AKT, and protein kinase C-theta (PKC-θ) levels were detected. The Th1 cell percentage, Th1-derived cytokines, and ratio of Th1/Th2 decreased in the presence of morphine in a concentration-dependent manner. However, Th2 cell percentage kept stable after morphine treatment. The phosphorylation of PI3K and AKT decreased, but the phosphorylation of PKC-θ did not change in the presence of morphine. The decreased percentage of Th1 cells and ratio of Th1/Th2 was recovered by naloxone concentration-dependently. Morphine can inhibit the differentiation of Th1 lymphocytes and decrease the ratio of Th1/Th2 via the pathway of PI3K/AKT. The effect can be inhibited by naloxone. PMID:26883517

  13. Th2 cell-specific cytokine expression and allergen-induced airway inflammation depend on JunB

    PubMed Central

    Hartenstein, Bettina; Teurich, Sibylle; Hess, Jochen; Schenkel, Johannes; Schorpp-Kistner, Marina; Angel, Peter

    2002-01-01

    Naïve CD4+ T cells differentiate into effector T helper 1 (Th1) or Th2 cells, which are classified by their specific set of cytokines. Here we demonstrate that loss of JunB in in vitro polarized Th2 cells led to a dysregulated expression of the Th2-specific cytokines IL-4 and IL-5. These cells produce IFN-γ and express T-bet, the key regulator of Th1 cells. In line with the essential role of Th2 cells in the pathogenesis of allergic asthma, mice with JunB-deficient CD4+ T cells exhibited an impaired allergen-induced airway inflammation. This study demonstrates novel functions of JunB in the development of Th2 effector cells, for a normal Th2 cytokine expression pattern and for a complete Th2-dependent immune response in mice. PMID:12456639

  14. Th1-skewed tissue responses to a mycolyl glycolipid in mycobacteria-infected rhesus macaques

    SciTech Connect

    Morita, Daisuke; Miyamoto, Ayumi; Hattori, Yuki; Komori, Takaya; Nakamura, Takashi; Igarashi, Tatsuhiko; Harashima, Hideyoshi; Sugita, Masahiko

    2013-11-08

    Highlights: •Glucose monomycolate (GMM) is a marker glycolipid for active tuberculosis. •Tissue responses to GMM involved up-regulation of Th1-attracting chemokines. •Th1-skewed local responses were mounted at the GMM-injected tissue. -- Abstract: Trehalose 6,6′-dimycolate (TDM) is a major glycolipid of the cell wall of mycobacteria with remarkable adjuvant functions. To avoid detection by the host innate immune system, invading mycobacteria down-regulate the expression of TDM by utilizing host-derived glucose as a competitive substrate for their mycolyltransferases; however, this enzymatic reaction results in the concomitant biosynthesis of glucose monomycolate (GMM) which is recognized by the acquired immune system. GMM-specific, CD1-restricted T cell responses have been detected in the peripheral blood of infected human subjects and monkeys as well as in secondary lymphoid organs of small animals, such as guinea pigs and human CD1-transgenic mice. Nevertheless, it remains to be determined how tissues respond at the site where GMM is produced. Here we found that rhesus macaques vaccinated with Mycobacterium bovis bacillus Calmette–Guerin mounted a chemokine response in GMM-challenged skin that was favorable for recruiting T helper (Th)1 T cells. Indeed, the expression of interferon-γ, but not Th2 or Th17 cytokines, was prominent in the GMM-injected tissue. The GMM-elicited tissue response was also associated with the expression of monocyte/macrophage-attracting CC chemokines, such as CCL2, CCL4 and CCL8. Furthermore, the skin response to GMM involved the up-regulated expression of granulysin and perforin. Given that GMM is produced primarily by pathogenic mycobacteria proliferating within the host, the Th1-skewed tissue response to GMM may function efficiently at the site of infection.

  15. Cellular networks controlling Th2 polarization in allergy and immunity.

    PubMed

    Kool, Mirjam; Hammad, Hamida; Lambrecht, Bart N

    2012-01-01

    In contrast to the development of Th1 (type 1 T helper cells), Th17 and Treg (regulatory T cells), little is known of the mechanisms governing Th2 development, which is important for immunity to helminths and for us to understand the pathogenesis of allergy. A picture is emerging in which mucosal epithelial cells instruct dendritic cells to promote Th2 responses in the absence of IL-12 (interleukin 12) production and provide instruction through thymic stromal lymphopoieitin (TSLP) or granulocyte-macrophage colony stimulating factor (GM-CSF). At the same time, allergens, helminths and chemical adjuvants elicit the response of innate immune cells like basophils, which provide more polarizing cytokines and IL-4 and reinforce Th2 immunity. This unique communication between cells will only be fully appreciated if we study Th2 immunity in vivo and in a tissue-specific context, and can only be fully understood if we compare several models of Th2 immune response induction. PMID:22403589

  16. Regulatory T Cells Control Th2-Dominant Murine Autoimmune Gastritis.

    PubMed

    Harakal, Jessica; Rival, Claudia; Qiao, Hui; Tung, Kenneth S

    2016-07-01

    Pernicious anemia and gastric carcinoma are serious sequelae of autoimmune gastritis (AIG). Our study indicates that in adult C57BL/6-DEREG mice expressing a transgenic diphtheria toxin receptor under the Foxp3 promoter, transient regulatory T cell (Treg) depletion results in long-lasting AIG associated with both H(+)K(+)ATPase and intrinsic factor autoantibody responses. Although functional Tregs emerge over time during AIG occurrence, the effector T cells rapidly become less susceptible to Treg-mediated suppression. Whereas previous studies have implicated dysregulated Th1 cell responses in AIG pathogenesis, eosinophils have been detected in gastric biopsy specimens from patients with AIG. Indeed, AIG in DEREG mice is associated with strong Th2 cell responses, including dominant IgG1 autoantibodies, elevated serum IgE, increased Th2 cytokine production, and eosinophil infiltration in the stomach-draining lymph nodes. In addition, the stomachs exhibit severe mucosal and muscular hypertrophy, parietal cell loss, mucinous epithelial cell metaplasia, and massive eosinophilic inflammation. Notably, the Th2 responses and gastritis severity are significantly ameliorated in IL-4- or eosinophil-deficient mice. Furthermore, expansion of both Th2-promoting IFN regulatory factor 4(+) programmed death ligand 2(+) dendritic cells and ILT3(+) rebounded Tregs was detected after transient Treg depletion. Collectively, these data suggest that Tregs maintain physiological tolerance to clinically relevant gastric autoantigens, and Th2 responses can be a pathogenic mechanism in AIG. PMID:27259856

  17. Th2 differentiation in distinct lymph nodes influences the site of mucosal Th2 immune-inflammatory responses.

    PubMed

    Alvarez, David; Arkinson, Janine L; Sun, Jiangfeng; Fattouh, Ramzi; Walker, Tina; Jordana, Manel

    2007-09-01

    Allergic individuals rarely present with concurrent multiple-organ disease but, rather, with manifestations that privilege a specific site such as the lung, skin, or gastrointestinal tract. Whether the site of allergic sensitization influences the localization of Th2 immune-inflammatory responses and, ultimately, the organ-specific expression of disease, remains to be determined. In this study, we investigated whether both the site of initial Ag exposure and concomitant Th2 differentiation in specific lymph nodes (LNs) privileges Th2 memory responses to mucosal and nonmucosal sites, and whether this restriction is associated with a differential expression in tissue-specific homing molecules. In mice exposed to Ag (OVA) via the peritoneum, lung, or skin, we examined several local and distal LNs to determine the site of Ag-specific proliferation and Th2 differentiation. Whereas respiratory and cutaneous Ag exposure led to Ag-specific proliferation and Th2 differentiation exclusively in lung- and skin-draining LNs, respectively, Ag delivery to the peritoneum evoked responses in gut-associated, as well as distal thoracic, LNs. Importantly, only mice that underwent Th2 differentiation in thoracic- or gut-associated LNs mounted Th2 immune-inflammatory responses upon respiratory or gastric Ag challenge, respectively, whereas cutaneous Th2 recall responses were evoked irrespective of the site of initial sensitization. In addition, we observed the differential expression of gut homing molecules (CCR9, alpha(4), beta(7)) in gut-associated LNs and, unexpectedly, a universal induction of skin-related homing molecules (CCR4, CCR10) in all LNs. These data suggest that the site of initial Th2 differentiation and differential homing molecule expression restricts Th2 immune-inflammatory responses to mucosal, but not cutaneous, tissues. PMID:17709545

  18. SerpinB2 is critical to Th2 immunity against enteric nematode infection

    Technology Transfer Automated Retrieval System (TEKTRAN)

    SerpinB2, a member of the serine protease inhibitor family, is expressed by macrophages and up-regulated significantly by inflammation. Recent studies implicated a role for SerpinB2 in the control of Th1 and Th2 immune responses, but the mechanisms of these effects are unknown. In the current study...

  19. Trypanosoma cruzi trans-sialidase prevents elicitation of Th1 cell response via interleukin 10 and downregulates Th1 effector cells.

    PubMed

    Ruiz Díaz, Pablo; Mucci, Juan; Meira, María Ana; Bogliotti, Yanina; Musikant, Daniel; Leguizamón, María Susana; Campetella, Oscar

    2015-05-01

    The trans-sialidases (TSs) from Trypanosoma cruzi, the agent of Chagas disease, are virulence factors shed to the bloodstream that induce strong alterations in the immune system. Here, we report that both enzymatically active TS (aTS) and its lectinlike isoform (iTS) disturb CD4 T cell physiology, inducing downregulation of Th1 cell functionality and in vivo cell expansion. By using ovalbumin-specific DO11.10 cells as tracers of clones developing the Th1 phenotype, we found that the infection induced significant amounts of gamma interferon (IFN-γ) but low levels of interleukin 2 (IL-2) and increased IL-4 production in vivo, in agreement with a mixed T helper response. The production of cytokines associated with the Th2 phenotype was prevented by passive transfer of anti-TS neutralizing antibodies. TSs also reduced the T cell receptor signaling as assayed by Zap-70 phosphorylation. TSs also reduced IL-2 and IFN-γ secretion, with a concomitant increase in IL-4 production and then an unbalancing of the CD4 T cell response toward the Th2 phenotype. This effect was prevented by using anti-IL-10 neutralizing antibodies or IL-10(-/-) antigen-presenting cells, supporting the subversion of this regulatory pathway. In support, TSs stimulated IL-10 secretion by antigen-presenting cells during their interaction with CD4 T cells. When polarized cells were stimulated in the presence of TSs, the secretion of IL-2 and IFN-γ was strongly downregulated in Th1 cells, while IL-2 production was upregulated in Th2 cells. Although the Th1 response is associated with host survival, it may simultaneously induce extensive damage to infected tissues. Thus, by delaying the elicitation of the Th1 response and limiting its effector properties, TSs restrain the cell response, supporting T. cruzi colonization and persistence while favoring host survival. PMID:25754197

  20. Functionally distinct Gata3/Chd4 complexes coordinately establish T helper 2 (Th2) cell identity

    PubMed Central

    Hosokawa, Hiroyuki; Tanaka, Tomoaki; Suzuki, Yutaka; Iwamura, Chiaki; Ohkubo, Shuichi; Endoh, Kanji; Kato, Miki; Endo, Yusuke; Onodera, Atsushi; Tumes, Damon John; Kanai, Akinori; Sugano, Sumio; Nakayama, Toshinori

    2013-01-01

    GATA binding protein 3 (Gata3) is a GATA family transcription factor that controls differentiation of naïve CD4 T cells into T helper 2 (Th2) cells. However, it is unknown how Gata3 simultaneously activates Th2-specific genes while repressing those of other Th lineages. Here we show that chromodomain helicase DNA-binding protein 4 (Chd4) forms a complex with Gata3 in Th2 cells that both activates Th2 cytokine transcription and represses the Th1 cytokine IFN-γ. We define a Gata3/Chd4/p300 transcriptional activation complex at the Th2 cytokine loci and a Gata3/Chd4–nucleosome remodeling histone deacetylase repression complex at the Tbx21 locus in Th2 cells. We also demonstrate a physiological role for Chd4 in Th2-dependent inflammation in an in vivo model of asthmatic inflammation. Thus, Gata3/Chd4 forms functionally distinct complexes, which mediate both positive and negative gene regulation to facilitate Th2 cell differentiation. PMID:23471993

  1. Blockade of CD86 ameliorates Leishmania major infection by down-regulating the Th2 response.

    PubMed

    Brown, J A; Titus, R G; Nabavi, N; Glimcher, L H

    1996-12-01

    The costimulatory molecules CD80 and CD86 affect the differentiation of Th1 and Th2 subsets in experimental allergic encephalomyelitis, an autoimmune disorder. It is reported that the CD86 costimulator significantly affects disease outcome in Leishmania major infection, a classic model of Th subset polarization. Treatment of both L. major-resistant (C57BL/6) and susceptible (BALB/c) strains of mice with anti-CD86 substantially decreased parasite burden. This was accompanied, in BALB/c mice, by a decrease in Th2 cytokines. In contrast, anti-CD80 treatment did not affect parasite burden or cytokine levels in either strain. These data illustrate that in L. major infection, anti-CD86 can abrogate Th2 differentiation in a Th2-dominated susceptible mouse and can ameliorate disease in a Th1-dominated resistant strain, although the mechanism involved in the latter is not clear. It is concluded that in L. major infection, Th2 subset differentiation is critically dependent on interaction with the CD86 costimulatory molecule. PMID:8940222

  2. The essential role of SIGIRR/TIR8 in regulation of Th2 immune response1

    PubMed Central

    Bulek, Katarzyna; Swaidani, Shadi; Qin, Jinzhong; Lu, Yi; Gulen, Muhammet F.; Herjan, Tomasz; Min, Booki; Kastelein, Robert A.; Aronica, Mark; Kosz-Vnenchak, Magdalena; Li, Xiaoxia

    2010-01-01

    A novel cytokine IL-33, an IL-1 family member, signals via ST2 receptor and promotes T helper type 2 (Th2) responses, through the activation of NFκB and MAP kinases. Previous studies reported that SIGIRR (single immunoglobulin IL-1R-related molecule)/TIR8 (Toll IL-1R8) acts as negative regulator for TLR-IL-1R-mediated signaling. We now found that SIGIRR formed a complex with ST2 upon IL-33 stimulation and specifically inhibited IL-33/ST2-mediated signaling in cell culture model. Furthermore, IL-33-induced Th2 response was enhanced in SIGIRR-deficient mice compared to that in wild-type control mice, suggesting a negative regulatory role of SIGIRR in IL-33/ST2 signaling in vivo. Similar to ST2, SIGIRR was highly expressed in in vitro polarized Th2 cells, but not Th1 cells. SIGIRR-deficient Th2 cells produce higher levels of “Th2 cytokines”, including IL-5, IL-4 and IL-13 than that in wild-type cells. Moreover, SIGIRR-deficient mice developed stronger Th2 immune response in OVA-challenged asthma model. Taken together, our results suggest that SIGIRR plays an important role in the regulation of Th2 response in vivo, possibly through its impact on IL-33-ST2-mediated signaling. PMID:19234154

  3. Transcription factor IRF4 drives dendritic cells to promote Th2 differentiation

    NASA Astrophysics Data System (ADS)

    Williams, Jesse W.; Tjota, Melissa Y.; Clay, Bryan S.; Vander Lugt, Bryan; Bandukwala, Hozefa S.; Hrusch, Cara L.; Decker, Donna C.; Blaine, Kelly M.; Fixsen, Bethany R.; Singh, Harinder; Sciammas, Roger; Sperling, Anne I.

    2013-12-01

    Atopic asthma is an inflammatory pulmonary disease associated with Th2 adaptive immune responses triggered by innocuous antigens. While dendritic cells (DCs) are known to shape the adaptive immune response, the mechanisms by which DCs promote Th2 differentiation remain elusive. Herein we demonstrate that Th2-promoting stimuli induce DC expression of IRF4. Mice with conditional deletion of Irf4 in DCs show a dramatic defect in Th2-type lung inflammation, yet retain the ability to elicit pulmonary Th1 antiviral responses. Using loss- and gain-of-function analysis, we demonstrate that Th2 differentiation is dependent on IRF4 expression in DCs. Finally, IRF4 directly targets and activates the Il-10 and Il-33 genes in DCs. Reconstitution with exogenous IL-10 and IL-33 recovers the ability of Irf4-deficient DCs to promote Th2 differentiation. These findings reveal a regulatory module in DCs by which IRF4 modulates IL-10 and IL-33 cytokine production to specifically promote Th2 differentiation and inflammation.

  4. Phenytoin promotes Th2 type immune response in mice

    PubMed Central

    Okada, K; Sugiura, T; Kuroda, E; Tsuji, S; Yamashita, U

    2001-01-01

    The effects of chronic administration of phenytoin, a common anticonvulsive drug, on immune responses were studied in mice. Anti-keyhole limpet haemocyanin (KLH) IgE antibody response after KLH-immunization was enhanced in phenytoin-treated mice. Proliferative responses of spleen cells induced with KLH, concanavalin A (ConA), lipopolysaccharide and anti-CD3 antibody were reduced in phenytoin-treated mice. Accessory function of spleen adherent cells on ConA-induced T cell proliferative response was reduced in phenytoin-treated mice. KLH-induced IL-4 production of spleen cells was enhanced, while IFN-γ production was reduced in phenytoin-treated mice. In addition, production of IL-1α, but not IL-6 and IL-12 by spleen adherent cells from phenytoin-treated mice was reduced. Natural killer cell activity was reduced in phenytoin-treated mice. These results suggest that phenytoin treatment preferentially induces a Th2 type response. We also observed that plasma ACTH and corticosterone levels were increased in phenytoin-treated mice, and speculated that phenytoin might act directly and indirectly, through HPA axis activation, on the immune system to modulate Th1/Th2 balance. PMID:11472401

  5. Oral administration of an immunodominant T-cell epitope downregulates Th1/Th2 cytokines and prevents experimental myasthenia gravis

    PubMed Central

    Baggi, Fulvio; Andreetta, Francesca; Caspani, Elisabetta; Milani, Monica; Longhi, Renato; Mantegazza, Renato; Cornelio, Ferdinando; Antozzi, Carlo

    1999-01-01

    The mucosal administration of the native antigen or peptide fragments corresponding to immunodominant regions is effective in preventing or treating several T cell–dependent models of autoimmune disease. No data are yet available on oral tolerance with immunodominant T-cell peptides in experimental autoimmune myasthenia gravis (EAMG), an animal model of B cell–dependent disease. We report that oral administration of the T-cell epitope α146-162 of the Torpedo californica acetylcholine receptor (TAChR) α-subunit suppressed T-cell responses to AChR and ameliorated the disease in C57Bl/6 (B6) mice. Protection from EAMG was associated with reduced serum Ab’s to mouse AChR and reduced AChR loss in muscle. The effect of Tα146-162 feeding was specific; treatment with a control peptide did not affect EAMG manifestations. The protective effect induced by peptide Tα146-162 was mediated by reduced production of IFN-γ, IL-2, and IL-10 by TAChR-reactive cells, suggesting T-cell anergy. TGF-β–secreting Th3 cells did not seem to be involved in tolerance induction. We therefore demonstrate that feeding a single immunodominant epitope can prevent an Ab-mediated experimental model of autoimmune disease. PMID:10545527

  6. Raising the Roof: The Preferential Pharmacological Stimulation of Th1 and Th2 Responses Mediated by NKT Cells

    PubMed Central

    East, James E.; Kennedy, Andrew J.; Webb, Tonya J.

    2014-01-01

    Natural killer T (NKT) cells serve as a bridge between the innate and adaptive immune systems, and manipulating their effector functions can have therapeutic significances in the treatment of autoimmunity, transplant biology, infectious disease, and cancer. NKT cells are a subset of T cells that express cell-surface markers characteristic of both natural killer cells and T cells. These unique immunologic cells have been demonstrated to serve as a link between the innate and adaptive immune systems through their potent cytokine production following the recognition of a range of lipid antigens, mediated through presentation of the major histocompatibility complex (MHC) class I like CD1d molecule, in addition to the NKT cell′s cytotoxic capabilities upon activation. Although a number of glycolipid antigens have been shown to complex with CD1d molecules, most notably the marine sponge derived glycolipid alpha-galactosylceramide (α-GalCer), there has been debate as to the identity of the endogenous activating lipid presented to the T-cell receptor (TCR) via the CD1d molecule on antigen-presenting cells (APCs). This review aims to survey the use of pharmacological agents and subsequent structure–activity relationships (SAR) that have given insight into the binding interaction of glycolipids with both the CD1d molecules as well as the TCR and the subsequent immunologic response of NKT cells. These studies not only elucidate basic binding interactions but also pave the way for future pharmacological modulation of NKT cell responses. PMID:23239102

  7. IL28B gene polymorphisms and Th1/Th2 cytokine levels might be associated with HTLV-associated arthropathy.

    PubMed

    de Sá, Keyla Santos Guedes; Santana, Bárbara Brasil; de Souza Ferreira, Tuane Carolina; Sousa, Rita Catarina Medeiros; Caldas, Cezar Augusto Muniz; Azevedo, Vânia Nakauth; Feitosa, Rosimar Neris Martins; Machado, Luiz Fernando Almeida; de Oliveira Guimarães Ishak, Marluísa; Ishak, Ricardo; Vallinoto, Antonio Carlos Rosário

    2016-01-01

    The present study is the first investigation of the association between single nucleotide polymorphisms (SNPs - rs8099917, rs12979860 and rs8103142) of the IL28B gene and the development of human T-lymphotropic virus (HTLV)-associated arthropathy (HAA). Individuals with HAA exhibited low interleukin (IL) 6 (p<0.05) and high IL-10 (p<0.05) levels compared with asymptomatic patients. TNF-α/CD4(+) T cell count, TNF-α/CD8(+) T cell count and IFN-γ/proviral load positively correlated in asymptomatic patients. The allelic and genotypic frequencies did not differ between patients with HAA and asymptomatic patients. Seven haplotypes were detected in the investigated population, with haplotype CCT (p<0.05) being the most frequent among the HTLV-infected individuals, while haplotype TTG (p<0.05) was detected in the group with HAA only. Compared with asymptomatic patients, individuals with HAA and genotype TT (rs8099917) exhibited larger numbers of CD8(+) T cells (p<0.05) and higher proviral load levels (p<0.05). Those patients with HAA and genotypes CC (rs12979860) and TT (rs8103142) exhibited high TNF-β (p<0.05) and IFN-γ (p<0.05) levels. Those patients with HAA and genotype CT/TT (rs12979860) exhibited high IL-10 levels (p<0.05). These results suggest that haplotypes CCT and TTG might be associated with susceptibility to HTLV infection and progression to HAA, respectively. Genotype TT (rs8099917) might be a risk factor for elevation of the proviral load and CD8(+) T cell count. In addition, genotypes CC (rs12979860) and TT (rs8103142) seem to be associated with increased TNF-β and IFN-γ levels. PMID:26546777

  8. Predominance of Th2 polarization by Vitamin D through a STAT6-dependent mechanism

    PubMed Central

    2011-01-01

    Background Vitamin D has several reported immunomodulatory properties including the reduced generation of pro-inflammatory CD4+ T helper 1 (Th1) cells and the increase in levels of the anti-inflammatory Th2 subset. Less clear has been the impact of vitamin D on the pro-inflammatory Th17 subset, and whether and how vitamin D may preferentially drive the polarization of one of the T helper subsets. Methods Using human peripheral blood-derived mononuclear cells and mouse splenocytes and lymph node cells in culture, we examined whether and how vitamin D preferentially skews T cells towards the Th1, Th2 or Th17 subsets. Mice afflicted with the multiple sclerosis-like condition, experimental autoimmune encephalomyelitis (EAE), were examined in vivo for the relevance of the tissue culture-derived results. Results We report that the biologically active form of vitamin D, 1,25-dihydroxyvitamin D3 {1,25(OH)2D3}, consistently generates human and murine Th2 cells in culture, frequently leaving unchanged the levels of Th1/Th17 cytokines. As a result, the ratio of Th2 to Th1 and Th17 is increased by 1,25(OH)2D3. The upregulation of Th2 to Th1 or Th17 subsets by 1,25(OH)2D3 is enabled by an increase of the GATA-3 transcription factor, which itself is promoted upstream by an elevation of the STAT6 transcription factor. In mice, the alleviation of EAE severity by 1,25(OH)2D3 is accompanied by elevation of levels of GATA-3 and STAT6. Significantly, the efficacy of 1,25(OH)2D3 in ameliorating EAE is completely lost in mice genetically deficient for STAT6, which was accompanied by the inability of 1,25(OH)2D3 to raise GATA-3 in STAT6 null lymphocytes. Conclusions These results of vitamin D promoting a Th2 shift through upstream GATA-3 and STAT6 transcription factors shed mechanistic understanding on the utility of vitamin D in MS. PMID:21605467

  9. Deficiency in Th2 cytokine responses exacerbate orthopoxvirus infection.

    PubMed

    Sakala, Isaac G; Chaudhri, Geeta; Eldi, Preethi; Buller, R Mark; Karupiah, Gunasegaran

    2015-01-01

    Ectromelia virus (ECTV) causes mousepox in mice, a disease very similar to smallpox in humans. ECTV and variola virus (VARV), the agent of smallpox, are closely related orthopoxviruses. Mousepox is an excellent small animal model to study the genetic and immunologic basis for resistance and susceptibility of humans to smallpox. Resistance to mousepox is dependent on a strong polarized type 1 immune response, associated with robust natural killer (NK) cell, cytotoxic T lymphocyte (CTL) and gamma interferon (IFN-γ) responses. In contrast, ECTV-susceptible mice generate a type 2 response, associated with weak NK cell, CTL and IFN-γ responses but robust IL-4 responses. Nonetheless, susceptible strains infected with mutant ECTV lacking virus-encoded IFN-γ binding protein (vIFN-γbp) (ECTV-IFN-γbpΔ) control virus replication through generation of type 1 response. Since the IL-4/IL-13/STAT-6 signaling pathways polarize type 2/T helper 2 (Th2) responses with a corresponding suppression of IFN-γ production, we investigated whether the combined absence of vIFN-γbp, and one or more host genes involved in Th2 response development, influence generation of protective immunity. Most mutant mouse strains infected with wild-type (WT) virus succumbed to disease more rapidly than WT animals. Conversely, the disease outcome was significantly improved in WT mice infected with ECTV-IFN-γbpΔ but absence of IL-4/IL-13/STAT-6 signaling pathways did not provide any added advantage. Deficiency in IL-13 or STAT-6 resulted in defective CTL responses, higher mortality rates and accelerated deaths. Deficiencies in IL-4/IL-13/STAT-6 signaling pathways significantly reduced the numbers of IFN-γ producing CD4 and CD8 T cells, indicating an absence of a switch to a Th1-like response. Factors contributing to susceptibility or resistance to mousepox are far more complex than a balance between Th1 and Th2 responses. PMID:25751266

  10. Deficiency in Th2 Cytokine Responses Exacerbate Orthopoxvirus Infection

    PubMed Central

    Sakala, Isaac G.; Chaudhri, Geeta; Eldi, Preethi; Buller, R. Mark; Karupiah, Gunasegaran

    2015-01-01

    Ectromelia virus (ECTV) causes mousepox in mice, a disease very similar to smallpox in humans. ECTV and variola virus (VARV), the agent of smallpox, are closely related orthopoxviruses. Mousepox is an excellent small animal model to study the genetic and immunologic basis for resistance and susceptibility of humans to smallpox. Resistance to mousepox is dependent on a strong polarized type 1 immune response, associated with robust natural killer (NK) cell, cytotoxic T lymphocyte (CTL) and gamma interferon (IFN-γ) responses. In contrast, ECTV-susceptible mice generate a type 2 response, associated with weak NK cell, CTL and IFN-γ responses but robust IL-4 responses. Nonetheless, susceptible strains infected with mutant ECTV lacking virus-encoded IFN-γ binding protein (vIFN-γbp) (ECTV-IFN-γbpΔ) control virus replication through generation of type 1 response. Since the IL-4/IL-13/STAT-6 signaling pathways polarize type 2/T helper 2 (Th2) responses with a corresponding suppression of IFN-γ production, we investigated whether the combined absence of vIFN-γbp, and one or more host genes involved in Th2 response development, influence generation of protective immunity. Most mutant mouse strains infected with wild-type (WT) virus succumbed to disease more rapidly than WT animals. Conversely, the disease outcome was significantly improved in WT mice infected with ECTV-IFN-γbpΔ but absence of IL-4/IL-13/STAT-6 signaling pathways did not provide any added advantage. Deficiency in IL-13 or STAT-6 resulted in defective CTL responses, higher mortality rates and accelerated deaths. Deficiencies in IL-4/IL-13/STAT-6 signaling pathways significantly reduced the numbers of IFN-γ producing CD4 and CD8 T cells, indicating an absence of a switch to a Th1-like response. Factors contributing to susceptibility or resistance to mousepox are far more complex than a balance between Th1 and Th2 responses. PMID:25751266

  11. Dectin-1 in the control of Th2-type T cell responses

    PubMed Central

    Upchurch, Katherine; Oh, SangKon; Joo, HyeMee

    2016-01-01

    Dendritic cells (DCs) are major antigen-presenting cells (APCs) that can induce and control host immune responses. DCs express pattern recognition receptors (PRRs), which can translate external and internal triggers into different types of T cell responses. The types of CD4+ T cell responses elicited by DCs (e.g., Th1, Th2, Th17, Th21, Th22 and regulatory T cells (Tregs)) are associated with either host immunity or inflammatory diseases, including allergic diseases and autoimmune diseases. In particular, the pathogenic functions of Th2-type T cells in allergic immune disorders have been well documented, although Th2-type T cell responses are crucial for immunity against certain parasite infections. Recent evidence also indicates that the inflammatory Th2 signatures in cancers, including breast and pancreatic cancers, are highly associated with poor clinical outcomes in patients. It is thus important to find cellular/molecular targets expressed in DCs that control such inflammatory Th2-type T cell responses. In a recent paper published in The Journal of Immunology, we demonstrated that Dectin-1 expressed on the two major human DC subsets, myeloid DCs (mDCs) and plasmacytoid DCs (pDCs), has opposing roles in the control of Th2-type CD4+ T cell responses. Dectin-1 expressed on mDCs decreases Th2-type CD4+ T cell responses, while Dectin-1 expressed on pDCs favors Th2-type CD4+ T cell responses. This finding expands our understanding of the roles of DCs and Dectin-1 expressed on DCs in the pathogenesis of Th2-associated diseases and in host immunity to microbial infections and cancers. PMID:27088111

  12. The other side of the coin: the protective role of the TH2 cytokines.

    PubMed

    Finkelman, F D; Urban, J F

    2001-05-01

    Although T(H)2 cytokine involvement in allergy makes these cytokines attractive therapeutic targets, they protect against ectoparasites and gastrointestinal worms and suppress inflammation induced by T(H)1 cytokines. T(H)2 cytokines induce mastocytosis, eosinophilia, IgE synthesis, and mucus production. Each element of this response protects against some worms; however, different worms are protected against by different elements of the total response. The induction of the entire response by most parasitic worms suggests that it is safer for the immune system to make a stereotyped worm-protective response than to attempt to match a more specific response to a particular worm. In contrast, the reciprocal antagonism between T(H)1 and T(H)2 cytokines suggests that it is safer for the immune system to limit immunopathology by suppressing inflammatory effector mechanisms not required for host protection against a particular pathogen class than to make an all-purpose inflammatory response. This, in turn, implies that innate immunity can distinguish different classes of parasites (eg, worms vs protozoa) but has limited ability to distinguish individual parasites within a class (eg, different worms). Although these considerations suggest that T(H)2 cytokine antagonists may increase the risk and severity of worm infections and T(H)1 cytokine-mediated inflammatory disorders, such therapy should be relatively safe if it is restricted to areas in which worm infections are rare and commonsense precautions are taken to minimize the risk of inducing T(H)1 cytokine-related inflammatory disease. PMID:11344341

  13. Bone marrow-derived mesenchymal stromal cells inhibit Th2-mediated allergic airways inflammation in mice.

    PubMed

    Goodwin, Meagan; Sueblinvong, Viranuj; Eisenhauer, Philip; Ziats, Nicholas P; LeClair, Laurie; Poynter, Matthew E; Steele, Chad; Rincon, Mercedes; Weiss, Daniel J

    2011-07-01

    Bone marrow-derived mesenchymal stromal cells (BMSCs) mitigate inflammation in mouse models of acute lung injury. However, specific mechanisms of BMSC actions on CD4 T lymphocyte-mediated inflammation in vivo remain poorly understood. Limited data suggests promotion of Th2 phenotype in models of Th1-mediated diseases. However, whether this might alleviate or worsen Th2-mediated diseases such as allergic asthma is unknown. To ascertain the effects of systemic administration of BMSCs in a mouse model of Th2-mediated allergic airways inflammation, ovalbumin (OVA)-induced allergic airways inflammation was induced in wild-type C57BL/6 and BALB/c mice as well as in interferon-γ (IFNγ) receptor null mice. Effects of systemic administration during antigen sensitization of either syngeneic or allogeneic BMSC on airways hyperreactivity, lung inflammation, antigen-specific CD4 T lymphocytes, and serum immunoglobulins were assessed. Both syngeneic and allogeneic BMSCs inhibited airways hyperreactivity and lung inflammation through a mechanism partly dependent on IFNγ. However, contrary to existing data, BMSCs did not affect antigen-specific CD4 T lymphocyte proliferation but rather promoted Th1 phenotype in vivo as assessed by both OVA-specific CD4 T lymphocyte cytokine production and OVA-specific circulating immunoglobulins. BMSCs treated to prevent release of soluble mediators and a control cell population of primary dermal skin fibroblasts only partly mimicked the BMSC effects and in some cases worsened inflammation. In conclusion, BMSCs inhibit Th2-mediated allergic airways inflammation by influencing antigen-specific CD4 T lymphocyte differentiation. Promotion of a Th1 phenotype in antigen-specific CD4 T lymphocytes by BMSCs is sufficient to inhibit Th2-mediated allergic airways inflammation through an IFNγ-dependent process. PMID:21544902

  14. Lck Mediates Th2 Differentiation through Effects on T-bet and GATA-3

    PubMed Central

    Kemp, Kyeorda L.; Levin, Steven D.; Bryce, Paul J.; Stein, Paul L.

    2016-01-01

    The Src family kinase Lck has been shown to be crucial in T cell signaling and development. However, its role in Th effector functions is not well understood. Lck has previously been shown to play a role in the cytokine expression of Th2 cells, but the mechanism by which Lck influences Th2 effector functions is unknown. Using a mouse model, we report that Lck is important in regulating the expression of IL-4 in Th2 skewed cells but is not as necessary for the expression of Th2 cytokines IL-5, IL-10, and IL-13. Furthermore, in the absence of Lck, T-bet and GATA-3 expression is aberrant. Moreover, this atypical expression pattern of T-bet and GATA-3 correlates with increased histone 3 acetylation at the Ifng locus and production of the Th1 cytokine IFN-γ. We find overexpression of GATA-3 restores IL-4 expression in lck−/− Th2 cells; this indicates that the decreased IL-4 expression is due in part to reduced amounts of GATA-3. Taken together, these data imply that Lck mediates Th2 differentiation through effects on T-bet and GATA-3. PMID:20237292

  15. Citrus Tachibana Leaf Extract Mitigates Symptoms of Food Allergy by Inhibiting Th2-Associated Responses.

    PubMed

    Chung, Min-Yu; Shin, Hee Soon; Choi, Dae Woon; Shon, Dong-Hwa

    2016-06-01

    Although the incidence of food allergy continues to rise, there have been no effective therapeutic strategies. Citrus fruits contain a number of bioactive flavonoids with immune-regulatory functions. The objective of this study was to determine whether Citrus tachibana (fruit body with peel, leaves, and branch) can protect against the development of food allergy and the mechanism behind it, and to identify the active compound(s) responsible. We found that C. tachibana leaf extract (CLE) mitigated ovalbumin (OVA)-induced food allergy symptoms including increased rectal temperature, diarrhea, and anaphylaxis. This mitigation was likely due to CLE-mediated decreases in cytokine release from T-helper 2 cells (Th2 cells) in mesenteric lymph nodes. Moreover, higher levels of CLE attenuated systemic Th2 cell-mediated responses in mouse splenocytes sensitized with OVA+Alum. This was evidenced by CLE-mediated reductions in Th2 cytokine release, including interleukin (IL)-4, IL-5, and IL-13, but not the Th1 cytokines IL-12 and interferon (IFN)-γ, which was attributable to decreased gene expression levels. We also identified kaempferol as the most potent compound for reducing Th2-associated responses in splenocytes. The findings of this study suggest that CLE suppresses Th2-cell-mediated immune responses, contributing to alleviation of food allergy symptoms, and that kaempferol is a flavonoid with potential antiallergenic activity that targets Th2 cell-induced responses. PMID:27121925

  16. Local treatment of a pleural mesothelioma tumor with ONCOS-102 induces a systemic antitumor CD8+ T-cell response, prominent infiltration of CD8+ lymphocytes and Th1 type polarization

    PubMed Central

    Ranki, Tuuli; Joensuu, Timo; Jäger, Elke; Karbach, Julia; Wahle, Claudia; Kairemo, Kalevi; Alanko, Tuomo; Partanen, Kaarina; Turkki, Riku; Linder, Nina; Lundin, Johan; Ristimäki, Ari; Kankainen, Matti; Hemminki, Akseli; Backman, Charlotta; Dienel, Kasper; von Euler, Mikael; Haavisto, Elina; Hakonen, Tiina; Juhila, Juuso; Jaderberg, Magnus; Priha, Petri; Vassilev, Lotta; Vuolanto, Antti; Pesonen, Sari

    2014-01-01

    Late stage cancer is often associated with reduced immune recognition and a highly immunosuppressive tumor microenvironment. The presence of tumor infiltrating lymphocytes (TILs) and specific gene-signatures prior to treatment are linked to good prognosis, while the opposite is true for extensive immunosuppression. The use of adenoviruses as cancer vaccines is a form of active immunotherapy to initialise a tumor-specific immune response that targets the patient's unique tumor antigen repertoire. We report a case of a 68-year-old male with asbestos-related malignant pleural mesothelioma who was treated in a Phase I study with a granulocyte-macrophage colony‑stimulating factor (GM-CSF)-expressing oncolytic adenovirus, Ad5/3-D24-GMCSF (ONCOS-102). The treatment resulted in prominent infiltration of CD8+ lymphocytes to tumor, marked induction of systemic antitumor CD8+ T-cells and induction of Th1-type polarization in the tumor. These results indicate that ONCOS-102 treatment sensitizes tumors to other immunotherapies by inducing a T-cell positive phenotype to an initially T-cell negative tumor. PMID:25941579

  17. Akt1-mediated Gata3 phosphorylation controls the repression of IFNγ in memory-type Th2 cells

    PubMed Central

    Hosokawa, Hiroyuki; Tanaka, Tomoaki; Endo, Yusuke; Kato, Miki; Shinoda, Kenta; Suzuki, Akane; Motohashi, Shinichiro; Matsumoto, Masaki; Nakayama, Keiichi I.; Nakayama, Toshinori

    2016-01-01

    Th2 cells produce Th2 cytokines such as IL-4, IL-5 and IL-13, but repress Th1 cytokine IFNγ. Recent studies have revealed various distinct memory-type Th2 cell subsets, one of which produces a substantial amount of IFNγ in addition to Th2 cytokines, however it remains unclear precisely how these Th2 cells produce IFNγ. We herein show that phosphorylation of Gata3 at Ser308, Thr315 and Ser316 induces dissociation of a histone deacetylase Hdac2 from the Gata3/Chd4 repressive complex in Th2 cells. We also identify Akt1 as a Gata3-phosphorylating kinase, and the activation of Akt1 induces derepression of Tbx21 and Ifng expression in Th2 cells. Moreover, T-bet-dependent IFNγ expression in IFNγ-producing memory Th2 cells appears to be controlled by the phosphorylation status of Gata3 in human and murine systems. Thus, this study highlights the molecular basis for posttranslational modifications of Gata3 that control the regulation of IFNγ expression in memory Th2 cells. PMID:27053161

  18. Akt1-mediated Gata3 phosphorylation controls the repression of IFNγ in memory-type Th2 cells.

    PubMed

    Hosokawa, Hiroyuki; Tanaka, Tomoaki; Endo, Yusuke; Kato, Miki; Shinoda, Kenta; Suzuki, Akane; Motohashi, Shinichiro; Matsumoto, Masaki; Nakayama, Keiichi I; Nakayama, Toshinori

    2016-01-01

    Th2 cells produce Th2 cytokines such as IL-4, IL-5 and IL-13, but repress Th1 cytokine IFNγ. Recent studies have revealed various distinct memory-type Th2 cell subsets, one of which produces a substantial amount of IFNγ in addition to Th2 cytokines, however it remains unclear precisely how these Th2 cells produce IFNγ. We herein show that phosphorylation of Gata3 at Ser308, Thr315 and Ser316 induces dissociation of a histone deacetylase Hdac2 from the Gata3/Chd4 repressive complex in Th2 cells. We also identify Akt1 as a Gata3-phosphorylating kinase, and the activation of Akt1 induces derepression of Tbx21 and Ifng expression in Th2 cells. Moreover, T-bet-dependent IFNγ expression in IFNγ-producing memory Th2 cells appears to be controlled by the phosphorylation status of Gata3 in human and murine systems. Thus, this study highlights the molecular basis for posttranslational modifications of Gata3 that control the regulation of IFNγ expression in memory Th2 cells. PMID:27053161

  19. Synthetic retinoid Am80 ameliorates chronic graft-versus-host disease by down-regulating Th1 and Th17.

    PubMed

    Nishimori, Hisakazu; Maeda, Yoshinobu; Teshima, Takanori; Sugiyama, Haruko; Kobayashi, Koichiro; Yamasuji, Yoshiko; Kadohisa, Sachiyo; Uryu, Hidetaka; Takeuchi, Kengo; Tanaka, Takehiro; Yoshino, Tadashi; Iwakura, Yoichiro; Tanimoto, Mitsune

    2012-01-01

    Chronic GVHD (cGVHD) is a main cause of late death and morbidity after allogeneic hematopoietic cell transplantation, but its pathogenesis remains unclear. We investigated the roles of Th subsets in cGVHD with the use of a well-defined mouse model of cGVHD. In this model, development of cGVHD was associated with up-regulated Th1, Th2, and Th17 responses. Th1 and Th2 responses were up-regulated early after BM transplantation, followed by a subsequent up-regulation of Th17 cells. Significantly greater numbers of Th17 cells were infiltrated in the lung and liver from allogeneic recipients than those from syngeneic recipients. We then evaluated the roles of Th1 and Th17 in cGVHD with the use of IFN-γ-deficient and IL-17-deficient mice as donors. Infusion of IFN-γ(-/-) or IL-17(-/-) T cells attenuated cGVHD in the skin and salivary glands. Am80, a potent synthetic retinoid, regulated both Th1 and Th17 responses as well as TGF-β expression in the skin, resulting in an attenuation of cutaneous cGVHD. These results suggest that Th1 and Th17 contribute to the development of cGVHD and that targeting Th1 and Th17 may therefore represent a promising therapeutic strategy for preventing and treating cGVHD. PMID:22077062

  20. Th2 cytokine genotypes are associated with a milder form of primary Sjögren's syndrome

    PubMed Central

    Pertovaara, M; Antonen, J; Hurme, M

    2006-01-01

    Background Immunohistological studies on salivary and lacrimal glands have yielded conflicting results on the Th1/Th2 balance in primary Sjögren's syndrome (pSS). Objective To establish whether pSS is a Th1 or Th2 directed autoimmune disease by analysing the polymorphism of the genes encoding for cytokines involved in the regulation of Th1/Th2 differentiation. Methods The polymorphisms of the genes encoding for interleukin 4 (IL4) −590 C/T, interleukin 13 (IL13) +2044 G/A, and interferon γ (IFNG) +874 T/A were analysed in 63 white Finnish patients with pSS (61 female, two male) and in 63 healthy controls. The clinical and immunological data on the pSS patients were analysed in relation to these cytokine gene polymorphisms. Results There were no significant differences in the genotype or allele frequencies of IL4 −590, IL13 +2044, or IFNG +874 between pSS patients and controls. The erythrocyte sedimentation rate and concentrations of serum IgA and serum β2 microglobulin were lower in pSS patients carrying the IL4 −590 T allele or the IL13 +2044 A allele than in those not carrying the respective alleles. The IL4 −509 T allele and IL13 +2044 A allele carriers less often had purpura than the corresponding non‐carriers. Conclusions The frequencies of the cytokine genotypes regulating Th1/Th2 differentiation did not differ between pSS patients and controls. However, the presence of cytokine genotypes with increased susceptibility to atopic and other Th2 diseases was associated with signs of a milder form of pSS. This finding would favour a hypothesis envisaging pSS as primarily a Th1 mediated autoimmune disease. PMID:16166103

  1. 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (EC-18) Modulates Th2 Immunity through Attenuation of IL-4 Expression

    PubMed Central

    Yoon, Sun Young; Kang, Ho Bum; Ko, Young-Eun; Shin, Su-Hyun; Kim, Young-Jun; Sohn, Ki-Young; Han, Yong-Hae; Chong, Saeho

    2015-01-01

    Controlling balance between T-helper type 1 (Th1) and T-helper type 2 (Th2) plays a pivotal role in maintaining the biological rhythm of Th1/Th2 and circumventing diseases caused by Th1/Th2 imbalance. Interleukin 4 (IL-4) is a Th2-type cytokine and often associated with hypersensitivity-related diseases such as atopic dermatitis and allergies when overexpressed. In this study, we have tried to elucidate the function of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (EC-18) as an essential modulator of Th1/Th2 balance. EC-18 has showed an inhibitory effect on the production of IL-4 in a dose-dependent manner. RT-PCR analysis has proved EC-18 affect the transcription of IL-4. By analyzing the phosphorylation status of Signal transducer and activator of transcription 6 (STAT6), which is a transcriptional activator of IL-4 expression, we discovered that EC-18 induced the decrease of STAT6 activity in several stimulated cell lines, which was also showed in STAT6 reporter analysis. Co-treatment of EC-18 significantly weakened atopy-like phenotypes in mice treated with an allergen. Collectively, our results suggest that EC-18 is a potent Th2 modulating factor by regulating the transcription of IL-4 via STAT6 modulation, and could be developed for immune-modulatory therapeutics. PMID:25922599

  2. 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (EC-18) Modulates Th2 Immunity through Attenuation of IL-4 Expression.

    PubMed

    Yoon, Sun Young; Kang, Ho Bum; Ko, Young-Eun; Shin, Su-Hyun; Kim, Young-Jun; Sohn, Ki-Young; Han, Yong-Hae; Chong, Saeho; Kim, Jae Wha

    2015-04-01

    Controlling balance between T-helper type 1 (Th1) and T-helper type 2 (Th2) plays a pivotal role in maintaining the biological rhythm of Th1/Th2 and circumventing diseases caused by Th1/Th2 imbalance. Interleukin 4 (IL-4) is a Th2-type cytokine and often associated with hypersensitivity-related diseases such as atopic dermatitis and allergies when overexpressed. In this study, we have tried to elucidate the function of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (EC-18) as an essential modulator of Th1/Th2 balance. EC-18 has showed an inhibitory effect on the production of IL-4 in a dose-dependent manner. RT-PCR analysis has proved EC-18 affect the transcription of IL-4. By analyzing the phosphorylation status of Signal transducer and activator of transcription 6 (STAT6), which is a transcriptional activator of IL-4 expression, we discovered that EC-18 induced the decrease of STAT6 activity in several stimulated cell lines, which was also showed in STAT6 reporter analysis. Co-treatment of EC-18 significantly weakened atopy-like phenotypes in mice treated with an allergen. Collectively, our results suggest that EC-18 is a potent Th2 modulating factor by regulating the transcription of IL-4 via STAT6 modulation, and could be developed for immune-modulatory therapeutics. PMID:25922599

  3. Cytokine production in peripheral blood cells of patients with differentiated thyroid cancer: elevated Th2/Th9 cytokine production before and reduced Th2 cytokine production after radioactive iodine therapy.

    PubMed

    Simonovic, Snezana Zivancevic; Mihaljevic, Olgica; Majstorovic, Ivana; Djurdjevic, Predrag; Kostic, Irena; Djordjevic, Olivera Milosevic; Teodorovic, Ljiljana Mijatovic

    2015-01-01

    Cytokines play a key role in the regulation of cells of the immune system and also have been implicated in the pathogenesis of malignant diseases. The aim of this study was to evaluate cytokine profiles in patients with differentiated thyroid cancer (DTC) before and 7 days after radioactive iodine (131-I) therapy. Cytokine levels were determined in supernatants obtained from phytohemagglutinin-stimulated whole blood cultures of 13 patients with DTC and 13 control subjects. The concentrations of selected cytokines: Th1-interferon gamma (IFN-γ), interleukin 2 (IL-2) and tumor necrosis factor alpha (TNF-α); Th2-interleukin 4 (IL-4), interleukin 5 (IL-5), interleukin 13 (IL-13) and interleukin 10 (IL-10); Th9-interleukin-9 (IL-9); and Th17-interleukin 17 (IL-17A) were measured using multiplex cytokine detection systems for Human Th1/Th2/Th9/Th17/Th22. We have shown that peripheral blood cells of DTC patients produce significantly higher concentrations of Th2/Th9 cytokines (IL-5, IL-13 and IL-9) than control subjects. The 131-I therapy led to reduced secretion of Th2 cytokines (IL-4, IL-5 and IL-13). Despite this, the calculated cytokine ratios (Th1/Th2) in DTC patients before and 7 days after 131-I therapy were not different from those in healthy subjects. DTC patients have significantly higher concentrations of Th2/Th9 cytokines (IL-5, IL-13 and IL-9) than control subjects. There is no influence of hypothyroidism or stage of disease on cytokine production in DTC patients before 131-I therapy. The radioactive 131-I therapy leads to reduced secretion of Th2 cytokines (IL-4, IL-5 and IL-13). Additional studies are needed to determine the significance of these findings. PMID:25297452

  4. T-cell-intrinsic Tif1α/Trim24 regulates IL-1R expression on TH2 cells and TH2 cell-mediated airway allergy.

    PubMed

    Perez-Lloret, Jimena; Okoye, Isobel S; Guidi, Riccardo; Kannan, Yashaswini; Coomes, Stephanie M; Czieso, Stephanie; Mengus, Gabrielle; Davidson, Irwin; Wilson, Mark S

    2016-02-01

    There is a paucity of new therapeutic targets to control allergic reactions and forestall the rising trend of allergic diseases. Although a variety of immune cells contribute to allergy, cytokine-secreting αβ(+)CD4(+) T-helper 2 (TH2) cells orchestrate the type-2-driven immune response in a large proportion of atopic asthmatics. To identify previously unidentified putative targets in pathogenic TH2 cells, we performed in silico analyses of recently published transcriptional data from a wide variety of pathogenic TH cells [Okoye IS, et al. (2014) Proc Natl Acad Sci USA 111(30):E3081-E3090] and identified that transcription intermediary factor 1 regulator-alpha (Tif1α)/tripartite motif-containing 24 (Trim24) was predicted to be active in house dust mite (HDM)- and helminth-elicited Il4(gfp+)αβ(+)CD4(+) TH2 cells but not in TH1, TH17, or Treg cells. Testing this prediction, we restricted Trim24 deficiency to T cells by using a mixed bone marrow chimera system and found that T-cell-intrinsic Trim24 is essential for HDM-mediated airway allergy and antihelminth immunity. Mechanistically, HDM-elicited Trim24(-/-) T cells have reduced expression of many TH2 cytokines and chemokines and were predicted to have compromised IL-1-regulated signaling. Following this prediction, we found that Trim24(-/-) T cells have reduced IL-1 receptor (IL-1R) expression, are refractory to IL-1β-mediated activation in vitro and in vivo, and fail to respond to IL-1β-exacerbated airway allergy. Collectively, these data identify a previously unappreciated Trim24-dependent requirement for IL-1R expression on TH2 cells and an important nonredundant role for T-cell-intrinsic Trim24 in TH2-mediated allergy and antihelminth immunity. PMID:26787865

  5. Human complement C3 deficiency: Th1 induction requires T cell-derived complement C3a and CD46 activation.

    PubMed

    Ghannam, Arije; Fauquert, Jean-Luc; Thomas, Caroline; Kemper, Claudia; Drouet, Christian

    2014-03-01

    Human T helper type 1 (Th1) responses are essential in defense. Although T cell receptor (TCR) and co-stimulator engagement are indispensable for T cell activation, stimulation of additional receptor pathways are also necessary for effector induction. For example, engagement of the complement regulator CD46 by its ligand C3b generated upon TCR activation is required for IFN-γ production as CD46-deficient patients lack Th1 responses. Utilizing T cells from two C3-deficient patients we demonstrate here that normal Th1 responses also depend on signals mediated by the anaphylatoxin C3a receptor (C3aR). Importantly, and like in CD46-deficient patients, whilst Th1 induction are impaired in C3-deficient patients in vitro, their Th2 responses are unaffected. Furthermore, C3-deficient CD4(+) T cells present with reduced expression of CD25 and CD122, further substantiating the growing notion that complement fragments regulate interleukin-2 receptor (IL-2R) assembly and that disturbance of complement-guided IL-2R assembly contributes to aberrant Th1 effector responses. Lastly, sustained intrinsic production of complement fragments may participate in the Th1 contraction phase as both C3a and CD46 engagement regulate IL-10 co-expression in Th1 cells. These data suggest that C3aR and CD46 activation via intrinsic generation of their respective ligands is an integral part of human Th1 (but not Th2) immunity. PMID:24321396

  6. Increased allergen-specific Th2 responses in vitro in atopic subjects receiving subclinical allergen challenge.

    PubMed

    Gabrielsson, S; Paulie, S; Roquet, A; Ihre, E; Lagging, E; van Hage-Hamsten, M; Härfast, B; Troye-Blomberg, M

    1997-08-01

    The study aimed to determine whether inhalation of subclinical allergen doses-leads to a shift in the balance between T helper (Th) 1 and Th2 cells in asthmatic patients. Elevated IgE requires allergen-specific T cells producing cytokines such as interleukin (IL)-4 or IL-13. Interferon-gamma (IFN-gamma) produced by Th1 cells counteracts the effects of IL-4. In nature, allergic persons are often exposed to low levels of allergen, leading to hyperreactivity, but not to acute allergic reactions. In this study, nine allergic persons inhaled low doses of allergen or placebo in a double-blind manner over seven consecutive weekdays. During the study, the bronchial responsiveness to histamine challenge increased, but no subject exhibited asthmatic symptoms. Blood was drawn on days 0, 1, 4, and 9, and the number of IL-4- and IFN-gamma-producing cells was measured by enzyme-linked immunospot (ELISPOT) assay after in vitro stimulation with a low-dose phytohemagglutinin (PHA) mixed with the relevant allergen or with PHA alone. In three of the four subjects receiving allergen, the IL-4/IFN-gamma ratio increased during the time of the study. No increase was seen in the placebo group. No increase was seen in serum IgE levels in any of the groups. We conclude that a shift in the balance between Th1 and Th2 cells can be detected in subjects exposed to subclinical allergen doses. PMID:9284986

  7. Mouse cytokine profile skewed towards Th2 in pregnancy during infection with Brucella abortus S19 strain.

    PubMed

    Wamonje, Francis O; Waihenya, Rebecca K; Ng'ang'a, Zipporah; Ngeranwa, Joseph N

    2011-04-01

    The two classes of cytokines Th1 and Th2 determine the type of immune response elicited. The Th2 immune response is associated with successful pregnancy. Brucellosis is an intracellular bacterium that elicits the Th1 response and is known to cause spontaneous abortion in mammalian species. This study sought to determine if Brucella infection causes spontaneous abortion by causing the circulating cytokine profile be Th1 dominant during pregnancy. Forty-eight Swiss white mice were used in this murine model and the S19 strain of Brucella abortus was used in as the infective agent. Pregnant mice in the test group were injected intraperitoneally with 10(5-8) CFU of Brucella and cytokine profile evaluated over the three trimesters of pregnancy. Pregnant mice in the control group were left to go through normal pregnancy and their cytokine profile evaluated over the three trimesters of pregnancy. Cytokines in serum samples were analyzed by Cytometric Bead Array. The data was analyzed using the Paired T- test and p < 0.05 was considered significant. IFN-γ and TNF-α represented the Th1 cytokines while IL-4 and IL-5 represented the Th2 cytokines. None of the mice in the test group had spontaneous abortion. IFN-γ and TNF-α had no significant differences between cytokine levels for infected and uninfected groups in all 3 trimesters of pregnancy. IL-4 levels had significant differences in all three trimesters of pregnancy (t = 13, P = 0.036, 0.0071 and 0.0277). IL-5 levels had significant differences second trimester (t = 14, P = 0.0075). The cytokine profile was robustly Th2. In conclusion, Brucella abortus cannot cause spontaneous abortion by altering the mouse cytokine profile towards Th1 in pregnancy. Elevated IL-4 levels with corresponding suppression of IFN-γ can be used as a marker for successful pregnancy in Brucellosis. PMID:25566611

  8. T-bet Activates Th1 Genes through Mediator and the Super Elongation Complex.

    PubMed

    Hertweck, Arnulf; Evans, Catherine M; Eskandarpour, Malihe; Lau, Jonathan C H; Oleinika, Kristine; Jackson, Ian; Kelly, Audrey; Ambrose, John; Adamson, Peter; Cousins, David J; Lavender, Paul; Calder, Virginia L; Lord, Graham M; Jenner, Richard G

    2016-06-21

    The transcription factor T-bet directs Th1 cell differentiation, but the molecular mechanisms that underlie this lineage-specific gene regulation are not completely understood. Here, we show that T-bet acts through enhancers to allow the recruitment of Mediator and P-TEFb in the form of the super elongation complex (SEC). Th1 genes are occupied by H3K4me3 and RNA polymerase II in Th2 cells, while T-bet-mediated recruitment of P-TEFb in Th1 cells activates transcriptional elongation. P-TEFb is recruited to both genes and enhancers, where it activates enhancer RNA transcription. P-TEFb inhibition and Mediator and SEC knockdown selectively block activation of T-bet target genes, and P-TEFb inhibition abrogates Th1-associated experimental autoimmune uveitis. T-bet activity is independent of changes in NF-κB RelA and Brd4 binding, with T-bet- and NF-κB-mediated pathways instead converging to allow P-TEFb recruitment. These data provide insight into the mechanism through which lineage-specifying factors promote differentiation of alternative T cell fates. PMID:27292648

  9. Polyclonal Th1 cells transfer oil-induced arthritis.

    PubMed Central

    Svelander, L; Müssener, A; Erlandsson-Harris, H; Kleinau, S

    1997-01-01

    T-cells play a critical role in oil-induced arthritis (OIA) in DA rats. The present study focuses on the involvement of CD4/CD8 T cells in OIA by using adoptive transfer. Mitogen-activated T cells from DA rats previously injected with incomplete Freund's adjuvant (IFA) were depleted of CD4+ T cells or CD8+ T cells before transfer to irradiated naive receipients. The results indicate that CD4+ T cells are essential for the induction of passively induced OIA. However, in vitro blocking experiments with monoclonal antibodies (mAb) to the CD4 molecule of the T cells before transfer did not affect the passive OIA. Neither was passive OIA inhibited by treating the CD4+ T cells with mAb to intracellular adhesion molecule-1 (ICAM-1) in order to block cell-cell interactions or migration. The arthritogenic CD4+ T cells were sensitive, however, to in vitro treatment with mAb to the interleukin-2 receptor, which inhibited the disease or delayed the onset of passive OIA in recipients. The arthritogenic CD4+ T cells were also analysed for expression of specific T-cell receptor (TCR) variable (V) beta chains, critical for recognition of autoantigen, by utilizing V beta gene-specific polymerase chain reaction (PCR). The results show a heterogeneous expression of V beta segments of the TCR, indicating a polyclonal origin of the pathogenic cells. Moreover, an investigation of the T helper (Th)1/Th2 status of the CD4+ T cells, defined by cytokine expression, was made at the mRNA level by using in situ hybridization. High numbers of interleukin-2 (IL-2) mRNA expressing cells and also interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha)-expressing cells could be identified. We conclude from this study that non-immunogenic IFA triggers polyclonal, IL-2-dependent Th1 cells which induce arthritis. The contribution of the CD4 or ICAM-1 molecules for arthritis induction seem to be of minor importance. PMID:9227326

  10. The CXCL12/CXCR4 axis is involved in the maintenance of Th2 bias at the maternal/fetal interface in early human pregnancy

    PubMed Central

    Piao, Hai-Lan; Tao, Yu; Zhu, Rui; Wang, Song-Cun; Tang, Chuan-Ling; Fu, Qiang; Du, Mei-Rong; Li, Da-Jin

    2012-01-01

    The regulatory mechanism of Th2 bias at the maternal/fetal interface remains unclear. In this study, we characterized cytokine production in decidual stromal cells (DSCs), decidual immune cells (DICs) and embryo-derived trophoblast cells, and investigated the regulation of CXCL12/CXCR4 interaction on Th2 bias at the maternal/fetal interface in early human pregnancy. We found differential production of Th1-type and Th2-type cytokines by trophoblasts, DSCs and DICs. The secretion of these cytokines varied in different cell cocultures, conduced to Th2 bias. Flow cytometry showed that coculture of trophoblasts with DSCs and DICs significantly increased IL-4 and IL-10 production in trophoblasts, and IL-10 production in DSCs. However, the coculture of trophoblasts with DSCs and DICs significantly increased interferon (IFN)-γ expression in DSCs, and tumor-necrosis factor (TNF)-α expression in DICs. No change was seen in Th1-type cytokine production in trophoblasts, and in Th2-type cytokine production in DICs in all cocultures. Furthermore, pre-treatment with anti-CXCR4 neutralizing antibody upregulated the production of the Th1-type cytokines IFN-γ and TNF-α, and downregulated the production of the Th2-type cytokines IL-4 and IL-10, in trophoblasts, DSCs, DICs or their cocultures. Interestingly, rhCXCL12 inhibited production of the Th1-type cytokine TNF-α and enhanced the expression of the Th2-type cytokines such as IL-4 and IL-10 in DICs; this effect was abrogated by anti-CXCR4 antibody. Our present study has elucidated the individual contributions of component cells to the shaping of Th2 bias, and uncovered a complicated cross-talk via the CXCL12/CXCR4 signal at the maternal/fetal interface in early human pregnancy. PMID:22885527

  11. Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control TH2 responses

    PubMed Central

    Zheng, Ye; Chaudhry, Ashutosh; Kas, Arnold; deRoos, Paul; Kim, Jeong M.; Chu, Tin-Tin; Corcoran, Lynn; Treuting, Piper; Klein, Ulf; Rudensky, Alexander Y.

    2010-01-01

    In the course of infection or autoimmunity, particular transcription factors orchestrate the differentiation of TH1, TH2 or TH17 effector cells, the responses of which are limited by a distinct lineage of suppressive regulatory T cells (Treg). Treg cell differentiation and function are guided by the transcription factor Foxp3, and their deficiency due to mutations in Foxp3 results in aggressive fatal autoimmune disease associated with sharply augmented TH1 and TH2 cytokine production1–3. Recent studies suggested that Foxp3 regulates the bulk of the Foxp3-dependent transcriptional program indirectly through a set of transcriptional regulators serving as direct Foxp3 targets4,5. Here we show that in mouse Treg cells, high amounts of interferon regulatory factor-4 (IRF4), a transcription factor essential for TH2 effector cell differentiation, is dependent on Foxp3 expression. We proposed that IRF4 expression endows Treg cells with the ability to suppress TH2 responses. Indeed, ablation of a conditional Irf4 allele in Treg cells resulted in selective dysregulation of TH2 responses, IL4-dependent immunoglobulin isotype production, and tissue lesions with pronounced plasma cell infiltration, in contrast to the mononuclear-cell-dominated pathology typical of mice lacking Treg cells. Our results indicate that Treg cells use components of the transcriptional machinery, promoting a particular type of effector CD4+ T cell differentiation, to efficiently restrain the corresponding type of the immune response. PMID:19182775

  12. Impaired dendritic cell maturation and increased T(H)2 responses in PIR-B(-/-) mice.

    PubMed

    Ujike, Azusa; Takeda, Kazuhiko; Nakamura, Akira; Ebihara, Shin; Akiyama, Kenichi; Takai, Toshiyuki

    2002-06-01

    Mice deficient for paired immunoglobulin (Ig)-like receptor B (PIR-B) show defective regulation of receptor-mediated activation in antigen-presenting cells. Older PIR-B(-/-) mice had an increased number of peritoneal B1 cells. Splenic PIR-B(-/-) B2 cells were constitutively activated and proliferated much more than those from wild-type mice upon B cell receptor ligation. T helper type 2 (T(H)2)-prone humoral responses were augmented in PIR-B(-/-) mice upon immunization with T-dependent antigens, including increased interleukin 4 and decreased interferon-gamma responses, as well as enhanced IgG1 and IgE production. Impaired maturation of dendritic cells (DCs), possibly due to perturbed intracellular signaling, was responsible for the skewed responses. Thus, PIR-B is critical for B cell suppression, DC maturation and for balancing T(H)1 and T(H)2 immune responses. PMID:12021780

  13. Proprotein convertase FURIN constrains Th2 differentiation and is critical for host resistance against Toxoplasma gondii.

    PubMed

    Oksanen, Anna; Aittomäki, Saara; Jankovic, Dragana; Ortutay, Zsuzsanna; Pulkkinen, Kati; Hämäläinen, Sanna; Rokka, Anne; Corthals, Garry L; Watford, Wendy T; Junttila, Ilkka; O'Shea, John J; Pesu, Marko

    2014-12-01

    The proprotein convertase subtilisin/kexin enzymes proteolytically convert immature proproteins into bioactive molecules, and thereby they serve as key regulators of cellular homeostasis. The archetype proprotein convertase subtilisin/kexin, FURIN, is a direct target gene of the IL-12/STAT4 pathway and it is upregulated in Th1 cells. We have previously demonstrated that FURIN expression in T cells critically regulates the maintenance of peripheral immune tolerance and the functional maturation of pro-TGF-β1 in vivo, but FURIN's role in cell-mediated immunity and Th polarization has remained elusive. In this article, we show that T cell-expressed FURIN is essential for host resistance against a prototypic Th1 pathogen, Toxoplasma gondii, and for the generation of pathogen-specific Th1 lymphocytes, including Th1-IL-10 cells. FURIN-deficient Th cells instead show elevated expression of IL-4R subunit α on cell surface, sensitized IL-4/STAT6 signaling, and a propensity to polarize toward the Th2 phenotype. By exploring FURIN-interacting proteins in Jurkat T cells with Strep-Tag purification and mass spectrometry, we further identify an association with a cytoskeleton modifying Ras-related C3 botulinum toxin substrate/dedicator of cytokinesis 2 protein complex and unravel that FURIN promotes F-actin polymerization, which has previously been shown to downregulate IL-4R subunit α cell surface expression and promote Th1 responses. In conclusion, our results demonstrate that in addition to peripheral immune tolerance, T cell-expressed FURIN is also a central regulator of cell-mediated immunity and Th1/2 cell balance. PMID:25355923

  14. The infiltration, and prognostic importance, of Th1 lymphocytes vary in molecular subgroups of colorectal cancer.

    PubMed

    Ling, Agnes; Lundberg, Ida V; Eklöf, Vincy; Wikberg, Maria L; Öberg, Åke; Edin, Sofia; Palmqvist, Richard

    2016-01-01

    Giving strong prognostic information, T-cell infiltration is on the verge of becoming an additional component in the routine clinical setting for classification of colorectal cancer (CRC). With a view to further improving the tools for prognostic evaluation, we have studied how Th1 lymphocyte infiltration correlates with prognosis not only by quantity, but also by subsite, within CRCs with different molecular characteristics (microsatellite instability, CpG island methylator phenotype status, and BRAF and KRAS mutational status). We evaluated the Th1 marker T-bet by immunohistochemistry in 418 archival tumour tissue samples from patients who underwent surgical resection for CRC. We found that a high number of infiltrating Th1 lymphocytes is strongly associated with an improved prognosis in patients with CRC, irrespective of intratumoural subsite, and that both extent of infiltration and patient outcome differ according to molecular subgroup. In brief, microsatellite instability, CpG island methylator phenotype-high and BRAF mutated tumours showed increased infiltration of Th1 lymphocytes, and the most pronounced prognostic effect of Th1 infiltration was found in these tumours. Interestingly, BRAF mutated tumours were found to be more highly infiltrated by Th1 lymphocytes than BRAF wild-type tumours whereas the opposite was seen for KRAS mutated tumours. These differences could be explained at least partly by our finding that BRAF mutated, in contrast to KRAS mutated, CRC cell lines and tumour specimens expressed higher levels of the Th1-attracting chemokine CXCL10, and reduced levels of CCL22 and TGFB1, stimulating Th2/Treg recruitment and polarisation. In conclusion, the strong prognostic importance of Th1 lymphocyte infiltration in CRC was found at all subsites evaluated, and it remained significant in multivariable analyses, indicating that T-bet may be a valuable marker in the clinical setting. Our results also indicate that T-bet is of value when analysed in

  15. Non-MHC-linked Th2 cell development induced by soluble protein administration predicts susceptibility to Leishmania major infection.

    PubMed

    Guéry, J C; Galbiati, F; Smiroldo, S; Adorini, L

    1997-09-01

    Continuous administration of soluble protein Ag followed by immunization with the same Ag in adjuvant results in the selective development of Ag-specific CD4+ Th2 cells in both normal and beta2-microglobulin-deficient BALB/c mice. In addition to chronic administration by mini-osmotic pump, single bolus i.p., but not i.v., injection of protein Ag induces Th2 cell expansion. Strong Th2 cell priming depends on a non-MHC-linked genetic polymorphism. It is observed in all congenic strains on BALB background tested, BALB/c, BALB/b, and BALB/k, but not in MHC-matched strains on disparate genetic background, B10.D2, C57BL/6, and C3H. DBA/2 mice appear to have an intermediate phenotype, as shown by their weaker capacity to mount Th2 responses as compared with BALB/c mice after soluble Ag administered by either mini-osmotic pumps or single bolus i.p. Conversely, induction of Th1 cell unresponsiveness by soluble protein is observed in any mouse strain tested, following any mode of Ag administration. These data demonstrate that non-MHC-linked genetic polymorphism controls the priming of Th2 but not the inhibition of Th1 cells induced by administration of soluble protein. The pattern of Th2 responses in these different strains is predictive of disease outcome following Leishmania major infection and supports the hypothesis that systemic Ag presentation in the absence of strong inflammatory signals may represent an important stimulus leading to selective Th2 cell development in susceptible mouse strains. PMID:9278301

  16. Lipopeptides of Borrelia burgdorferi outer surface proteins induce Th1 phenotype development in alphabeta T-cell receptor transgenic mice.

    PubMed Central

    Infante-Duarte, C; Kamradt, T

    1997-01-01

    Induction of the appropriate T helper cell (Th) subset is crucial for the resolution of infectious diseases and the prevention of immunopathology. Some pathogens preferentially induce Th1 or Th2 responses. How microorganisms influence Th phenotype development is unknown. We asked if Borrelia burgdorferi, the spirochete which causes Lyme arthritis, can promote a cytokine milieu in which T cells which are not specific for B. burgdorferi are induced to produce proinflammatory cytokines. Using alphabeta T-cell receptor transgenic mice as a source of T cells with a defined specificity other than for B. burgdorferi, we found that B. burgdorferi induced Th1 phenotype development in ovalbumin-specific transgenic T cells. Small synthetic lipopeptides corresponding to the N-terminal sequences of B. burgdorferi outer surface lipoproteins had similar effects. B. burgdorferi and its lipopeptides induced host cells to produce interleukin-12. When the peptides were used in delipidated form, they did not induce Th1 development. These findings may be of pathogenic importance, since it is currently assumed that a Th2-mediated antibody response is protective against B. burgdorferi. Bacteria associated with reactive arthritis, namely, Yersinia enterocolitica, Shigella flexneri, and Salmonella enteritidis, had different effects. The molecular definition of pathogen-host interactions determining cytokine production should facilitate rational therapeutic interventions directing the host response towards the desired cytokine response. Here, we describe small synthetic molecules capable of inducing Th1 phenotype development. PMID:9317013

  17. Pleural cavity type 2 innate lymphoid cells precede Th2 expansion in murine Litomosoides sigmodontis infection.

    PubMed

    Boyd, Alexis; Killoran, Kristin; Mitre, Edward; Nutman, Thomas B

    2015-12-01

    Recently, a family of innate cells has been identified that respond to IL-25 and IL-33 in murine intestinal helminths. Termed Type 2 innate lymphoid cells (ILC2s) they facilitate the development of Th2 responses responsible for helminth clearance. We evaluated these cells in a tissue-invasive helminth model. Using Litomosides sigmodontis (a strong Th2 polarizing filarial infection) we observed a robust Th2 response in the pleural cavity, where adult worms reside, marked by increased levels of IL-5 and IL-13 in infected mice. In parallel, ILC2s were expanded in the pleural cavity early in the infection, peaking during the pre-patent period. L. sigmodontis also elicits a strong systemic Th2 response, which includes significantly increased levels of IgG1, IgE and IL-5 in the plasma of infected mice. Although ILC2s were expanded locally, they were not expanded in the spleen, blood, or mediastinal lymph nodes in response to L. sigmodontis infection, suggesting that ILC2s function primarily at the site of infection. The increase in ILC2s in the pleural cavity and the expansion in Th2 responses indicates a probable role for these cells in initiating and maintaining the Th2 response and highlights the importance of these cells in helminth infections and their role in Th2 immunity. PMID:26394284

  18. Immunostimulatory oligonucleotides block allergic airway inflammation by inhibiting Th2 cell activation and IgE-mediated cytokine induction

    PubMed Central

    Hessel, Edith M.; Chu, Mabel; Lizcano, Jennifer O.; Chang, Bonnie; Herman, Nancy; Kell, Sariah A.; Wills-Karp, Marsha; Coffman, Robert L.

    2005-01-01

    A single treatment with a CpG-containing immunostimulatory DNA sequence (ISS) given before allergen challenge can inhibit T helper type 2 cell (Th2)–mediated airway responses in animal models of allergic asthma; however, the mechanism of this inhibition remains largely undefined. Here, we demonstrate that airway delivery of ISS before allergen challenge in Th2-primed mice acts in two distinct ways to prevent the allergic responses to this challenge. The first is to prevent induction of cytokines from allergen-specific Th2 cells, as demonstrated by the nearly complete inhibition of Th2 cytokine production, Th2-dependent functional responses, and gene induction patterns. ISS inhibits the Th2 response by rendering lung antigen-presenting cells (APCs) unable to effectively present antigen to Th2 cells, but not to Th1 cells. This loss of APC function correlates with a reduced expression of costimulatory molecules, including programmed cell death ligand (PD-L)1, PD-L2, CD40, CD80, CD86, and inducible T cell costimulator, and of major histocompatibility complex class II on CD11c+APCs from the airways of ISS-treated mice. The second important action of ISS is inhibition of immunoglobulin E–dependent release of Th2 cytokines, especially interleukin 4, from basophils and/or mast cells in the airways of Th2-primed mice. Thus, inhibition by ISS of allergic responses can be explained by two novel mechanisms that culminate in the inhibition of the principal sources of type 2 cytokines in the airways. PMID:16314434

  19. Functional and Pathogenic Differences of Th1 and Th17 Cells in Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Domingues, Helena S.; Mues, Marsilius; Lassmann, Hans; Wekerle, Hartmut; Krishnamoorthy, Gurumoorthy

    2010-01-01

    Background There is consensus that experimental autoimmune encephalomyelitis (EAE) can be mediated by myelin specific T cells of Th1 as well as of Th17 phenotype, but the contribution of either subset to the pathogenic process has remained controversial. In this report, we compare functional differences and pathogenic potential of “monoclonal” T cell lines that recognize myelin oligodendrocyte glycoprotein (MOG) with the same transgenic TCR but are distinguished by an IFN-γ producing Th1-like and IL-17 producing Th17-like cytokine signature. Methods and Findings CD4+ T cell lines were derived from the transgenic mouse strain 2D2, which expresses a TCR recognizing MOG peptide 35–55 in the context of I-Ab. Adoptive transfer of Th1 cells into lymphopenic (Rag2−/−) recipients, predominantly induced “classic” paralytic EAE, whereas Th17 cells mediated “atypical” ataxic EAE in approximately 50% of the recipient animals. Combination of Th1 and Th17 cells potentiated the encephalitogenicity inducing classical EAE exclusively. Th1 and Th17 mediated EAE lesions differed in their composition but not in their localization within the CNS. While Th1 lesions contained IFN-γ, but no IL-17 producing T cells, the T cells in Th17 lesions showed plasticity, substantially converting to IFN-γ producing Th1-like cells. Th1 and Th17 cells differed drastically by their lytic potential. Th1 but not Th17 cells lysed autoantigen presenting astrocytes and fibroblasts in vitro in a contact-dependent manner. In contrast, Th17 cells acquired cytotoxic potential only after antigenic stimulation and conversion to IFN-γ producing Th1 phenotype. Conclusions Our data demonstrate that both Th1 and Th17 lineages possess the ability to induce CNS autoimmunity but can function with complementary as well as differential pathogenic mechanisms. We propose that Th17-like cells producing IL-17 are required for the generation of atypical EAE whereas IFN-γ producing Th1 cells induce

  20. Preventative effect of an herbal preparation (HemoHIM) on development of airway inflammation in mice via modulation of Th1/2 cells differentiation.

    PubMed

    Kim, Jong-Jin; Cho, Hyun Wook; Park, Hae-Ran; Jung, Uhee; Jo, Sung-Kee; Yee, Sung-Tae

    2013-01-01

    HemoHIM, an herbal preparation of three edible herbs (Angelica gigas Nakai, Cnidium officinale Makino, Paeonia japonica Miyabe) is known to increase the Th1 immune response as well as reduce the allergic response in human mast cells. Here, our goal was to determine whether or not HemoHIM could induce Th1 cell differentiation as well as inhibit the development of airway inflammation. To study Th1/Th2 cell differentiation, naive CD4(+) T cells isolated from C57BL/6 mouse spleens were cultured with or without HemoHIM. To examine airway inflammation, C57BL/6 mice were fed HemoHIM for 4 weeks before sensitization and provocation with ovalbumin (OVA). In an in vitro experiment, naive CD4(+) T cells displayed increased Th1 (IFN-γ(+) cell) as well as decreased Th2 (IL-4(+) cell) differentiation in a HemoHIM concentration-dependent manner. Furthermore, in an airway inflammation mice model, eosinophil numbers in BALF, serum levels of OVA-specific IgE and IgG1, and cytokine (IL-4, IL-5, and IL-13) levels in BALF and the supernatant of splenocytes all decreased upon HemoHIM (100 mg/kg body weight) pretreatment (4 weeks). These results show that HemoHIM attenuated allergic airway inflammation in the mouse model through regulation of the Th1/Th2 balance. PMID:23844220

  1. Preventative Effect of an Herbal Preparation (HemoHIM) on Development of Airway Inflammation in Mice via Modulation of Th1/2 Cells Differentiation

    PubMed Central

    Kim, Jong-Jin; Cho, Hyun Wook; Park, Hae-Ran; Jung, Uhee; Jo, Sung-Kee; Yee, Sung-Tae

    2013-01-01

    HemoHIM, an herbal preparation of three edible herbs (Angelica gigas Nakai, Cnidium officinale Makino, Paeonia japonica Miyabe) is known to increase the Th1 immune response as well as reduce the allergic response in human mast cells. Here, our goal was to determine whether or not HemoHIM could induce Th1 cell differentiation as well as inhibit the development of airway inflammation. To study Th1/Th2 cell differentiation, naive CD4+ T cells isolated from C57BL/6 mouse spleens were cultured with or without HemoHIM. To examine airway inflammation, C57BL/6 mice were fed HemoHIM for 4 weeks before sensitization and provocation with ovalbumin (OVA). In an in vitro experiment, naive CD4+ T cells displayed increased Th1 (IFN-γ+ cell) as well as decreased Th2 (IL-4+ cell) differentiation in a HemoHIM concentration-dependent manner. Furthermore, in an airway inflammation mice model, eosinophil numbers in BALF, serum levels of OVA-specific IgE and IgG1, and cytokine (IL-4, IL-5, and IL-13) levels in BALF and the supernatant of splenocytes all decreased upon HemoHIM (100 mg/kg body weight) pretreatment (4 weeks). These results show that HemoHIM attenuated allergic airway inflammation in the mouse model through regulation of the Th1/Th2 balance. PMID:23844220

  2. Immunological consequences of stress-related proteins--cytosolic tryparedoxin peroxidase and chaperonin TCP20--identified in splenic amastigotes of Leishmania donovani as Th1 stimulatory, in experimental visceral leishmaniasis.

    PubMed

    Jaiswal, Anil Kumar; Khare, Prashant; Joshi, Sumit; Rawat, Keerti; Yadav, Narendra; Sundar, Shyam; Dube, Anuradha

    2015-04-01

    In earlier studies, proteomic characterization of splenic amastigote fractions from clinical isolates of Leishmania donovani, exhibiting significant cellular responses in cured Leishmania subjects, led to the identification of cytosolic tryparedoxin peroxidase (LdcTryP) and chaperonin-TCP20 (LdTCP20) as Th1-stimulatory proteins. Both the proteins, particularly LdTCP20 for the first time, were successfully cloned, overexpressed, purified and were found to be localized in the cytosol of purified splenic amastigotes. When evaluated against lymphocytes of cured Leishmania-infected hamsters, the purified recombinant proteins (rLdcTryP and rLdTCP20) induced their proliferations as well as nitric oxide production. Similarly, these proteins also generated Th1-type cytokines (IFN-γ/IL-12) from stimulated PBMCs of cured/endemic Leishmania patients. Further, vaccination with rLdcTryP elicited noticeable delayed-type hypersensitivity response and offered considerably good prophylactic efficacy (~78% inhibition) against L. donovani challenge in hamsters, which was well supported by the increased mRNA expression of Th1 and Th2 cytokines. However, animals vaccinated with rLdTCP20 exhibited comparatively lesser prophylactic efficacy (~55%) with inferior immunological response. The results indicate the potentiality of rLdcTryP protein, between the two, as a suitable anti-leishmanial vaccine. Since, rLdTCP20 is also an important target, for optimization, further attempts towards determination of immunodominant regions for designing fusion peptides may be taken up. PMID:25498563

  3. Specific Dietary Oligosaccharides Increase Th1 Responses in a Mouse Respiratory Syncytial Virus Infection Model

    PubMed Central

    Schijf, Marcel A.; Kruijsen, Debby; Bastiaans, Jacqueline; Coenjaerts, Frank E. J.; Garssen, Johan; van Bleek, Grada M.

    2012-01-01

    Breast feeding reduces the risk of developing severe respiratory syncytial virus (RSV) infections in infants. In addition to maternal antibodies, other immune-modulating factors in human milk contribute to this protection. Specific dietary prebiotic oligosaccharides, similar to oligosaccharides present in human milk, were evaluated in a C57BL/6 mouse RSV infection model. During primary RSV infection, increased numbers of RSV-specific CD4+ T cells producing gamma interferon (IFN-γ) were found in the lungs at days 8 to 10 postinfection in mice receiving diet containing short-chain galactooligosacharides, long-chain fructooligosaccharides, and pectin-derived acidic oligosaccharides (termed scGOS/lcFOS/pAOS). In a Th2-skewed formalin-inactivated (FI)-RSV vaccination model, the prebiotic diet reduced RSV-specific Th2 cytokine (interleukin-4 [IL-4], IL-5, and IL-13)-producing CD4+ T cells in the lung and the magnitude of airway eosinophilia at day 4 and 6 after infection. This was accompanied by a decreased influx of inflammatory dendritic cells (CD11b+/CD11c+) and increased numbers of IFN-γ-producing CD4+ and CD8+ T cells at day 8 after viral challenge. These findings suggest that specific dietary oligosaccharides can influence trafficking and/or effector functions of innate immune, CD4+, and CD8+ T cell subsets in the lungs of RSV-infected mice. In our models, scGOS/lcFOS/pAOS had no effect on weight but increased viral clearance in FI-RSV-vaccinated mice 8 days after infection. The increased systemic Th1 responses potentiated by scGOS/lcFOS/pAOS might contribute to an accelerated Th1/Th2 shift of the neonatal immune system, which might favor protective immunity against viral infections with a high attack rate in early infancy, such as RSV. PMID:22896622

  4. Specific dietary oligosaccharides increase Th1 responses in a mouse respiratory syncytial virus infection model.

    PubMed

    Schijf, Marcel A; Kruijsen, Debby; Bastiaans, Jacqueline; Coenjaerts, Frank E J; Garssen, Johan; van Bleek, Grada M; van't Land, Belinda

    2012-11-01

    Breast feeding reduces the risk of developing severe respiratory syncytial virus (RSV) infections in infants. In addition to maternal antibodies, other immune-modulating factors in human milk contribute to this protection. Specific dietary prebiotic oligosaccharides, similar to oligosaccharides present in human milk, were evaluated in a C57BL/6 mouse RSV infection model. During primary RSV infection, increased numbers of RSV-specific CD4(+) T cells producing gamma interferon (IFN-γ) were found in the lungs at days 8 to 10 postinfection in mice receiving diet containing short-chain galactooligosacharides, long-chain fructooligosaccharides, and pectin-derived acidic oligosaccharides (termed scGOS/lcFOS/pAOS). In a Th2-skewed formalin-inactivated (FI)-RSV vaccination model, the prebiotic diet reduced RSV-specific Th2 cytokine (interleukin-4 [IL-4], IL-5, and IL-13)-producing CD4(+) T cells in the lung and the magnitude of airway eosinophilia at day 4 and 6 after infection. This was accompanied by a decreased influx of inflammatory dendritic cells (CD11b(+)/CD11c(+)) and increased numbers of IFN-γ-producing CD4(+) and CD8(+) T cells at day 8 after viral challenge. These findings suggest that specific dietary oligosaccharides can influence trafficking and/or effector functions of innate immune, CD4(+), and CD8(+) T cell subsets in the lungs of RSV-infected mice. In our models, scGOS/lcFOS/pAOS had no effect on weight but increased viral clearance in FI-RSV-vaccinated mice 8 days after infection. The increased systemic Th1 responses potentiated by scGOS/lcFOS/pAOS might contribute to an accelerated Th1/Th2 shift of the neonatal immune system, which might favor protective immunity against viral infections with a high attack rate in early infancy, such as RSV. PMID:22896622

  5. Th1-orientated immunological properties of the bacterial extract OM-85-BV.

    PubMed

    Huber, M; Mossmann, H; Bessler, W G

    2005-05-20

    The bacterial extract OM-85-BV prepared from 21 pathogenic bacterial strains is administered orally to adults and children for the treatment and prevention of recurrent infections of the respiratory tract. We analyzed in vitro and in vivo the immunomodulatory effects of the extract. The lysate acted as a non specific macrophage activator, inducing NO production as well as the translocation of transcription factor NF-kappaB into the nucleus in murine bone marrow-derived macrophages. Besides stimulating unspecifically the immune system, a bacteria-specific humoral immune response was revealed. After oral application, a trend to increase bacteria-specific IgG and IgA in serum was observed. Also a marked increase of bacteria specific IgA in saliva as well as in supernatants of Peyer's patches and mesenteric lymph nodes-derived cell cultures was found. The immunomodulatory properties of the extract were also investigated with respect to shifting the Th1/Th2 bias in an in vivo allergy model. BALB/c mice were orally immunized with OM-85-BV and subsequently sensitized intraperitoneally with the allergen ovalbumin. The group pretreated with OM-85-BV showed a decrease of both total and ovalbumin specific IgE. Accordingly, in spleen cell supernatants the Th1-associated cytokine IFN-gamma was increased, and the Th2-associated cytokine IL-4 was downregulated. Our findings suggest that the immunoprotective effects of OM-85-BV observed in human beings may be correlated to its Th1 augmenting properties. PMID:15946922

  6. Forced Exercise Preconditioning Attenuates Experimental Autoimmune Neuritis by Altering Th1 Lymphocyte Composition and Egress.

    PubMed

    Calik, Michael W; Shankarappa, Sahadev A; Langert, Kelly A; Stubbs, Evan B

    2015-01-01

    A short-term exposure to moderately intense physical exercise affords a novel measure of protection against autoimmune-mediated peripheral nerve injury. Here, we investigated the mechanism by which forced exercise attenuates the development and progression of experimental autoimmune neuritis (EAN), an established animal model of Guillain-Barré syndrome. Adult male Lewis rats remained sedentary (control) or were preconditioned with forced exercise (1.2 km/day × 3 weeks) prior to P2-antigen induction of EAN. Sedentary rats developed a monophasic course of EAN beginning on postimmunization day 12.3 ± 0.2 and reaching peak severity on day 17.0 ± 0.3 (N = 12). By comparison, forced-exercise preconditioned rats exhibited a similar monophasic course but with significant (p < .05) reduction of disease severity. Analysis of popliteal lymph nodes revealed a protective effect of exercise preconditioning on leukocyte composition and egress. Compared with sedentary controls, forced exercise preconditioning promoted a sustained twofold retention of P2-antigen responsive leukocytes. The percentage distribution of pro-inflammatory (Th1) lymphocytes retained in the nodes from sedentary EAN rats (5.1 ± 0.9%) was significantly greater than that present in nodes from forced-exercise preconditioned EAN rats (2.9 ± 0.6%) or from adjuvant controls (2.0 ± 0.3%). In contrast, the percentage of anti-inflammatory (Th2) lymphocytes (7-10%) and that of cytotoxic T lymphocytes (∼20%) remained unaltered by forced exercise preconditioning. These data do not support an exercise-inducible shift in Th1:Th2 cell bias. Rather, preconditioning with forced exercise elicits a sustained attenuation of EAN severity, in part, by altering the composition and egress of autoreactive proinflammatory (Th1) lymphocytes from draining lymph nodes. PMID:26186926

  7. Dendritic Cell-Induced Th1 and Th17 Cell Differentiation for Cancer Therapy.

    PubMed

    Terhune, Julia; Berk, Erik; Czerniecki, Brian J

    2013-01-01

    The success of cellular immunotherapies against cancer requires the generation of activated CD4⁺ and CD8⁺ T-cells. The type of T-cell response generated (e.g., Th1 or Th2) will determine the efficacy of the therapy, and it is generally assumed that a type-1 response is needed for optimal cancer treatment. IL-17 producing T-cells (Th17/Tc17) play an important role in autoimmune diseases, but their function in cancer is more controversial. While some studies have shown a pro-cancerous role for IL-17, other studies have shown an anti-tumor function. The induction of polarized T-cell responses can be regulated by dendritic cells (DCs). DCs are key regulators of the immune system with the ability to affect both innate and adaptive immune responses. These properties have led many researchers to study the use of ex vivo manipulated DCs for the treatment of various diseases, such as cancer and autoimmune diseases. While Th1/Tc1 cells are traditionally used for their potent anti-tumor responses, mounting evidence suggests Th17/Tc17 cells should be utilized by themselves or for the induction of optimal Th1 responses. It is therefore important to understand the factors involved in the induction of both type-1 and type-17 T-cell responses by DCs. PMID:26344346

  8. Modulation of Dendritic Cell Activation and Subsequent Th1 Cell Polarization by Lidocaine.

    PubMed

    Jeon, Young-Tae; Na, Hyeongjin; Ryu, Heeju; Chung, Yeonseok

    2015-01-01

    Dendritic cells play an essential role in bridging innate and adaptive immunity by recognizing cellular stress including pathogen- and damage-associated molecular patterns and by shaping the types of antigen-specific T cell immunity. Although lidocaine is widely used in clinical settings that trigger cellular stress, it remains unclear whether such treatment impacts the activation of innate immune cells and subsequent differentiation of T cells. Here we showed that lidocaine inhibited the production of IL-6, TNFα and IL-12 from dendritic cells in response to toll-like receptor ligands including lipopolysaccharide, poly(I:C) and R837 in a dose-dependent manner. Notably, the differentiation of Th1 cells was significantly suppressed by the addition of lidocaine while the same treatment had little effect on the differentiation of Th17, Th2 and regulatory T cells in vitro. Moreover, lidocaine suppressed the ovalbumin-specific Th1 cell responses in vivo induced by the adoptive transfer of ovalbumin-pulsed dendritic cells. These results demonstrate that lidocaine inhibits the activation of dendritic cells in response to toll-like receptor signals and subsequently suppresses the differentiation of Th1 cell responses. PMID:26445366

  9. Proprotein convertase FURIN constrains Th2 differentiation and is critical for host resistance against Toxoplasma gondii

    PubMed Central

    Oksanen, Anna; Aittomäki, Saara; Jankovic, Dragana; Ortutay, Zsuzsanna; Pulkkinen, Kati; Hämäläinen, Sanna; Rokka, Anne; Corthals, Garry L.; Watford, Wendy T.; Junttila, Ilkka; O’Shea, John J.; Pesu, Marko

    2014-01-01

    The proprotein convertase subtilisin/kexin (PCSK) enzymes proteolytically convert immature proproteins into bioactive molecules and thereby they serve as key regulators of cellular homeostasis. The archetype PCSK, FURIN is a direct target gene of the IL-12/STAT4 pathway and it is upregulated in T helper 1 type cells. We have previously demonstrated that FURIN expression in T cells critically regulates the maintenance of peripheral immune tolerance and the functional maturation of pro-TGFβ-1 in vivo, but FURIN’s role in cell-mediated immunity and Th polarization has remained elusive. Here, we show that T-cell-expressed FURIN is essential for host resistance against a prototypic Th1 pathogen, Toxoplasma gondii and for the generation of pathogen-specific Th1 lymphocytes, including Th1-IL-10 cells. FURIN-deficient Th cells instead show elevated expression of IL-4 receptor subunit alpha (IL-4Rα) on cell surface, sensitized IL-4/STAT6 signaling and a propensity to polarize towards the Th2 phenotype. By exploring FURIN-interacting proteins in Jurkat T cells with Strep-Tag purification and mass-spectrometry we further identify an association with a cytoskeleton modifying RAC/DOCK2 protein complex and unravel that FURIN promotes F-actin polymerization, which has previously been shown to down-regulate IL-4Rα cell surface expression and promote Th1 responses. In conclusion, our results demonstrate that in addition to peripheral immune tolerance, T-cell-expressed FURIN is also a central regulator of cell-mediated immunity and Th1/2 cell balance. PMID:25355923

  10. Dopamine Receptor D3 Signaling on CD4+ T Cells Favors Th1- and Th17-Mediated Immunity.

    PubMed

    Contreras, Francisco; Prado, Carolina; González, Hugo; Franz, Dafne; Osorio-Barrios, Francisco; Osorio, Fabiola; Ugalde, Valentina; Lopez, Ernesto; Elgueta, Daniela; Figueroa, Alicia; Lladser, Alvaro; Pacheco, Rodrigo

    2016-05-15

    Dopamine receptor D3 (DRD3) expressed on CD4(+) T cells is required to promote neuroinflammation in a murine model of Parkinson's disease. However, how DRD3 signaling affects T cell-mediated immunity remains unknown. In this study, we report that TCR stimulation on mouse CD4(+) T cells induces DRD3 expression, regardless of the lineage specification. Importantly, functional analyses performed in vivo using adoptive transfer of OVA-specific OT-II cells into wild-type recipients show that DRD3 deficiency in CD4(+) T cells results in attenuated differentiation of naive CD4(+) T cells toward the Th1 phenotype, exacerbated generation of Th2 cells, and unaltered Th17 differentiation. The reciprocal regulatory effect of DRD3 signaling in CD4(+) T cells favoring Th1 generation and impairing the acquisition of Th2 phenotype was also reproduced using in vitro approaches. Mechanistic analysis indicates that DRD3 signaling evokes suppressor of cytokine signaling 5 expression, a negative regulator of Th2 development, which indirectly favors acquisition of Th1 phenotype. Accordingly, DRD3 deficiency results in exacerbated eosinophil infiltration into the airways of mice undergoing house dust mite-induced allergic response. Interestingly, our results show that, upon chronic inflammatory colitis induced by transfer of naive CD4(+) T cells into lymphopenic recipients, DRD3 deficiency not only affects Th1 response, but also the frequency of Th17 cells, suggesting that DRD3 signaling also contributes to Th17 expansion under chronic inflammatory conditions. In conclusion, our findings indicate that DRD3-mediated signaling in CD4(+) T cells plays a crucial role in the balance of effector lineages, favoring the inflammatory potential of CD4(+) T cells. PMID:27183640

  11. Lack of Galectin-3 Drives Response to Paracoccidioides brasiliensis toward a Th2-Biased Immunity

    PubMed Central

    Ruas, Luciana Pereira; Bernardes, Emerson Soares; Fermino, Marise Lopes; de Oliveira, Leandro Licursi; Hsu, Daniel K.; Liu, Fu-Tong; Chammas, Roger; Roque-Barreira, Maria-Cristina

    2009-01-01

    There is recent evidence that galectin-3 participates in immunity to infections, mostly by tuning cytokine production. We studied the balance of Th1/Th2 responses to P. brasiliensis experimental infection in the absence of galectin-3. The intermediate resistance to the fungal infection presented by C57BL/6 mice, associated with the development of a mixed type of immunity, was replaced with susceptibility to infection and a Th2-polarized immune response, in galectin-3-deficient (gal3−/−) mice. Such a response was associated with defective inflammatory and delayed type hypersensitivity (DTH) reactions, high IL-4 and GATA-3 expression and low nitric oxide production in the organs of infected animals. Gal3−/− macrophages exhibited higher TLR2 transcript levels and IL-10 production compared to wild-type macrophages after stimulation with P. brasiliensis antigens. We hypothesize that, during an in vivo P. brasiliensis infection, galectin-3 exerts its tuning role on immunity by interfering with the generation of regulatory macrophages, thus hindering the consequent Th2-polarized type of response. PMID:19229338

  12. A Unique Dermal Dendritic Cell Subset That Skews the Immune Response toward Th2

    PubMed Central

    Hashimoto, Shin-ichi; Nagai, Shigenori; Hattori, Masahira; Irimura, Tatsuro

    2013-01-01

    Dendritic cell (DC) subsets in the skin and draining lymph nodes (LNs) are likely to elicit distinct immune response types. In skin and skin-draining LNs, a dermal DC subset expressing macrophage galactose-type C-type lectin 2 (MGL2/CD301b) was found distinct from migratory Langerhans cells (LCs) or CD103+ dermal DCs (dDCs). Lower expression levels of Th1-promoting and/or cross-presentation-related molecules were suggested by the transcriptome analysis and verified by the quantitative real-time PCR analysis in MGL2+ dDCs than in CD103+ dDCs. Transfer of MGL2+ dDCs but not CD103+ dDCs from FITC-sensitized mice induced a Th2-type immune response in vivo in a model of contact hypersensitivity. Targeting MGL2+ dDCs with a rat monoclonal antibody against MGL2 efficiently induced a humoral immune response with Th2-type properties, as determined by the antibody subclass. We propose that the properties of MGL2+ dDCs, are complementary to those of CD103+ dDCs and skew the immune response toward a Th2-type response. PMID:24039898

  13. Cathepsin B in antigen-presenting cells controls mediators of the Th1 immune response during Leishmania major infection.

    PubMed

    Gonzalez-Leal, Iris J; Röger, Bianca; Schwarz, Angela; Schirmeister, Tanja; Reinheckel, Thomas; Lutz, Manfred B; Moll, Heidrun

    2014-09-01

    Resistance and susceptibility to Leishmania major infection in the murine model is determined by the capacity of the host to mount either a protective Th1 response or a Th2 response associated with disease progression. Previous reports involving the use of cysteine cathepsin inhibitors indicated that cathepsins B (Ctsb) and L (Ctsl) play important roles in Th1/Th2 polarization during L. major infection in both susceptible and resistant mouse strains. Although it was hypothesized that these effects are a consequence of differential patterns of antigen processing, the mechanisms underlying these differences were not further investigated. Given the pivotal roles that dendritic cells and macrophages play during Leishmania infection, we generated bone-marrow derived dendritic cells (BMDC) and macrophages (BMM) from Ctsb-/- and Ctsl-/- mice, and studied the effects of Ctsb and Ctsl deficiency on the survival of L. major in infected cells. Furthermore, the signals used by dendritic cells to instruct Th cell polarization were addressed: the expression of MHC class II and co-stimulatory molecules, and cytokine production. We found that Ctsb-/- BMDC express higher levels of MHC class II molecules than wild-type (WT) and Ctsl-/- BMDC, while there were no significant differences in the expression of co-stimulatory molecules between cathepsin-deficient and WT cells. Moreover, both BMDC and BMM from Ctsb-/- mice significantly up-regulated the levels of interleukin 12 (IL-12) expression, a key Th1-inducing cytokine. These findings indicate that Ctsb-/- BMDC display more pro-Th1 properties than their WT and Ctsl-/- counterparts, and therefore suggest that Ctsb down-regulates the Th1 response to L. major. Moreover, they propose a novel role for Ctsb as a regulator of cytokine expression. PMID:25255101

  14. Selective enhancement of systemic Th1 immunity in immunologically immature rats with an orally administered bacterial extract.

    PubMed

    Bowman, L M; Holt, P G

    2001-06-01

    Infant rats primed during the first week of life with soluble antigen displayed adult-equivalent levels of T-helper 2 (Th2)-dependent immunological memory development as revealed by production of secondary immunoglobulin G1 (IgG1) antibody responses to subsequent challenge, but in contrast to adults failed to prime for Th1-dependent IgG2b responses. We demonstrate that this Th2 bias in immune function can be redressed by oral administration to neonates of a bacterial extract (Broncho-Vaxom OM-85) comprising lyophilized fractions of several common respiratory tract bacterial pathogens. Animals given OM-85 displayed a selective upregulation in primary and secondary IgG2b responses, accompanied by increased gamma interferon and decreased interleukin-4 production (both antigen specific and polyclonal), and increased capacity for development of Th1-dependent delayed hypersensitivity to the challenge antigen. We hypothesize that the bacterial extract functions via enhancement of the process of postnatal maturation of Th1 function, which is normally driven by stimuli from the gastrointestinal commensal microflora. PMID:11349036

  15. Selective Enhancement of Systemic Th1 Immunity in Immunologically Immature Rats with an Orally Administered Bacterial Extract

    PubMed Central

    Bowman, L. M.; Holt, P. G.

    2001-01-01

    Infant rats primed during the first week of life with soluble antigen displayed adult-equivalent levels of T-helper 2 (Th2)-dependent immunological memory development as revealed by production of secondary immunoglobulin G1 (IgG1) antibody responses to subsequent challenge, but in contrast to adults failed to prime for Th1-dependent IgG2b responses. We demonstrate that this Th2 bias in immune function can be redressed by oral administration to neonates of a bacterial extract (Broncho-Vaxom OM-85) comprising lyophilized fractions of several common respiratory tract bacterial pathogens. Animals given OM-85 displayed a selective upregulation in primary and secondary IgG2b responses, accompanied by increased gamma interferon and decreased interleukin-4 production (both antigen specific and polyclonal), and increased capacity for development of Th1-dependent delayed hypersensitivity to the challenge antigen. We hypothesize that the bacterial extract functions via enhancement of the process of postnatal maturation of Th1 function, which is normally driven by stimuli from the gastrointestinal commensal microflora. PMID:11349036

  16. Two Histone Variants TH2A and TH2B Enhance Human Induced Pluripotent Stem Cell Generation.

    PubMed

    Huynh, Linh My; Shinagawa, Toshie; Ishii, Shunsuke

    2016-02-01

    There are two major methods of reprogramming: generation of induced pluripotent stem cells (iPSCs) by overexpressing embryonic stem cell-specific transcription factors (OCT4, SOX2, KLF4, and c-MYC) and somatic cell nuclear transfer by oocyte-specific factors. Previously, we reported oocyte-enriched histone variants TH2A, TH2B, and the histone chaperone nucleoplasmin (NPM2) enhance the reprogramming by OSKM in mice by inducing open chromatin structure. In this study, we showed that human TH2A, TH2B, and NPM2 enhance the OSKM-induced reprogramming of adult and neonatal human dermal fibroblasts and umbilical vein endothelial cells. Pluripotency of iPSCs generated by coexpressing OSKM, TH2A, TH2B, and NPM2 was shown by in vitro and in vivo differentiation assays. These iPSCs gave rise to highly differentiated teratomas compared to iPSCs induced by OSKM alone. Genome-wide analysis suggests a possibility that TH2A, TH2B, and NPM2 might regulate genes that are involved in naïve stem cell stage. Thus, TH2A, TH2B, and NPM2 enhance reprogramming of human somatic cells and improve the quality of human iPSCs. PMID:26649967

  17. Immunosuppression of the trimellitic anhydride-induced th2 response by novel nonanatural products mixture in mice.

    PubMed

    Bae, Min-Jung; Shin, Hee Soon; Shon, Dong-Hwa

    2013-01-01

    Many natural dietary products prevent or cure allergic inflammation; however, the ability of mixtures of these natural medicinals to suppress allergic skin inflammation is unknown. We examined the inhibitory effects of nonanatural products mixture (NPM-9), which provides immunoregulatory activation, on Th2-mediated skin allergic inflammation. Oral administration of NPM-9 in mice reduced ear thickness and specific IgE production in trimellitic anhydride- (TMA-)induced contact hypersensitivity (CHS). NPM-9 also suppressed IL-4 and IL-1β production in splenocytes but prevented only TMA-induced IL-1β production in inflamed ears. To characterize the mechanism of this effect, we examined NPM-9 immunosuppression on an OVA-induced Th2 allergic state. Oral administration of NPM-9 inhibited Th2-mediated serum IgE overproduction. NPM-9 also downregulated the polarized Th2 response, whereas it upregulated Th1 response in splenocytes. These data suggest that NPM-9 may be a useful therapeutic agent for allergic inflammatory diseases through its suppression of the Th2-mediated allergic response. PMID:24348718

  18. STAT6-dependent and -independent mechanisms in Th2 polarization

    PubMed Central

    Maier, Elisabeth; Duschl, Albert; Horejs-Hoeck, Jutta

    2012-01-01

    Th2 cells play a key role in directing immune responses against helminths. Additionally, Th2 cells are crucial for many types of allergic reactions. Whereas the molecular mechanisms underlying the differentiation of other types of Th cells are well understood, Th2 differentiation is still a controversial topic. IL-4 and its downstream transcription factor signal transducer and activator of transcription (STAT)6 are well-known key mediators in Th2 differentiation. The fact that Th2 cells themselves are the most potent source of IL-4 suggests that additional mechanisms promoting the initiation of Th2 differentiation exist. This article gives an overview on STAT6-dependent and -independent mechanisms involved in the process of Th2 polarization, including Notch, mTORC2, IL-2/STAT5, and Wnt. Furthermore, we emphasize the role of STAT6 not only as a transcriptional activator promoting Th2 development, but also in fine-tuning alternative signaling pathways which are involved in the initiation of Th2 polarization. PMID:23041833

  19. IL-6 receptor-mediated lung Th2 cytokine networking in silica-induced pulmonary fibrosis.

    PubMed

    Tripathi, Shambhoo Sharan; Mishra, Vani; Shukla, Mamta; Verma, Mukesh; Chaudhury, Bhushan Pradosh; Kumar, Pradeep; Chhabra, Jasmeet Kaur; Pandey, Haushila Prasad; Paul, Bholanath

    2010-12-01

    Pulmonary silicosis is a deadly disease which kills thousands of people every year worldwide. The disease initially develops as an inflammatory response with recruitment of inflammatory cells into the lung controlled by multiple cytokines. The question whether these cytokines exert biological functions through signal transducing pathway remains unanswered along with the potential role of interleukin-6 receptor α (IL-6Rα) in regulating inflammatory cytokines. We aimed to assess the status of signal transducers and activator of transcription (Stat3), suppressor of cytokine signalling 3(Socs3) and inflammatory cytokines in airways of silica-exposed mice, and their relationship with IL-6Rα. Silica-exposed and silica-exposed IL-6Rα gene knockdown Balb/c mice were used in the study. Lung function was measured by plethysmography, mRNA expression of cytokines and signal molecules by qRT(2)-PCR and lung architecture by histopathology; T helper cell-type 2 (Th2) cytokines in broncho-alveolar lavage fluids were evaluated by ELISA and hydroxyproline in lung by colorimetry. Elevated levels of collagen deposition, signs of lung fibrosis, infiltration of inflammatory cells and presence of exfoliated mucosa in the lung of silica-exposed mice with concurrent increase in methacholine-induced specific resistance of airways were observed on day 60 post-exposure. In parallel, heightened expression of Th2 cytokines (IL-4, IL-5, IL-6) and signal molecules (Stat3 and Socs3) were observed in the airways of silica-exposed mice. Th1 (IL-1β and TNF-α) cytokines are underexpressed in majority of the airways tissues of silica-exposed mice. Silencing IL-6Rα in lung of silica-exposed mice down regulated the hypermorphic mRNA pool of potential Th2 cytokines and signal molecules. Hypermorphic expression of Th2 cytokines and signal molecules in airways of silica-exposed mice are mediated through IL-6Rα. PMID:20490462

  20. TET1 and TET3 are essential in induction of Th2-type immunity partly through regulation of IL-4/13A expression in zebrafish model.

    PubMed

    Yang, Chao; Li, Zhuo; Kang, Wei; Tian, Yu; Yan, Yuzhu; Chen, Wei

    2016-10-10

    It has been considered that epigenetic modulation can affect a diverse array of cellular activities, in which ten eleven translocation (TET) methylcytosine dioxygenase family members refer to a group of fundamental components involved in catalyzation of 5-hydroxymethylcytosine and modification of gene expression. Even though the function of TET proteins has been gradually revealed, their roles in immune regulation are still largely unknown. Recent studies provided clues that TET2 could regulate several innate immune-related inflammatory mediators in mammals. This study sought to explore the function of TET family members in potential T-helper (Th) cell differentiation involved in adaptive immunity by utilizing a zebrafish model. As shown by results, soluble antigens could induce expression of zebrafish IL-4/13A (i.e. a pivotal Th2-type cytokine essential in Th2 cell differentiation and functions), and further trigger the expression of Th1- and Th2-related genes. It is noteworthy that this response was accompanied by the up-regulation of two TET family members (TET1 and TET3) both in immune organs (spleen and kidney) and cells (peripheral lymphocytes). Knocking-down of TET1 and TET3 will give rise to the decreased responses of IL-4/13A induction against exogenous soluble antigen stimulation, and further restrain the expression of Th2-related genes, which indicates a restrained Th2 cell differentiation. Nonetheless, TET2 did not exhibit effect on the modification of Th1/Th2 related gene expression. Hence, these data showed that TET1 and TET3 might be two significant epigenetic regulators involved in Th2 differentiation through regulation of IL-4/13A expression. This is the first report to show that TET family members play indispensable roles in Th2-type immunity, indicating an epigenetic modulation manner involved in adaptive immune regulations and responses. PMID:27418527

  1. Transfer of a CD4+ Th1 cell line to nude mice effects clearance of Rhodococcus equi from the lung.

    PubMed Central

    Kanaly, S T; Hines, S A; Palmer, G H

    1996-01-01

    Rhodococcus equi, and intracellular respiratory pathogen, causes sever e granulomatous pneumonia in humans with AIDS and in young horses. Pulmonary clearance of R. equi requires functional CD4+ T cells and gamma interferon (IFN-gamma) expression from bronchial lymph node cells. The purpose of this study was to investigate whether R. equi-specific CD4+ Th1 cells could effect clearance of R. equi from the lung. Adoptive transfer of a clearance of R. equi from the lungs. In contrast, mice transfused with a R. equi-specific CD4+ Th2 cell line expressed interleukin-4 but not IFN-gamma mRNA, failed to clear pulmonary infection, and developed granulomas in the lung. Control mice, which did not receive cells, did not produce IFN-gamma or interleukin-4 and developed small pulmonary granulomas. These results clearly show that a Th1 response is sufficient to effect pulmonary clearance of R. equi. PMID:8606068

  2. Soluble flagellin coimmunization attenuates Th1 priming to Salmonella and clearance by modulating dendritic cell activation and cytokine production

    PubMed Central

    Flores‐Langarica, Adriana; Bobat, Saeeda; Marshall, Jennifer L.; Yam‐Puc, Juan Carlos; Cook, Charlotte N.; Serre, Karine; Kingsley, Robert A.; Flores‐Romo, Leopoldo; Uematsu, Satoshi; Akira, Shizuo; Henderson, Ian R.; Toellner, Kai M.

    2015-01-01

    Soluble flagellin (sFliC) from Salmonella Typhimurium (STm) can induce a Th2 response to itself and coadministered antigens through ligation of TLR5. These properties suggest that sFliC could potentially modulate responses to Th1 antigens like live STm if both antigens are given concurrently. After coimmunization of mice with sFliC and STm there was a reduction in Th1 T cells (T‐bet+IFN‐γ+ CD4 T cells) compared to STm alone and there was impaired clearance of STm. In contrast, there was no significant defect in the early extrafollicular B‐cell response to STm. These effects are dependent upon TLR5 and flagellin expression by STm. The mechanism for these effects is not related to IL‐4 induced to sFliC but rather to the effects of sFliC coimmunization on DCs. After coimmunization with STm and sFliC, splenic DCs had a lower expression of costimulatory molecules and profoundly altered kinetics of IL‐12 and TNFα expression. Ex vivo experiments using in vivo conditioned DCs confirmed the effects of sFliC were due to altered DC function during a critical window in the coordinated interplay between DCs and naïve T cells. This has marked implications for understanding how limits in Th1 priming can be achieved during infection‐induced, Th1‐mediated inflammation. PMID:26036767

  3. Soluble flagellin coimmunization attenuates Th1 priming to Salmonella and clearance by modulating dendritic cell activation and cytokine production.

    PubMed

    Flores-Langarica, Adriana; Bobat, Saeeda; Marshall, Jennifer L; Yam-Puc, Juan Carlos; Cook, Charlotte N; Serre, Karine; Kingsley, Robert A; Flores-Romo, Leopoldo; Uematsu, Satoshi; Akira, Shizuo; Henderson, Ian R; Toellner, Kai M; Cunningham, Adam F

    2015-08-01

    Soluble flagellin (sFliC) from Salmonella Typhimurium (STm) can induce a Th2 response to itself and coadministered antigens through ligation of TLR5. These properties suggest that sFliC could potentially modulate responses to Th1 antigens like live STm if both antigens are given concurrently. After coimmunization of mice with sFliC and STm there was a reduction in Th1 T cells (T-bet(+) IFN-γ(+) CD4 T cells) compared to STm alone and there was impaired clearance of STm. In contrast, there was no significant defect in the early extrafollicular B-cell response to STm. These effects are dependent upon TLR5 and flagellin expression by STm. The mechanism for these effects is not related to IL-4 induced to sFliC but rather to the effects of sFliC coimmunization on DCs. After coimmunization with STm and sFliC, splenic DCs had a lower expression of costimulatory molecules and profoundly altered kinetics of IL-12 and TNFα expression. Ex vivo experiments using in vivo conditioned DCs confirmed the effects of sFliC were due to altered DC function during a critical window in the coordinated interplay between DCs and naïve T cells. This has marked implications for understanding how limits in Th1 priming can be achieved during infection-induced, Th1-mediated inflammation. PMID:26036767

  4. A Small Molecule Inhibitor of ITK and RLK Impairs Th1 Differentiation and Prevents Colitis Disease Progression

    PubMed Central

    Cho, Hyoung-Soo; Shin, Hyun Mu; Haberstock-Debic, Helena; Xing, Yan; Owens, Timothy D.; Funk, Jens Oliver; Hill, Ronald J.; Bradshaw, J. Michael

    2015-01-01

    In T cells, the Tec kinases IL-2–inducible T cell kinase (ITK) and resting lymphocyte kinase (RLK) are activated by TCR stimulation and are required for optimal downstream signaling. Studies of CD4+ T cells from Itk−/− and Itk−/−Rlk−/− mice have indicated differential roles of ITK and RLK in Th1, Th2, and Th17 differentiation and cytokine production. However, these findings are confounded by the complex T cell developmental defects in these mice. In this study, we examine the consequences of ITK and RLK inhibition using a highly selective and potent small molecule covalent inhibitor PRN694. In vitro Th polarization experiments indicate that PRN694 is a potent inhibitor of Th1 and Th17 differentiation and cytokine production. Using a T cell adoptive transfer model of colitis, we find that in vivo administration of PRN694 markedly reduces disease progression, T cell infiltration into the intestinal lamina propria, and IFN-γ production by colitogenic CD4+ T cells. Consistent with these findings, Th1 and Th17 cells differentiated in the presence of PRN694 show reduced P-selectin binding and impaired migration to CXCL11 and CCL20, respectively. Taken together, these data indicate that ITK plus RLK inhibition may have therapeutic potential in Th1-mediated inflammatory diseases. PMID:26466958

  5. Th1 and Th17 Cells Induce Proliferative Glomerulonephritis

    PubMed Central

    Summers, Shaun A.; Steinmetz, Oliver M.; Li, Ming; Kausman, Joshua Y.; Semple, Timothy; Edgtton, Kristy L.; Borza, Dorin-Bogdan; Braley, Hal; Holdsworth, Stephen R.

    2009-01-01

    Th1 effector CD4+ cells contribute to the pathogenesis of proliferative and crescentic glomerulonephritis, but whether effector Th17 cells also contribute is unknown. We compared the involvement of Th1 and Th17 cells in a mouse model of antigen-specific glomerulonephritis in which effector CD4+ cells are the only components of adaptive immunity that induce injury. We planted the antigen ovalbumin on the glomerular basement membrane of Rag1−/− mice using an ovalbumin-conjugated non-nephritogenic IgG1 monoclonal antibody against α3(IV) collagen. Subsequent injection of either Th1- or Th17-polarized ovalbumin-specific CD4+ effector cells induced proliferative glomerulonephritis. Mice injected with Th1 cells developed progressive albuminuria over 21 d, histologic injury including 5.5 ± 0.9% crescent formation/segmental necrosis, elevated urinary nitrate, and increased renal NOS2, CCL2, and CCL5 mRNA. Mice injected with Th17 cells developed albuminuria by 3 d; compared with Th1-injected mice, their glomeruli contained more neutrophils and greater expression of renal CXCL1 mRNA. In conclusion, Th1 and Th17 effector cells can induce glomerular injury. Understanding how these two subsets mediate proliferative forms of glomerulonephritis may lead to targeted therapies. PMID:19820122

  6. Th1 and Th17 cells induce proliferative glomerulonephritis.

    PubMed

    Summers, Shaun A; Steinmetz, Oliver M; Li, Ming; Kausman, Joshua Y; Semple, Timothy; Edgtton, Kristy L; Borza, Dorin-Bogdan; Braley, Hal; Holdsworth, Stephen R; Kitching, A Richard

    2009-12-01

    Th1 effector CD4+ cells contribute to the pathogenesis of proliferative and crescentic glomerulonephritis, but whether effector Th17 cells also contribute is unknown. We compared the involvement of Th1 and Th17 cells in a mouse model of antigen-specific glomerulonephritis in which effector CD4+ cells are the only components of adaptive immunity that induce injury. We planted the antigen ovalbumin on the glomerular basement membrane of Rag1(-/-) mice using an ovalbumin-conjugated non-nephritogenic IgG1 monoclonal antibody against alpha3(IV) collagen. Subsequent injection of either Th1- or Th17-polarized ovalbumin-specific CD4+ effector cells induced proliferative glomerulonephritis. Mice injected with Th1 cells developed progressive albuminuria over 21 d, histologic injury including 5.5 +/- 0.9% crescent formation/segmental necrosis, elevated urinary nitrate, and increased renal NOS2, CCL2, and CCL5 mRNA. Mice injected with Th17 cells developed albuminuria by 3 d; compared with Th1-injected mice, their glomeruli contained more neutrophils and greater expression of renal CXCL1 mRNA. In conclusion, Th1 and Th17 effector cells can induce glomerular injury. Understanding how these two subsets mediate proliferative forms of glomerulonephritis may lead to targeted therapies. PMID:19820122

  7. A novel function of interferon regulatory factor-1: inhibition of Th2 cells by down-regulating the Il4 gene during Listeria infection.

    PubMed

    Maruyama, Saho; Kanoh, Makoto; Matsumoto, Akira; Kuwahara, Makoto; Yamashita, Masakatsu; Asano, Yoshihiro

    2015-03-01

    Infection with certain pathogens induces a shift of the Th subset balance to a Th1 dominant state. This, in turn, results in the suppression of Th2 responses. We focused on the involvement of interferon regulatory factor-1 (IRF-1) in the suppression of Th2 cells during Listeria infection. We found that the inhibition of IL-4 production by Th2 cells is mediated by a soluble factor (LmSN) produced by Listeria-infected antigen-presenting cells. The inhibition is not observed with T cells from Irf1 gene-targeted mice. IRF-1 suppresses transcription of the Il4 gene in Th2 cells. Under the influence of the LmSN, IRF-1 binds to the 3' untranslated region (UTR) region of the Il4 gene and down-regulates Il4 gene transcription. Finally, we identified IL-1α and IL-1β as the mediator of the LmSN activity. Signaling through IL-1R induces the stabilization and/or nuclear translocation of IRF-1. We propose that IRF-1 functions to induce the T-cell subset shift via a novel mechanism. Under the influence of IL-1, IRF-1 translocates into the nucleus and acts on the 3'UTR region of the Il4 gene, thus inhibiting its transcription in Th2 cells. As a result, the immune system shifts predominantly to a Th1 response during Listeria infection, resulting in effective protection of the host. PMID:25280793

  8. Immunomodulatory mediators from pollen enhance the migratory capacity of dendritic cells and license them for Th2 attraction.

    PubMed

    Mariani, Valentina; Gilles, Stefanie; Jakob, Thilo; Thiel, Martina; Mueller, Martin J; Ring, Johannes; Behrendt, Heidrun; Traidl-Hoffmann, Claudia

    2007-06-15

    The immune response of atopic individuals against allergens is characterized by increased levels of Th2 cytokines and chemokines. However, the way in which the cytokine/chemokine profile is matched to the type of invading allergen, and why these profiles sometimes derail and lead to disease, is not well understood. We recently demonstrated that pollen modulates dendritic cell (DC) function in a way that results in an enhanced capacity to initiate Th2 responses in vitro. Here, we examined the effects of aqueous birch pollen extracts (Bet.-APE) on chemokine receptor expression and chemokine production by human monocyte-derived DCs. Bet.-APE strongly induced expression and function of CXCR4 and reduced CCR1 and CCR5 expression on immature DCs. In addition, DC treatment with Bet.-APE significantly reduced LPS-induced production of CXCL10/IP-10, CCL5/RANTES; induced CCL22/macrophage-derived chemokine; and did not significantly change release of CCL17/thymus and activation-regulated chemokine. At a functional level, Bet.-APE increased the capacity of LPS-stimulated DCs to attract Th2 cells, whereas the capacity to recruit Th1 cells was reduced. Bet.-APE significantly and dose-dependently enhanced intracellular cAMP, suggesting that water-soluble factors from pollen grains bind a G(alphas)-protein-coupled receptor. E(1)-Phytoprostanes were identified to be one player in the Th2-polarizing potential of aqueous pollen extracts. In summary, our results demonstrate that pollen itself releases regulatory mediators which generate a Th2-promoting micromilieu with preferential recruitment of Th2 cells to the site of pollen exposure. PMID:17548598

  9. A phase trial of the oral Lactobacillus casei vaccine polarizes Th2 cell immunity against transmissible gastroenteritis coronavirus infection.

    PubMed

    Jiang, Xinpeng; Hou, Xingyu; Tang, Lijie; Jiang, Yanping; Ma, Guangpeng; Li, Yijing

    2016-09-01

    Transmissible gastroenteritis coronavirus (TGEV) is a member of the genus Coronavirus, family Coronaviridae, order Nidovirales. TGEV is an enteropathogenic coronavirus that causes highly fatal acute diarrhoea in newborn pigs. An oral Lactobacillus casei (L. casei) vaccine against anti-transmissible gastroenteritis virus developed in our laboratory was used to study mucosal immune responses. In this L. casei vaccine, repetitive peptides expressed by L. casei (specifically the MDP and tuftsin fusion protein (MT)) were repeated 20 times and the D antigenic site of the TGEV spike (S) protein was repeated 6 times. Immunization with recombinant Lactobacillus is crucial for investigations of the effect of immunization, such as the first immunization time and dose. The first immunization is more important than the last immunization in the series. The recombinant Lactobacillus elicited specific systemic and mucosal immune responses. Recombinant L. casei had a strong potentiating effect on the cellular immunity induced by the oral L. casei vaccine. However, during TGEV infection, the systemic and local immune responses switched from Th1 to Th2-based immune responses. The systemic humoral immune response was stronger than the cellular immune response after TGEV infection. We found that the recombinant Lactobacillus stimulated IL-17 expression in both the systemic and mucosal immune responses against TGEV infection. Furthermore, the Lactobacillus vaccine stimulated an anti-TGEV infection Th17 pathway. The histopathological examination showed tremendous potential for recombinant Lactobacillus to enable rapid and effective treatment for TGEV with an intestinal tropism in piglets. The TGEV immune protection was primarily dependent on mucosal immunity. PMID:27020282

  10. Prenatal secondhand cigarette smoke promotes Th2 polarization and impairs goblet cell differentiation and airway mucus formation.

    PubMed

    Singh, Shashi P; Gundavarapu, Sravanthi; Peña-Philippides, Juan C; Rir-Sima-ah, Jules; Mishra, Neerad C; Wilder, Julie A; Langley, Raymond J; Smith, Kevin R; Sopori, Mohan L

    2011-11-01

    Parental, particularly maternal, smoking increases the risk for childhood allergic asthma and infection. Similarly, in a murine allergic asthma model, prenatal plus early postnatal exposure to secondhand cigarette smoke (SS) exacerbates airways hyperreactivity and Th2 responses in the lung. However, the mechanism and contribution of prenatal versus early postnatal SS exposure on allergic asthma remain unresolved. To identify the effects of prenatal and/or early postnatal SS on allergic asthma, BALB/c dams and their offspring were exposed gestationally and/or 8-10 wk postbirth to filtered air or SS. Prenatal, but not postnatal, SS strongly increased methacholine and allergen (Aspergillus)-induced airway resistance, Th2 cytokine levels, and atopy and activated the Th2-polarizing pathway GATA3/Lck/ERK1/2/STAT6. Either prenatal and/or early postnatal SS downregulated the Th1-specific transcription factor T-bet and, surprisingly, despite high levels of IL-4/IL-13, dramatically blocked the allergen-induced mucous cell metaplasia, airway mucus formation, and the expression of mucus-related genes/proteins: Muc5ac, γ-aminobutyric acid A receptors, and SAM pointed domain-containing Ets-like factor. Given that SS/nicotine exposure of normal adult mice promotes mucus formation, the results suggested that fetal and neonatal lung are highly sensitive to cigarette smoke. Thus, although the gestational SS promotes Th2 polarization/allergic asthma, it may also impair and/or delay the development of fetal and neonatal lung, affecting mucociliary clearance and Th1 responses. Together, this may explain the increased susceptibility of children from smoking parents to allergic asthma and childhood respiratory infections. PMID:21930963

  11. Uncaria tomentosa aqueous-ethanol extract triggers an immunomodulation toward a Th2 cytokine profile.

    PubMed

    Domingues, Alexandre; Sartori, Alexandrina; Valente, Ligia Maria Marino; Golim, Marjorie Assis; Siani, Antonio Carlos; Viero, Rosa Marlene

    2011-08-01

    Uncaria tomentosa (Willd.) DC (Rubiaceae) is a large woody vine that is native to the Amazon and Central American rainforests and is used widely in traditional medicine for its immunomodulatory and antiinflammatory activities. The present work used in vivo immunotoxic and in vitro immunomodulatory experiments to investigate the effects of a pentacyclic oxindole alkaloid extract from U. tomentosa bark on lymphocyte phenotype, Th1/Th2 cytokine production, cellular proliferation and cytotoxicity. For the in vivo immunotoxicity testing, BALB/c male mice were treated once a day with 125, 500 or 1250 mg/kg of U. tomentosa extract for 28 days. For the in vitro protocol, lymphocytes were cultured with 10-500 μg/mg of the extract for 48 h. The extract increased the cellularity of splenic white pulp and the thymic medulla and increased the number of T helper lymphocytes and B lymphocytes. Also, a large stimulatory effect on lymphocyte viability was observed. However, mitogen-induced T lymphocyte proliferation was significantly inhibited at higher concentrations of U. tomentosa extract. Furthermore, an immunological polarization toward a Th2 cytokine profile was observed. These results suggest that the U. tomentosa aqueous-ethanol extract was not immunotoxic to mice and was able to modulate distinct patterns of the immune system in a dose-dependent manner. PMID:21656603

  12. Th2 and eosinophil responses suppress inflammatory arthritis

    PubMed Central

    Chen, Zhu; Andreev, Darja; Oeser, Katharina; Krljanac, Branislav; Hueber, Axel; Kleyer, Arnd; Voehringer, David; Schett, Georg; Bozec, Aline

    2016-01-01

    Th2–eosinophil immune responses are well known for mediating host defence against helminths. Herein we describe a function of Th2–eosinophil responses in counteracting the development of arthritis. In two independent models of arthritis, Nippostrongylus brasiliensis infection leads to Th2 and eosinophil accumulation in the joints associated with robust inhibition of arthritis and protection from bone loss. Mechanistically, this protective effect is dependent on IL-4/IL-13-induced STAT6 pathway. Furthermore, we show that eosinophils play a central role in the modulation of arthritis probably through the increase of anti-inflammatory macrophages into arthritic joints. The presence of these pathways in human disease is confirmed by detection of GATA3-positive cells and eosinophils in the joints of rheumatoid arthritis patients. Taken together, these results demonstrate that eosinophils and helminth-induced activation of the Th2 pathway axis effectively mitigate the course of inflammatory arthritis. PMID:27273006

  13. Th2 and eosinophil responses suppress inflammatory arthritis.

    PubMed

    Chen, Zhu; Andreev, Darja; Oeser, Katharina; Krljanac, Branislav; Hueber, Axel; Kleyer, Arnd; Voehringer, David; Schett, Georg; Bozec, Aline

    2016-01-01

    Th2-eosinophil immune responses are well known for mediating host defence against helminths. Herein we describe a function of Th2-eosinophil responses in counteracting the development of arthritis. In two independent models of arthritis, Nippostrongylus brasiliensis infection leads to Th2 and eosinophil accumulation in the joints associated with robust inhibition of arthritis and protection from bone loss. Mechanistically, this protective effect is dependent on IL-4/IL-13-induced STAT6 pathway. Furthermore, we show that eosinophils play a central role in the modulation of arthritis probably through the increase of anti-inflammatory macrophages into arthritic joints. The presence of these pathways in human disease is confirmed by detection of GATA3-positive cells and eosinophils in the joints of rheumatoid arthritis patients. Taken together, these results demonstrate that eosinophils and helminth-induced activation of the Th2 pathway axis effectively mitigate the course of inflammatory arthritis. PMID:27273006

  14. Yeast-surface expressed BVDV E2 protein induces a Th1/Th2 response in naïve T cells

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Yeast species such as Saccharomyces cerevisiae (S. cerevisiae) are well documented as being potent activators of the immune system. S. cerevisiae activates the innate immune system by engaging pattern recognition receptors such as toll like receptor 2 (TLR2) and dectin-1. In the current project, w...

  15. The Imbalance in Serum Concentration of Th-1- and Th-2-Derived Chemokines as One of the Factors Involved in Pathogenesis of Atopic Dermatitis

    PubMed Central

    Narbutt, Joanna; Lesiak, Aleksandra; Sysa-Jedrzeiowska, Anna; Zakrzewski, Marcin; Bogaczewicz, Jarosław; Stelmach, Iwona; Kuna, Piotr

    2009-01-01

    Atopic dermatitis (AD) is an inflammatory skin disease in which pathogenesis chemokines are partially involved. The aim of the paper was to assess the serum level of CXCL-9, CXCL-10, CXCL-11, CXCL-12, CCL-17, CCL-20, CCL-21, CCL-22, CCL-27, and IL-18 chosen in AD patients by ELISA assay. Forty patients (mean age 11.4 years old) with AD and 50 healthy controls were enrolled into the study. The patients and controls were divided into two age categories: under 10 years old (Group 1 and Control 1) and over 10 years old (Group 2 and Control 2). Significantly lower serum concentration of CXCL-9, CXCL-10, CCL-17, and IL-18 and higher concentration of CXCL-12 and CCL-27 were found in Group 1 when compared to Control 1. In Group 2 serum concentration of CXCL-12, CCL-17, CCL-22 was higher than in Control 2. The obtained results indicate the imbalance in chemokine serum levels in AD what suggests their role in the disease pathogenesis. PMID:19639049

  16. Immunotherapeutic vitamin E nanoemulsion synergies the antiproliferative activity of paclitaxel in breast cancer cells via modulating Th1 and Th2 immune response.

    PubMed

    Pawar, Vivek K; Panchal, Samir B; Singh, Yuvraj; Meher, Jaya Gopal; Sharma, Komal; Singh, Pankaj; Bora, Himangshu K; Singh, Akhilesh; Datta, Dipak; Chourasia, Manish K

    2014-12-28

    Paclitaxel (PTX) is used as first line treatment for metastatic breast cancer but the relief comes at a heavy cost in terms of accompanying adverse effects. The pharmaceutical credentials of PTX are further dampened by the intrinsically low aqueous solubility. In order to sideline such insidious tendencies, PTX was incorporated in a vitamin E nanoemulsion using high pressure homogenization. The encapsulation efficiency of PTX in nanoemulsion was 97.81±2.7% and a sustained drug release profile was obtained. PTX loaded nanoemulsion exhibited higher cytotoxicity in breast cancer cell line (MCF-7) when compared to free PTX and marketed formulation (Taxol). Cell cycle arrest study depicted that MCF-7 cells treated with PTX loaded nanoemulsion showed high arrest in G2-M phase. Moreover blank nanoemulsion induced additional apoptosis in breast cancer cells through G1-S arrest by disrupting mitochondrial membrane potential. Cytokine estimation study in macrophages showed that both PTX loaded nanoemulsion and blank nanoemulsion enhanced secretion of IL-12 and downregulated secretion of IL-4 and IL-10. Results suggest that inclusion of vitamin E in nanoemulsion opened multiple complementary molecular effects which not only magnified the principle antiproliferative activity of PTX but also independently showcased potential in restoring the proactive nature of the breast cancer slackened chronic immune response. In-vivo anticancer activity showed significantly improved efficacy of PTX loaded nanoemlsion compare to Taxol and free PTX. The list of plausible advantages of PTX nanoemulsification was further substantiated by acceptable haemolytic potential, reduced in-vivo toxicity and conveniently modified pharmacokinetic profile in which the AUC and MRT were extended considerably. Overall, there were strong evidences that developed formulation can serve as a viable alternative to currently available PTX options. PMID:25459427

  17. Th1 versus Th2 T cell polarization by whole-cell and acellular childhood pertussis vaccines persists upon re-immunization in adolescence and adulthood.

    PubMed

    Bancroft, Tara; Dillon, Myles B C; da Silva Antunes, Ricardo; Paul, Sinu; Peters, Bjoern; Crotty, Shane; Lindestam Arlehamn, Cecilia S; Sette, Alessandro

    2016-01-01

    The recent increase in cases of whooping cough among teenagers in the US suggests that the acellular Bordetella pertussis vaccine (aP) that became standard in the mid 1990s might be relatively less effective than the whole-bacteria formulation (wP) previously used since the 1950s. To understand this effect, we compared antibody and T cell responses to a booster immunization in subjects who received either the wP or aP vaccine as their initial priming dose in childhood. Antibody responses in wP- and aP-primed donors were similar. Magnitude of T cell responses was higher in aP-primed individuals. Epitope mapping revealed the T cell immunodominance patterns were similar for both vaccines. Further comparison of the ratios of IFNγ and IL-5 revealed that IFNγ strongly dominates the T cell response in wP-primed donors, while IL-5 is dominant in aP primed individuals. Surprisingly, this differential pattern is maintained after booster vaccination, at times from eighteen years to several decades after the original aP/wP priming. These findings suggest that childhood aP versus wP vaccination induces functionally different T cell responses to pertussis that become fixed and are unchanged even upon boosting. PMID:27212461

  18. Submicroscopic infection of placenta by Plasmodium produces Th1/Th2 cytokine imbalance, inflammation and hypoxia in women from north-west Colombia

    PubMed Central

    2014-01-01

    Background A large-scale study was set up in order to study the epidemiology, clinical aspects, and immunopathology of gestational and placental malaria in north-west Colombia. In this region, recent reports using a qPCR technique, confirmed frequencies of infection, by Plasmodium falciparum or Plasmodium vivax, up to 45%. Given the high rates of infection observed both in mother and placenta, a first exploratory study was proposed in order to characterize the effect on the inflammation status, tissue damage and hypoxia in Plasmodium spp. infected placentas. Methods A descriptive, prospective, cross-sectional design was applied to pregnant women with (PM+) and without (PM-) placental malaria. Messenger RNA expression of Fas, FasL; COX-1, COX-2, HIF, VEGF, and the cytokines IL-2, IL-4, IL-10, IFN-γ and TNF, were measured in peripheral and placental blood using a quantitative PCR. The percentage of apoptotic cells was determined with a TUNEL assay. Results In total 50 placentas were studied: 25 were positive for submicroscopic infection and 25 were negative for Plasmodium infection. Expression of IL-4 and IL-10 was observed high in placental tissue of PM+, while IL-2 was high in peripheral blood of the same group. Expression of TNF and IFNγ in peripheral blood of the PM + group was high. Similarly, the apoptotic index and Fas expression were significantly high in PM+. However, FasL expression was observed low in PM + compared to PM-. Inflammation markers (HIF, VEGF) and hypoxia markers (COX-1, COX-2) were high in the PM + group. Conclusion During placental malaria expression of some pro-inflammatory cytokines is up-regulated and markers of hypoxia and tissue damage are increased in cases of submicroscopic infection. PMID:24673747

  19. Transcriptome signature for dampened Th2 dominance in acellular pertussis vaccine-induced CD4+ T cell responses through TLR4 ligation

    PubMed Central

    Brummelman, Jolanda; Raeven, René H. M.; Helm, Kina; Pennings, Jeroen L. A.; Metz, Bernard; van Eden, Willem; van Els, Cécile A. C. M.; Han, Wanda G. H.

    2016-01-01

    Current acellular pertussis (aP) vaccines promote a T helper 2 (Th2)-dominated response, while Th1/Th17 cells are protective. As our previous study showed, after adding a non-toxic TLR4 ligand, LpxL1, to the aP vaccine in mice, the Bordetella pertussis-specific Th2 response is decreased and Th1/Th17 responses are increased as measured at the cytokine protein level. However, how this shift in Th response by LpxL1 addition is regulated at the gene expression level remains unclear. Transcriptomics analysis was performed on purified CD4+ T cells of control and vaccinated mice after in vitro restimulation with aP vaccine antigens. Multiple key factors in Th differentiation, including transcription factors, cytokines, and receptors, were identified within the differentially expressed genes. Upregulation of Th2- and downregulation of follicular helper T cell-associated genes were found in the CD4+ T cells of both aP- and aP+LpxL1-vaccinated mice. Genes exclusively upregulated in CD4+ T cells of aP+LpxL1-vaccinated mice included Th1 and Th17 signature cytokine genes Ifng and Il17a respectively. Overall, our study indicates that after addition of LpxL1 to the aP vaccine the Th2 component is not downregulated at the gene expression level. Rather an increase in expression of Th1- and Th17-associated genes caused the shift in Th subset outcome. PMID:27118638

  20. Prevention of Th2-like cell responses by coadministration of IL-12 and IL-18 is associated with inhibition of antigen-induced airway hyperresponsiveness, eosinophilia, and serum IgE levels.

    PubMed

    Hofstra, C L; Van Ark, I; Hofman, G; Kool, M; Nijkamp, F P; Van Oosterhout, A J

    1998-11-01

    Allergic asthma is thought to be regulated by Th2 cells, and inhibiting this response is a promising mode of intervention. Many studies have focused on differentiation of Th cells to the Th1 or Th2 subset in vitro. IL-4 is essential for Th2 development, while IL-12 induces Th1 development, which can be enhanced by IL-18. In the present study, we investigated whether IL-12 and IL-18 were able to interfere in Th2 development and the associated airway symptoms in a mouse model of allergic asthma. Mice were sensitized with OVA using a protocol that induces IgE production. Repeated challenges by OVA inhalation induced elevated serum levels of IgE, airway hyperresponsiveness, and a predominantly eosinophilic infiltrate in the bronchoalveolar lavage concomitant with the appearance of Ag-specific Th2-like cells in lung tissue and lung-draining lymph nodes. Whereas treatments with neither IL-12 nor IL-18 during the challenge period were effective, combined treatment of IL-12 and IL-18 inhibited Ag-specific Th2-like cell development. This inhibition was associated with an absence of IgE up-regulation, airway hyperresponsiveness, and cellular infiltration in the lavage. These data show that, in vivo, the synergistic action of IL-12 and IL-18 is necessary to prevent Th2-like cell differentiation, and consequently inhibits the development of airway symptoms in a mouse model of allergic asthma. PMID:9794443

  1. Phosphodiesterase 4B is essential for TH2-cell function and development of airway hyperresponsiveness in allergic asthma

    PubMed Central

    Catherine Jin, S.-L.; Goya, Sho; Nakae, Susumu; Wang, Dan; Bruss, Matthew; Hou, Chiaoyin; Umetsu, Dale; Conti, Marco

    2010-01-01

    Background Cyclic AMP (cAMP) signaling modulates functions of inflammatory cells involved in the pathogenesis of asthma, and type 4 cAMP-specific phosphodiesterases (PDE4s) are essential components of this pathway. Induction of the PDE4 isoform PDE4B is necessary for Toll-like receptor signaling in monocytes and macrophages and is associated with T cell receptor/CD3 in T cells; however, its exact physiological function in the development of allergic asthma remains undefined. Objectives We investigated the role of PDE4B in the development of allergen-induced airway hyperresponsiveness (AHR) and TH2-driven inflammatory responses. Methods Wild-type and PDE4B−/− mice were sensitized and challenged with ovalbumin and AHR measured in response to inhaled methacholine. Airway inflammation was characterized by analyzing leukocyte infiltration and cytokine accumulation in the airways. Ovalbumin-stimulated cell proliferation and TH2 cytokine production were determined in cultured bronchial lymph node cells. Results Mice deficient in PDE4B do not develop AHR. This protective effect was associated with a significant decrease in eosinophils recruitment to the lungs and decreased TH2 cytokine levels in the bronchoalveolar lavage fluid. Defects in T-cell replication, TH2 cytokine production, and dendritic cell migration were evident in cells from the airway-draining lymph nodes. Conversely, accumulation of the TH1 cytokine IFN-γ was not affected in PDE4B−/− mice. Ablation of the orthologous PDE4 gene PDE4A has no impact on airway inflammation. Conclusion By relieving a cAMP-negative constraint, PDE4B plays an essential role in TH2-cell activation and dendritic cell recruitment during airway inflammation. These findings provide proof of concept that PDE4 inhibitors with PDE4B selectivity may have efficacy in asthma treatment. PMID:21047676

  2. Th17 and Th1 Lymphocytes Are Correlated with Chronic Periodontitis.

    PubMed

    Chen, Xiao-Tao; Chen, Li-Li; Tan, Jing-Yi; Shi, Dan-Hui; Ke, Ting; Lei, Li-Hong

    2016-01-01

    T cells are involved in the homeostasis of periodontal tissues and mediate bone loss in periodontitis, but the involvement of T-helper cells in chronic periodontitis (CP) in a Chinese population is still unclear. This study aimed to assess the distribution of peripheral and local T helper (Th17) and Th1 in CP. Sixty-eight patients with CP and 43 healthy controls were recruited from April 2012 to July 2014 at the Department of Stomatology, People's Hospital of Xinjiang Uygur Autonomous Region (China). The proportions of Th17 (CD3(+)CD4(+)IL-17(+)) and Th1 (CD3(+)CD4(+)IFN-γ(+)) T-cells in peripheral blood samples were assessed by flow cytometry. Immunohistochemistry was used to quantify interleukin-17 (IL-17) and interferon-gamma (IFN-γ) protein levels in gingival biopsy samples. mRNA levels of IL-17, IFN-γ RORγt, and T-bet in gingival biopsy samples were measured by quantitative real-time polymerase chain reaction (qRT-PCR). The proportions of circulating Th17 cells and Th1 cells were both more abundant in CP patients than in controls (Th17: 1.05% ± 0.87% vs. 0.62% ± 0.49%, P < 0.01; Th1: 13.93% ± 7.94% vs. 8.22% ± 4.50%, P < 0.001). Positive correlations were obtained between the proportion of circulating Th17 cells and probing depth (PD) (r = 0.320, P = 0.001) and between the proportion of circulating Th1 cells and PD (r = 0.372, P < 0.001). IL-17 and IFN-γ protein levels in gingival biopsy samples were markedly increased in CP compared to controls (both P < 0.05). Relative IFN-γ, IL-17A, and T-bet mRNA levels in CP biopsies were higher compared to controls (all P < 0.05). These results suggest that elevated peripheral and local Th17 and Th1 cells might be involved in the pathogenesis of CP. PMID:27019379

  3. Innate Immune Function of TH2 Cells in vivo

    PubMed Central

    Guo, Liying; Huang, Yuefeng; Chen, Xi; Hu-Li, Jane; Urban, Joseph F.; Paul, William E.

    2015-01-01

    Type 2 helper T (TH) cells produce interleukin 13 (IL-13) when stimulated by papain or house dust mites (HDM) and induce eosinophilic inflammation. This innate response is dependent on IL-33 but not T cell antigen receptors (TCRs). While type 2 innate lymphoid cells (ILC2s) are the dominant innate producers of IL-13 in naïve animals, we show here that in helminth-infected mice, TH2 cell numbers increased and became major mediators of innate type II responses. TH2 cells made important contributions to HDM-induced antigen–non-specific eosinophilic inflammation and protected mice recovering from Ascaris suum infection against subsequent infection with the phylogenetically distant nematode Nippostrongylus brasiliensis. Our findings reveal a previously unappreciated role of effector TH2 cells during TCR-independent innate-like immune responses. PMID:26322482

  4. Generation of rat Th2-like cells in vitro is interleukin-4-dependent and inhibited by interferon-gamma.

    PubMed Central

    Noble, A; Staynov, D Z; Kemeny, D M

    1993-01-01

    Differentiation of naive T cells into effector cells producing T helper type 1 (Th1) and Th2 cytokines is regulated by the presence of specific cytokines in the T-cell microenvironment. The effect of interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) on Th1- and Th2-like cell development was investigated in cultures of mixed rat spleen cells. These cells were cultured for 4 days in medium containing concanavalin A (Con A) with or without additional IL-2, IFN-gamma or IL-4. The cells were then washed and their capacity to produce IL-4, IL-5 and IFN-gamma determined following stimulation with phorbol 12-myristate 13-acetate (PMA) and ionomycin. Freshly isolated cells stimulated with PMA and ionomycin expressed detectable levels of IL-4 and IL-5 mRNA as measured by a quantitative polymerase chain reaction (PCR) procedure and much higher levels of IFN-gamma mRNA. Cells cultured with Con A for 4 days, washed, and restimulated with PMA + ionomycin were unable to express detectable levels of IL-4 and IL-5 mRNA, but produced high levels of IFN-gamma mRNA. Addition of IL-4, or anti-IFN-gamma antibody, to Con A-driven splenocyte cultures restored the ability of restimulated cells to express IL-4 and IL-5. CD4+ T cells isolated from these cultures also showed an increased capacity to secrete IL-4 and IL-5 when anti-IFN-gamma and IL-4 were present in the culture medium. When cultured for 4 days with Con-A, IL-4 and anti-IFN-gamma splenocytes showed an increased capacity to proliferate in response to recombinant IL-2 and proliferated in response to IL-4 alone. IL-2 had no effect on cytokine production by cultured splenocytes. These results indicate that: (1) IL-4 is essential for the generation of Th2-like cells; (2) IFN-gamma inhibits IL-4 production by mixed spleen cells and suppresses generation of IL-4 responsive T cells; (3) in mixed spleen cell cultures mitogenic stimulation favours differentiation of naive rat T cells into effector cells expressing a Th1, and not Th2

  5. The Pseudomonas aeruginosa Mannose Sensitive Hamemagglutination Strain (PA-MSHA) Induces a Th1-Polarizing Phenotype by Promoting Human Dendritic Cells Maturation.

    PubMed

    Zhang, Yunyan; Wang, Hongtao; Li, Youqiang; Chen, Ke; Ye, Jinmei; Liao, Xin; Chen, Yiyang; Ran, Wei

    2014-06-01

    Pseudomonas aeruginosa mannose sensitive hamemagglutination strain (PA-MSHA) is a kind of peritrichous P. aeruginosa strain with MSHA fimbriae and has been shown to activate kinds of immunocytes. Dendritic cells (DCs) are specialized antigen-presenting cells required for the stimulating and priming CD4(+) T cells toward the T helper cell type 1 (Th1), Th2 and other different phenotypes. PA-MSHA effecting on Th1 remains an important missing link. Here we demonstrated that PA-MSHA augmented monocytes derived-dendritic cells (Mo-DCs) expression of HLA-DR, co-stimulatory and adhesion molecules, and induced Th1-promoting interleukin-12 and tumor necrosis factor α secretion, in addition, PA-MSHA treated Mo-DCs displayed lesser endocytic capacity. Furthermore, in mixed lymphocyte reactions, allostimulatory capacity of Mo-DCs was enhanced by PA-MSHA, CD4(+) T cells stimulated by PA-MSHA -activated Mo-DCs showed a Th1-polarized cytokine production, increasing secretion of IFN-γ and decreasing secretion of IL-10 and IL-4. Our findings identified PA-MSHA as an important exogenous factor that induced DCs maturation toward a Th1-promoting phenotype. PMID:25320417

  6. Construction, purification, and characterization of a chimeric TH1 antagonist

    PubMed Central

    Bello-Rivero, Iraldo; Torrez-Ruiz, Yeny; Blanco-Garcés, Elizabeth; Pentón-Rol, Giselle; Fernández-Batista, Osmani; Javier-González, Luís; Gerónimo-Perez, Haydee; López-Saura, Pedro

    2006-01-01

    Background TH1 immune response antagonism is a desirable approach to mitigate some autoimmune and inflammatory reactions during the course of several diseases where IL-2 and IFN-γ are two central players. Therefore, the neutralization of both cytokines could provide beneficial effects in patients suffering from autoimmune or inflammatory illnesses. Results A chimeric antagonist that can antagonize the action of TH1 immunity mediators, IFN-γ and IL-2, was designed, engineered, expressed in E. coli, purified and evaluated for its in vitro biological activities. The TH1 antagonist molecule consists of the extracellular region for the human IFNγ receptor chain 1 fused by a four-aminoacid linker peptide to human 60 N-terminal aminoacid residues of IL-2. The corresponding gene fragments were isolated by RT-PCR and cloned in the pTPV-1 vector. E. coli (W3110 strain) was transformed with this vector. The chimeric protein was expressed at high level as inclusion bodies. The protein was partially purified by pelleting and washing. It was then solubilized with strong denaturant and finally refolded by gel filtration. In vitro biological activity of chimera was demonstrated by inhibition of IFN-γ-dependent HLA-DR expression in Colo 205 cells, inhibition of IFN-γ antiproliferative effect on HEp-2 cells, and by a bidirectional effect in assays for IL-2 T-cell dependent proliferation: agonism in the absence versus inhibition in the presence of IL-2. Conclusion TH1 antagonist is a chimeric protein that inhibits the in vitro biological activities of human IFN-γ, and is a partial agonist/antagonist of human IL-2. With these attributes, the chimera has the potential to offer a new opportunity for the treatment of autoimmune and inflammatory diseases. PMID:16716222

  7. Compensation Low-Frequency Errors in TH-1 Satellite

    NASA Astrophysics Data System (ADS)

    Wang, Jianrong; Wang, Renxiang; Hu, Xin

    2016-06-01

    The topographic mapping products at 1:50,000 scale can be realized using satellite photogrammetry without ground control points (GCPs), which requires the high accuracy of exterior orientation elements. Usually, the attitudes of exterior orientation elements are obtained from the attitude determination system on the satellite. Based on the theoretical analysis and practice, the attitude determination system exists not only the high-frequency errors, but also the low-frequency errors related to the latitude of satellite orbit and the time. The low-frequency errors would affect the location accuracy without GCPs, especially to the horizontal accuracy. In SPOT5 satellite, the latitudinal model was proposed to correct attitudes using approximately 20 calibration sites data, and the location accuracy was improved. The low-frequency errors are also found in Tian Hui 1 (TH-1) satellite. Then, the method of compensation low-frequency errors is proposed in ground image processing of TH-1, which can detect and compensate the low-frequency errors automatically without using GCPs. This paper deal with the low-frequency errors in TH-1: First, the analysis about low-frequency errors of the attitude determination system is performed. Second, the compensation models are proposed in bundle adjustment. Finally, the verification is tested using data of TH-1. The testing results show: the low-frequency errors of attitude determination system can be compensated during bundle adjustment, which can improve the location accuracy without GCPs and has played an important role in the consistency of global location accuracy.

  8. Cockroach allergen Bla g 7 promotes TIM4 expression in dendritic cells leading to Th2 polarization.

    PubMed

    Xu, Lingxiao; Zhang, Miaojia; Ma, Wenjing; Jin, Shanshan; Song, Weijuan; He, Shaoheng

    2013-01-01

    As one of the most common sources of indoor aeroallergens worldwide, cockroach is important in causing rhinitis and asthma while the mechanisms underlying remain obscure. Since T helper (Th) type 2 polarization plays an important role in the pathogenesis of allergic diseases, we investigated the effect of Bla g 7, a pan-allergen from Blattella germanica (B. germanica), on Th polarization which is controlled by monocyte-derived dendritic cells (DCs). Challenged by recombinant Bla g 7 (rBla g 7), immature DCs obtained from human exhibited upregulated levels of TIM4, CD80, and CD86 and increased IL-13 secretion. Cocultured with CD4+ T cells, challenged DCs increased the ratio of IL-4+ versus IFN-γ+ of CD4+ T cells, suggesting a balance shift from Th1 to Th2. Moreover, antibodies against TIM4, CD80, and CD86 reversed the enhancement of IL-4+/IFN-γ+ ratio and alleviated the IL-13 release induced by rBla g 7, indicating that the Th2 polarization provoked by rBla g 7 challenged DCs is via TIM4-, CD80-, and CD86-dependent mechanisms. In conclusion, the present findings implied a crucial role of Bla g 7 in the development of cockroach allergy and highlighted an involvement of DCs-induced Th2 polarization in cockroach allergy. PMID:24204099

  9. Type 3 muscarinic receptors contribute to intestinal mucosal homeostasis and clearance of Nippostrongylus brasiliensis through induction of TH2 cytokines.

    PubMed

    McLean, Leon P; Smith, Allen; Cheung, Lumei; Urban, Joseph F; Sun, Rex; Grinchuk, Viktoriya; Desai, Neemesh; Zhao, Aiping; Raufman, Jean-Pierre; Shea-Donohue, Terez

    2016-07-01

    Despite increased appreciation for the role of nicotinic receptors in the modulation of and response to inflammation, the contribution of muscarinic receptors to mucosal homeostasis, clearance of enteric pathogens, and modulation of immune cell function remains relatively undefined. Uninfected and Nippostrongylus brasiliensis-infected wild-type and type 3 muscarinic receptor (M3R)-deficient (Chrm3(-/-)) mice were studied to determine the contribution of M3R to mucosal homeostasis as well as host defense against the TH2-eliciting enteric nematode N. brasiliensis Intestinal permeability and expression of TH1/TH17 cytokines were increased in uninfected Chrm3(-/-) small intestine. Notably, in Chrm3(-/-) mice infected with N. brasiliensis, small intestinal upregulation of TH2 cytokines was attenuated and nematode clearance was delayed. In Chrm3(-/-) mice, TH2-dependent changes in small intestinal function including smooth muscle hypercontractility, increased epithelial permeability, decreased epithelial secretion and absorption, and goblet cell expansion were absent despite N. brasiliensis infection. These findings identify an important role for M3R in host defense and clearance of N. brasiliensis, and support the expanding role of cholinergic muscarinic receptors in maintaining mucosal homeostasis. PMID:27173511

  10. Mode of dendritic cell activation: the decisive hand in Th2/Th17 cell differentiation. Implications in asthma severity?

    PubMed

    Vroman, Heleen; van den Blink, Bernt; Kool, Mirjam

    2015-02-01

    Asthma is a heterogeneous chronic inflammatory disease of the airways, with reversible airflow limitations and airway remodeling. The classification of asthma phenotypes was initially based on different combinations of clinical symptoms, but they are now unfolding to link biology to phenotype. As such, patients can suffer from a predominant eosinophilic, neutrophilic or even mixed eosinophilic/neutrophilic inflammatory response. In adult asthma patients, eosinophilic inflammation is usually seen in mild-to-moderate disease and neutrophilic inflammation in more severe disease. The underlying T cell response is predominated by T helper (Th) 2, Th17, or a mixed Th2/Th17 cell immune response. Dendritic cells (DCs) are "professional" antigen presenting cells (APCs), since their principal function is to present antigens and induce a primary immune response in resting naive T cells. DCs also drive the differentiation into distinctive Th subsets. The expression of co-stimulatory molecules and cytokines by DCs and surrounding cells determines the outcome of Th cell differentiation. The nature of DC activation will determine the expression of specific co-stimulatory molecules and cytokines, specifically needed for induction of the different Th cell programs. Thus DC activation is crucial for the subsequent effector Th immune responses. In this review, we will discuss underlying mechanisms that initiate DC activation in favor of Th2 differentiation versus Th1/Th17 and Th17 differentiation in the development of mild versus moderate to severe asthma. PMID:25245013

  11. Galectin-1 suppresses autoimmune retinal disease by promoting concomitant Th2- and T regulatory-mediated anti-inflammatory responses.

    PubMed

    Toscano, Marta A; Commodaro, Alessandra G; Ilarregui, Juan M; Bianco, Germán A; Liberman, Ana; Serra, Horacio M; Hirabayashi, Jun; Rizzo, Luiz V; Rabinovich, Gabriel A

    2006-05-15

    Intraocular inflammatory diseases are a common cause of severe visual impairment and blindness. In this study, we investigated the immunoregulatory role of galectin-1 (Gal-1), an endogenous lectin found at sites of T cell activation and immune privilege, in experimental autoimmune uveitis (EAU), a Th1-mediated model of retinal disease. Treatment with rGal-1 either early or late during the course of interphotoreceptor retinoid-binding protein-induced EAU was sufficient to suppress ocular pathology, inhibit leukocyte infiltration, and counteract pathogenic Th1 cells. Administration of rGal-1 at the early or late phases of EAU ameliorated disease by skewing the uveitogenic response toward nonpathogenic Th2 or T regulatory-mediated anti-inflammatory responses. Consistently, adoptive transfer of CD4(+) regulatory T cells obtained from rGal-1-treated mice prevented the development of active EAU in syngeneic recipients. In addition, increased levels of apoptosis were detected in lymph nodes from mice treated with rGal-1 during the efferent phase of the disease. Our results underscore the ability of Gal-1 to counteract Th1-mediated responses through different, but potentially overlapping anti-inflammatory mechanisms and suggest a possible therapeutic use of this protein for the treatment of human uveitic diseases of autoimmune etiology. PMID:16670344

  12. Airway epithelial cells activate Th2 cytokine production in mast cells via IL-1 and thymic stromal lymphopoietin

    PubMed Central

    Nagarkar, Deepti R.; Poposki, Julie A.; Comeau, Michael R.; Biyasheva, Assel; Avila, Pedro C.; Schleimer, Robert P.; Kato, Atsushi

    2012-01-01

    Background Airway epithelial cells are important regulators of innate and adaptive immunity. Although mast cells are known to play a central role in manifestations of allergic inflammation and are found in the epithelium in Th2-related diseases, their role is incompletely understood. Objectives The objective of this study was to investigate the role of airway epithelial cells in production of Th2 cytokines in mast cells. Methods Normal human bronchial epithelial cells (NHBE) were stimulated with TNF, IL-4, IFN-γ, IL -17A and dsRNA alone or in combination. Human mast cells were stimulated with epithelial cell-derived supernatants, or co-cultured with NHBE. Th2 cytokine responses were blocked with neutralizing antibodies. Results Supernatants from IL-4 and dsRNA stimulated NHBE significantly enhanced Th2 cytokine production from mast cells. The combination of IL-4 and dsRNA itself or supernatants from NHBE stimulated with other cytokines did not activate mast cells, suggesting that mast cell responses were induced by epithelial cell factors that were only induced by IL-4 and dsRNA. Epithelial supernatant-dependent Th2 cytokine production in mast cells was suppressed by anti-IL-1 and anti-TSLP, and was enhanced by anti-IL-1Ra. Similar results were observed in co-culture experiments. Finally, we found dsRNA-dependent production of IL-1, TSLP, and IL-1Ra in NHBE was regulated by Th cytokines, and their ratio in NHBE correlated with Th2 cytokine production in mast cells. Conclusions Pathogens producing dsRNA, such as respiratory viral infections, may amplify local Th2 inflammation in asthmatics via the production of TSLP and IL-1 by epithelial cells and subsequent activation of Th2 cytokine production by mast cells in the airways. PMID:22633328

  13. Amphiregulin-a Th2 cytokine enhancing resistance to nematodes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Intestinal nematode infections remain a major health threat to humans despite improved sanitation. Protection is mainly mediated by Type 2-biased immune responses, characterized by Th2 lymphocytes and other cells secreting a set of cytokines including Interleukin 4 (IL-4), IL-5, IL-10, and IL-13. I...

  14. Innate immunological function of TH2 cells in vivo

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Th2 cells produce IL-13 when stimulated by papain or house dust mites (HDM) and induce eosinophilic inflammation. This innate response of cells of the adaptive immune system is dependent on IL-33-, not T cell receptor-, based stimulation. While type 2 innate lymphoid cells (ILC2s) are the dominant ...

  15. Airway Surface Mycosis in Chronic Th2-Associated Airway Disease

    PubMed Central

    Porter, Paul; Lim, Dae Jun; Maskatia, Zahida Khan; Mak, Garbo; Tsai, Chu-Lin; Citardi, Martin J; Fakhri, Samer; Shaw, Joanne L.; Fothergil, Annette; Kheradmand, Farrah; Corry, David B; Luong, Amber

    2014-01-01

    Background Environmental fungi have been linked to T helper type 2 (Th2) cell-related airway inflammation and the Th2-associated chronic airway diseases asthma, chronic rhinosinusitis with nasal polyps (CRSwNP) and allergic fungal rhinosinusitis (AFRS), but whether these organisms participate directly or indirectly in disease pathology remains unknown. Objective To determine the frequency of fungus isolation and fungus-specific immunity in Th2-associated and non-associated airway disease patients. Methods Sinus lavage fluid and blood were collected from sinus surgery patients (n=118) including CRS patients with and without nasal polyps and AFRS and non-CRS/non-asthmatic control patients. Asthma status was deteremined from medical history. Sinus lavage fluids were cultured and directly examined for evidence of viable fungi. Peripheral blood mononuclear cells were restimulated with fungal antigens in an enzyme linked immunocell spot (ELISpot) assay to determine total memory fungus-specific IL-4-secreting cells. These data were compared to fungus-specific IgE levels measured from plasma by ELISA. Results Filamentous fungi were significantly more commonly cultured from Th2-associated airway disease subjects (asthma, CRSwNP, or AFRS: n=68) compared to non-Th2-associated control patients (n=31); 74% vs 16% respectively, p<0.001. Both fungus-specific IL-4 ELISpot (n=48) and specific IgE (n=70) data correlated with Th2-associated diseases (sensitivity 73% and specificity 100% vs. 50% and 77%, respectively). Conclusions The frequent isolation of fungi growing directly within the airways accompanied by specific immunity to these organisms only in patients with Th2-associated chronic airway diseases suggests that fungi participate directly in the pathogenesis of these conditions. Efforts to eradicate airway fungi from the airways should be considered in selected patients. Clinical Implications Airway fungi may contribute to the expression of sinusitis with nasal polyps and

  16. Berberine ameliorates TNBS induced colitis by inhibiting inflammatory responses and Th1/Th17 differentiation.

    PubMed

    Li, Chengzhen; Xi, Yebin; Li, Shan; Zhao, Qing; Cheng, Wenjing; Wang, Zhengting; Zhong, Jie; Niu, Xiaoyin; Chen, Guangjie

    2015-10-01

    Th1 and Th17 cells, and their associated cytokines, have been associated with the pathogenesis of Crohn's disease. Berberine (BBR), a compound long used in traditional Chinese medicines, has been reported to have therapeutic effects in treating experimental colitis. In this study, we show that BBR had a protective effect on mice with TNBS-induced colitis. BBR inhibited levels of IFN-γ, IL-17, IL-6, IL-1β and TNF-α both in the local colon and sera, and transiently increased levels of IL-22. BBR also markedly increased sIgA expression in the colon. BBR had pronounced effects on macrophage populations. Treatment with BBR adjusted the M2/M1 ratio. In addition, BBR exerted effects on adaptive immunity by suppressing numbers of Th1 and Th17 cells, as well as expression levels of their associated cytokines and transcriptional factors. BBR downregulated STAT3 and STAT1 phosphorylation, and inhibited phosphorylation of NF-kB. In vitro experiments showed that BBR inhibited the differentiation of Th17 and, to a lesser degree, Th1 cells, without affecting regulatory T cells. Therefore, we conclude that BBR plays a regulatory role in modulating the balance of immune responses in TNBS-induced colitis. Our study will help us understand the regulatory mechanisms exerted by BBR in the treatment of IBD. PMID:26224047

  17. Looking beyond the induction of Th2 responses to explain immunomodulation by helminths

    PubMed Central

    Nutman, Thomas B.

    2015-01-01

    Although helminth infections are characteristically associated with Th2-mediated responses that include the production of the prototypical cytokines IL-4, IL-5, and IL-13 by CD4+ cells, the production of IgE, peripheral blood eosinophilia and mucus production in localized sites, these responses are largely attenuated when helminth infections become less acute. This modulation of the immune response that occurs with chronic helminth infection is often induced by molecules secreted by helminth parasites, by non-Th2 regulatory CD4+ cells, and by non-classical B cells, macrophages and dendritic cells. This review will focus on those parasite- and host-mediated mechanisms underlying the modulated T cell response that occurs as the default in chronic helminth infections. PMID:25869527

  18. Relative Contribution of Th1 and Th17 Cells in Adaptive Immunity to Bordetella pertussis: Towards the Rational Design of an Improved Acellular Pertussis Vaccine

    PubMed Central

    Ross, Pádraig J.; Allen, Aideen C.; Walsh, Kevin; Misiak, Alicja; Lavelle, Ed C.; McLoughlin, Rachel M.; Mills, Kingston H. G.

    2013-01-01

    Whooping cough caused by Bordetella pertussis is a re-emerging infectious disease despite the introduction of safer acellular pertussis vaccines (Pa). One explanation for this is that Pa are less protective than the more reactogenic whole cell pertussis vaccines (Pw) that they replaced. Although Pa induce potent antibody responses, and protection has been found to be associated with high concentrations of circulating IgG against vaccine antigens, it has not been firmly established that host protection induced with this vaccine is mediated solely by humoral immunity. The aim of this study was to examine the relative contribution of Th1 and Th17 cells in host immunity to infection with B. pertussis and in immunity induced by immunization with Pw and Pa and to use this information to help rationally design a more effective Pa. Our findings demonstrate that Th1 and Th17 both function in protective immunity induced by infection with B. pertussis or immunization with Pw. In contrast, a current licensed Pa, administered with alum as the adjuvant, induced Th2 and Th17 cells, but weak Th1 responses. We found that IL-1 signalling played a central role in protective immunity induced with alum-adsorbed Pa and this was associated with the induction of Th17 cells. Pa generated strong antibody and Th2 responses, but was fully protective in IL-4-defective mice, suggesting that Th2 cells were dispensable. In contrast, Pa failed to confer protective immunity in IL-17A-defective mice. Bacterial clearance mediated by Pa-induced Th17 cells was associated with cell recruitment to the lungs after challenge. Finally, protective immunity induced by an experimental Pa could be enhanced by substituting alum with a TLR agonist that induces Th1 cells. Our findings demonstrate that alum promotes protective immunity through IL-1β-induced IL-17A production, but also reveal that optimum protection against B. pertussis requires induction of Th1, but not Th2 cells. PMID:23592988

  19. Chondroitin nanocapsules enhanced doxorubicin induced apoptosis against leishmaniasis via Th1 immune response.

    PubMed

    Chaurasia, Mohini; Pawar, Vivek K; Jaiswal, Anil K; Dube, Anuradha; Paliwal, Sarvesh K; Chourasia, Manish K

    2015-08-01

    Current leishmaniasis treatment is strangled due to concealed residence of parasite and reduced host cell mediated immune response. To circumvent above challenges, novel macrophage targeted oily core polymeric shell based doxorubicin (DOX) loaded nanocapsules (NCAPs) were fabricated employing chondroitin sulphate (CHD) for complimentary immunotherapy coupled chemotherapy against leishmaniasis. Excellent encapsulation efficiency along with pH dependent drug release was demonstrated by NCAPs. Improved cell cycle arrest at G1-S phase (1.56 folds) and apoptosis against promastigotes (6.26 folds), support the remarkable in-vitro antileishmanial activity of NCAPs (IC50: 0.254±0.038 μg/ml) compared to free DOX (IC50: 0.543±0.012 μg/ml). In-vivo antileishmanial activity in hamsters represented a significantly enhanced parasitic inhibition by NCAPs (1.42 folds). Improved activity was mediated via immunotherapeutic activity of NCAPs which up-regulated Th1 immune response (IL-12, INF-γ, and TNF-α) and down-regulated Th2 immune response (IL-4, IL-10, and TGF-β). In conclusion, current novel nano-formulation could be a viable option against leishmaniasis. PMID:25931395

  20. Neutrophils Exert a Suppressive Effect on Th1 Responses to Intracellular Pathogen Brucella abortus

    PubMed Central

    Ordoñez-Rueda, Diana; Arce-Gorvel, Vilma; Alfaro-Alarcón, Alejandro; Lepidi, Hubert; Malissen, Bernard; Malissen, Marie; Gorvel, Jean-Pierre; Moreno, Edgardo

    2013-01-01

    Polymorphonuclear neutrophils (PMNs) are the first line of defense against microbial pathogens. In addition to their role in innate immunity, PMNs may also regulate events related to adaptive immunity. To investigate the influence of PMNs in the immune response during chronic bacterial infections, we explored the course of brucellosis in antibody PMN-depleted C57BL/6 mice and in neutropenic mutant Genista mouse model. We demonstrate that at later times of infection, Brucella abortus is killed more efficiently in the absence of PMNs than in their presence. The higher bacterial removal was concomitant to the: i) comparatively reduced spleen swelling; ii) augmented infiltration of epithelioid histiocytes corresponding to macrophages/dendritic cells (DCs); iii) higher recruitment of monocytes and monocyte/DCs phenotype; iv) significant activation of B and T lymphocytes, and v) increased levels of INF-γ and negligible levels of IL4 indicating a balance of Th1 over Th2 response. These results reveal that PMNs have an unexpected influence in dampening the immune response against intracellular Brucella infection and strengthen the notion that PMNs actively participate in regulatory circuits shaping both innate and adaptive immunity. PMID:23458832

  1. Neutrophils exert a suppressive effect on Th1 responses to intracellular pathogen Brucella abortus.

    PubMed

    Barquero-Calvo, Elías; Martirosyan, Anna; Ordoñez-Rueda, Diana; Arce-Gorvel, Vilma; Alfaro-Alarcón, Alejandro; Lepidi, Hubert; Malissen, Bernard; Malissen, Marie; Gorvel, Jean-Pierre; Moreno, Edgardo

    2013-02-01

    Polymorphonuclear neutrophils (PMNs) are the first line of defense against microbial pathogens. In addition to their role in innate immunity, PMNs may also regulate events related to adaptive immunity. To investigate the influence of PMNs in the immune response during chronic bacterial infections, we explored the course of brucellosis in antibody PMN-depleted C57BL/6 mice and in neutropenic mutant Genista mouse model. We demonstrate that at later times of infection, Brucella abortus is killed more efficiently in the absence of PMNs than in their presence. The higher bacterial removal was concomitant to the: i) comparatively reduced spleen swelling; ii) augmented infiltration of epithelioid histiocytes corresponding to macrophages/dendritic cells (DCs); iii) higher recruitment of monocytes and monocyte/DCs phenotype; iv) significant activation of B and T lymphocytes, and v) increased levels of INF-γ and negligible levels of IL4 indicating a balance of Th1 over Th2 response. These results reveal that PMNs have an unexpected influence in dampening the immune response against intracellular Brucella infection and strengthen the notion that PMNs actively participate in regulatory circuits shaping both innate and adaptive immunity. PMID:23458832

  2. TH1-Dominant Granulomatous Pathology Does Not Inhibit Fibrosis or Cause Lethality during Murine Schistosomiasis

    PubMed Central

    Leeto, Mosiuoa; Herbert, De’Broski R.; Marillier, Reece; Schwegmann, Anita; Fick, Lizette; Brombacher, Frank

    2006-01-01

    Schistosoma mansoni egg-induced inflammation is accompanied by TH2 cell polarization and development of fibrotic granulomas in host tissue. The interleukin (IL)-4 receptor α (IL-4Rα), which mediates IL-4 and IL-13 signaling, is essential for granulomatous pathology through a putative CD4+ T-cell-dependent mechanism. In this study, we asked whether CD4+ T-cell-specific IL-4Rα-deficient mice (LckCreIL-4Rα−/lox) developed granulomas and egg-driven collagen production. Although eosinophilia and goblet cell hyperplasia were impaired in LckCreIL-4Rα−/lox mice, there was no reduction in size or collagen content of lung and liver granulomas. The lack of CD4+ T-cell IL-4Rα expression caused significant increases in interferon-γ-producing cells, inducible nitric-oxide synthetase production, and hepatic damage, compared with similarly infected wild-type mice. Interestingly, this TH1-associated liver injury did not lead to premature mortality in this strain. Instead, lower levels of serum endotoxin in LckCreIL-4Rα−/lox mice suggest that intestinal barrier function may be the dominant factor for survival during natural infection. PMID:17071593

  3. Overexpression of Methyl-CpG Binding Protein 2 Impairs TH1 Responses

    PubMed Central

    Yang, Tianshu; Ramocki, Melissa B.; Neul, Jeffrey L.; Lu, Wen; Roberts, Luz; Knight, John; Ward, Christopher S.; Zoghbi, Huda Y.; Kheradmand, Farrah; Corry, David B.

    2013-01-01

    The DNA binding protein methyl-CpG binding protein 2 (MeCP2) critically influences neuronal and brain function by modulating gene expression, and children with overexpression of the MECP2 gene exhibit postnatal neurological syndromes. We demonstrate that some children with MECP2 duplication also display variable immunological abnormalities that include reductions in memory T and B cells and natural killer cells and immunoglobulin assay responses. Moreover, whereas mice with MeCP2 overexpression were unable to control infection with the intra-macrophage parasite Leishmania major and secrete interferon-γ (IFN-γ) from involved lymph nodes, they were able to control airway fungal infection by Aspergillus niger and mount protective T helper cell type 2 (TH2)–dependent allergic responses. Relative to normal T cells, TH cells from children and mice with MECP2 duplication displayed similar impairments in IFN-γ secretion and TH1 responses that were due to both MeCP2-dependent suppression of IFN-γ transcription and sequestration of the IFN-γ locus as assessed by chromatin immunoprecipitation assay. Thus, overexpressed MeCP2 aberrantly suppresses IFN-γ secretion from TH cells, potentially leading to a partially immunodeficient state. Our findings establish a rational basis for identifying, treating, and preventing infectious complications potentially affecting children with MECP2 duplication. PMID:23220634

  4. Hyaluronan synthesis is necessary for autoreactive T-cell trafficking, activation, and Th1 polarization

    PubMed Central

    Kuipers, Hedwich F.; Rieck, Mary; Gurevich, Irina; Nagy, Nadine; Negrin, Robert S.; Wight, Thomas N.; Steinman, Lawrence; Bollyky, Paul L.

    2016-01-01

    The extracellular matrix polysaccharide hyaluronan (HA) accumulates at sites of autoimmune inflammation, including white matter lesions in multiple sclerosis (MS), but its functional importance in pathogenesis is unclear. We have evaluated the impact of 4-methylumbelliferone (4-MU), an oral inhibitor of HA synthesis, on disease progression in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Treatment with 4-MU decreases the incidence of EAE, delays its onset, and reduces the severity of established disease. 4-MU inhibits the activation of autoreactive T cells and prevents their polarization toward a Th1 phenotype. Instead, 4-MU promotes polarization toward a Th2 phenotpye and induction of Foxp3+ regulatory T cells. Further, 4-MU hastens trafficking of T cells through secondary lymphoid organs, impairs the infiltration of T cells into the CNS parenchyma, and limits astrogliosis. Together, these data suggest that HA synthesis is necessary for disease progression in EAE and that treatment with 4-MU may be a potential therapeutic strategy in CNS autoimmunity. Considering that 4-MU is already a therapeutic, called hymecromone, that is approved to treat biliary spasm in humans, we propose that it could be repurposed to treat MS. PMID:26787861

  5. Profound tumor-specific Th2 bias in patients with malignant glioma

    PubMed Central

    2012-01-01

    Background Vaccination against tumor-associated antigens is one promising approach to immunotherapy against malignant gliomas. While previous vaccine efforts have focused exclusively on HLA class I-restricted peptides, class II-restricted peptides are necessary to induce CD4+ helper T cells and sustain effective anti-tumor immunity. In this report we investigated the ability of five candidate peptide epitopes derived from glioma-associated antigens MAGE and IL-13 receptor α2 to detect and characterize CD4+ helper T cell responses in the peripheral blood of patients with malignant gliomas. Methods Primary T cell responses were determined by stimulating freshly isolated PBMCs from patients with primary glioblastoma (GBM) (n = 8), recurrent GBM (n = 5), meningioma (n = 7), and healthy controls (n = 6) with each candidate peptide, as well as anti-CD3 monoclonal antibody (mAb) and an immunodominant peptide epitope derived from myelin basic protein (MBP) serving as positive and negative controls, respectively. ELISA was used to measure IFN-γ and IL-5 levels, and the ratio of IFN-γ/IL-5 was used to determine whether the response had a predominant Th1 or Th2 bias. Results We demonstrate that novel HLA Class-II restricted MAGE-A3 and IL-13Rα2 peptides can detect T cell responses in patients with GBMs as well as in healthy subjects. Stimulation with a variety of peptide antigens over-expressed by gliomas is associated with a profound reduction in the IFN-γ/IL-5 ratio in GBM patients relative to healthy subjects. This bias is more pronounced in patients with recurrent GBMs. Conclusions Therapeutic vaccine strategies to shift tumor antigen-specific T cell response to a more immunostimulatory Th1 bias may be needed for immunotherapeutic trials to be more successful clinically. PMID:23186108

  6. Oral administration of poly-γ-glutamate ameliorates atopic dermatitis in Nc/Nga mice by suppressing Th2-biased immune response and production of IL-17A.

    PubMed

    Lee, Tae-Young; Kim, Doo-Jin; Won, Ji-Na; Lee, Il-Han; Sung, Moon-Hee; Poo, Haryoung

    2014-03-01

    Atopic dermatitis (AD) is a chronic inflammatory skin disease that is closely related to dysregulation of the T helper type 1 and 2 (Th1)/Th2 balance. A previous study showed that high molecular mass poly-γ-glutamate (γ-PGA) isolated from Bacillus subtilis sp. Chungkookjang induces the production of IL-12 from dendritic cells (DCs). Here, we investigated the effect of γ-PGA on AD-like skin disease using an Nc/Nga mouse model. In vitro, γ-PGA activated DCs and induced IL-12 production in mice. In vivo, oral administration of γ-PGA markedly reduced the AD symptoms, similar to the response seen in the dexamethasone (Dex)-treated group. Treatment with γ-PGA also decreased the serum levels of IgG1, the skin levels of Th2 cytokines, the extent of skin inflammation, and the accumulation of mast cells. Furthermore, γ-PGA was effective against established AD, significantly decreasing serum IgE and Th2 cytokines in the inflamed tissue. Interestingly, the production of IL-17A in splenocytes was also suppressed by γ-PGA, indicating that it inhibits both Th2 and Th17 immune responses. Collectively, these results suggest that oral administration of γ-PGA could be a therapeutic strategy for treating AD via the modulation of Th2-biased immune responses in an Nc/Nga mouse model. PMID:24025551

  7. House Dust Mite-Derived Chitin Enhances Th2 Cell Response to Inhaled Allergens, Mainly via a TNF-α-Dependent Pathway

    PubMed Central

    Choi, Jun-Pyo; Lee, Sang-Min; Choi, Hyun-Il; Kim, Min-Hye; Jeon, Seong Gyu; Jang, Myoung Ho; Jee, Young-Koo; Yang, Sanghwa; Cho, Young-Joo

    2016-01-01

    Purpose Chitin is a potent adjuvant in the development of immune response to inhaled allergens in the airways. According to other studies, chitin is known as multi-faced adjuvants which can induce Th2 responses. Recently, we found that TNF-α is a key mediator in the development of Th2 cell response to inhaled allergens. Here, we evaluated the immunologic mechanisms in the development of airway hypersensitivity to inhaled allergens, enhanced by house dust mite (HDM)-derived chitin. Methods The role of TNF-α and TLRs was evaluated in an airway hypersensitivity mouse model induced by a sensitization with an allergen (ovalbumin, OVA) and HDM-derived chitin using mice with the null mutation of target genes. Results The present study showed that airway sensitization with HDM-derived chitin plus OVA enhanced OVA-induced airway inflammation v. OVA alone. This phenotype was associated with the increased expression of Th1, Th2, and Th17 cytokines and also with the enhanced production of OVA-specific IgE, IgG1, and IgG2a. As for T cell responses, OVA-specific Th2 cell response, enhanced by chitin, was abolished by the treatment of chitinase, whereas Th1 and Th17 cell responses enhanced by this treatment. Moreover, the null mutation of the TNF-α gene revealed similar effects as the chitinase treatment. In contrast, all the OVA-specific T cell responses, enhanced by chitin, were blocked by the absence of TLR2, but not of TLR1, TLR4, or TLR6. Conclusions In conclusion, these data suggest that HDM-derived chitin may enhance airway hypersensitivity to inhaled allergens, via the TLR2-dependent pathway, and that chitin-induced TNF-α can be a key mediator in the development of Th2 cell response to inhaled allergens. PMID:27126730

  8. 27-Hydroxycholesterol and 7alpha-hydroxycholesterol trigger a sequence of events leading to migration of CCR5-expressing Th1 lymphocytes

    SciTech Connect

    Kim, Sun-Mi; Kim, Bo-Young; Lee, Sae-A; Eo, Seong-Kug; Yun, Yungdae; Kim, Chi-Dae; Kim, Koanhoi

    2014-02-01

    Th1 lymphocyte recruitment in a cholesterol-rich milieu. We propose a model via which 27OHChol and 7αOHChol contribute to the predominance of Th1 cells in atherosclerotic lesions on the basis of our results and previous findings. Cholesterol deposited in the artery undergoes oxidative modification to oxysterols. Exposure of monocytic cells to 27OHChol or 7αOHChol results in increased transcription and secretion of CCR5 ligands, like CCL3 and CCL4, which leads to a concentration gradient of the chemokines. Among the lymphocytes attached to cell adhesion molecules expressed on endothelial cells, Th1 cells that express CCR5 recognize the gradient and follow the signal of increasing chemokine concentration towards the source of the chemokines, whereas other subtypes of T cells that do not express CCR5 (Tregs and Th2 cells) do not respond. The preferential infiltration of Th1 cells leads to predominance of Th1 cells. Since oxidized LDL (oxLDL) enhances the expression of cell adhesion molecules on endothelial cells, existence of oxLDL will accelerate the recruitment of Th1 lymphocytes into atherosclerotic lesions in response to the oxysterols. - Highlights: • High-cholesterol diet induces CCR5L expression, like CCL3 and CCL4, in ApoE{sup −/−} mice. • 27OHChol and 7αOHChol enhance secretion of CCL3 and CCL4 by monocytic cells. • The secreted CCR5 ligands promote migration of CCR5-expressing Th1 cells. • We report a mechanism underlying Th1 cell recruitment into atherosclerotic lesions.

  9. Selective development of T helper (Th)2 cells induced by continuous administration of low dose soluble proteins to normal and beta(2)-microglobulin-deficient BALB/c mice.

    PubMed

    Guery, J C; Galbiati, F; Smiroldo, S; Adorini, L

    1996-02-01

    Continuous administration of soluble proteins, delivered over a 10-d period by a mini-osmotic pump implanted subcutaneously, induces a long-lasting inhibition of antigen-specific T cell proliferation in lymph node cells from BALB/c mice subsequently primed with antigen in adjuvant. The decreased T cell proliferative response is associated with a down-regulation of the T helper cell (Th)1 cytokines interleukin (IL)-2 and interferon (IFN)-gamma and with a strong increase in the secretion of the Th2 cytokines IL-4 and IL-5 by antigen specific CD4+ T cells. This is accompanied by predominant inhibition of antigen-specific antibody production of IgG2a and IgG2b, rather than IgG1 isotype. Interestingly, inhibition of Th1 and priming of Th2 cells is also induced in beta(2) microglobulin-deficient BALB/c mice, indicating that neither CD8+ nor CD4+ NK1.1+ T cells, respectively, are required. The polarization in Th2 cells is stably maintained by T cell lines, all composed of CD4+/CD8- cells expressing T cell receptor for antigen (TCR) alpha/beta chains, derived from BALB/c mice treated with continuous antigen administration, indicating that they originate from Th2 cells fully differentiated in vivo. This polarization is induced in BALB/c mice by continuous administration of any protein antigen tested, including soluble extracts from pathogenic microorganisms. Priming of Th2 cells is dose dependent and it is optimal for low rather than high doses of protein. Blocking endogenous IL-4 in vivo inhibits expansion of antigen-specific Th2 cells, but does not restore IFN-gamma production by T cells from mice treated with soluble antigen-specific Th2 cells, but does not restore IFN-gamma production by T cells from mice treated with soluble antigen, indicating the involvement of two independent mechanisms. Consistent with this, Th2 cell development, but not inhibition of Th1 cells, depends on non-major histocompatibility complex genetic predisposition, since the Th2 response is

  10. Heavy metal mediated innate immune responses of the Indian green frog, Euphlyctis hexadactylus (Anura: Ranidae): Cellular profiles and associated Th1 skewed cytokine response.

    PubMed

    Jayawardena, Uthpala A; Ratnasooriya, Wanigasekara D; Wickramasinghe, Deepthi D; Udagama, Preethi V

    2016-10-01

    Immune cell and cytokine profiles in relation to metal exposure though much studied in mammals has not been adequately investigated in amphibians, due mainly to lack of suitable reagents for cytokine profiling in non-model species. However, interspecies cross reactivity of cytokines permitted us to assay levels of IFNγ, TNFα, IL6 and IL10in a common anuran, the Indian green frog (Euphlyctis hexadactylus), exposed to heavy metals (Cd, Cr, Cu, Zn and Pb, at ~5ppm each) under field and laboratory settings in Sri Lanka. Enumeration of immune cells in blood and melanomacrophages in the liver, assay of serum and hepatic cytokines, and Th1/Th2 cytokine polarisation were investigated. Immune cell counts indicated overall immunosuppression with decreasing total WBC and splenocyte counts while neutrophil/lymphocyte ratio increased with metal exposure, indicating metal mediated stress. Serum IL6 levels of metal exposed frogs reported the highest (~9360pg/mL) of all cytokines tested. Significantly elevated IFNγ production (P<0.05) was evident in heavy metal exposed frogs. Th1/Th2 cytokine ratio in both serum and liver tissue homogenates was Th1 skewed due to significantly higher production of pro-inflammatory cytokines, IFNγ in serum and TNFα in the liver (P<0.01).Metal mediated aggregations of melanomacrophages in the liver were positively and significantly (P<0.05) correlated with the hepatic expression of TNFα, IL6 and IL10 activity. Overall, Th1 skewed response may well be due to oxidative stress mediated nuclear factor κ-light chain enhancer of activated B cells (NFκB) which enhances the transcription of pro-inflammatory cytokines. Xenobiotic stress has recently imposed an unprecedented level of threat to wildlife, particularly to sensitive species such as amphibians. Therefore, understanding the interactions between physiological stress and related immune responses is fundamental to conserve these environmental sentinels in the face of emerging eco

  11. CryJ-LAMP DNA Vaccines for Japanese Red Cedar Allergy Induce Robust Th1-Type Immune Responses in Murine Model

    PubMed Central

    Connolly, Michael; Marketon, Anthony

    2016-01-01

    Allergies caused by Japanese Red Cedar (JRC) pollen affect up to a third of Japanese people, necessitating development of an effective therapeutic. We utilized the lysosomal targeting property of lysosomal-associated membrane protein-1 (LAMP-1) to make DNA vaccines that encode LAMP-1 and the sequences of immunodominant allergen CryJ1 or CryJ2 from the JRC pollen. This novel strategy is designed to skew the CD4 T cell responses to the target allergens towards a nonallergenic Th1 response. CryJ1-LAMP and CryJ2-LAMP were administrated to BALB/c mice and antigen-specific Th1-type IgG2a and Th2-type IgG1 antibodies, as well as IgE antibodies, were assayed longitudinally. We also isolated different T cell populations from immunized mice and adoptively transferred them into naïve mice followed by CryJ1/CryJ2 protein boosts. We demonstrated that CryJ-LAMP immunized mice produce high levels of IFN-γ and anti-CryJ1 or anti-CryJ2 IgG2a antibodies and low levels of IgE antibodies, suggesting that a Th1 response was induced. In addition, we found that CD4+ T cells are the immunological effectors of DNA vaccination in this allergy model. Together, our results suggest the CryJ-LAMP Vaccine has a potential as an effective therapeutic for JRC induced allergy by skewing Th1/Th2 responses. PMID:27239481

  12. CryJ-LAMP DNA Vaccines for Japanese Red Cedar Allergy Induce Robust Th1-Type Immune Responses in Murine Model.

    PubMed

    Su, Yan; Connolly, Michael; Marketon, Anthony; Heiland, Teri

    2016-01-01

    Allergies caused by Japanese Red Cedar (JRC) pollen affect up to a third of Japanese people, necessitating development of an effective therapeutic. We utilized the lysosomal targeting property of lysosomal-associated membrane protein-1 (LAMP-1) to make DNA vaccines that encode LAMP-1 and the sequences of immunodominant allergen CryJ1 or CryJ2 from the JRC pollen. This novel strategy is designed to skew the CD4 T cell responses to the target allergens towards a nonallergenic Th1 response. CryJ1-LAMP and CryJ2-LAMP were administrated to BALB/c mice and antigen-specific Th1-type IgG2a and Th2-type IgG1 antibodies, as well as IgE antibodies, were assayed longitudinally. We also isolated different T cell populations from immunized mice and adoptively transferred them into naïve mice followed by CryJ1/CryJ2 protein boosts. We demonstrated that CryJ-LAMP immunized mice produce high levels of IFN-γ and anti-CryJ1 or anti-CryJ2 IgG2a antibodies and low levels of IgE antibodies, suggesting that a Th1 response was induced. In addition, we found that CD4(+) T cells are the immunological effectors of DNA vaccination in this allergy model. Together, our results suggest the CryJ-LAMP Vaccine has a potential as an effective therapeutic for JRC induced allergy by skewing Th1/Th2 responses. PMID:27239481

  13. Th1-Biased Immunomodulation and Therapeutic Potential of Artemisia annua in Murine Visceral Leishmaniasis

    PubMed Central

    Islamuddin, Mohammad; Chouhan, Garima; Farooque, Abdullah; Dwarakanath, Bilikere S.; Sahal, Dinkar; Afrin, Farhat

    2015-01-01

    Background In the absence of vaccines and limitations of currently available chemotherapy, development of safe and efficacious drugs is urgently needed for visceral leishmaniasis (VL) that is fatal, if left untreated. Earlier we reported in vitro apoptotic antileishmanial activity of n-hexane fractions of Artemisia annua leaves (AAL) and seeds (AAS) against Leishmania donovani. In the present study, we investigated the immunostimulatory and therapeutic efficacy of AAL and AAS. Methodology/Principal Findings Ten-weeks post infection, BALB/c mice were orally administered AAL and AAS for ten consecutive days. Significant reduction in hepatic (86.67% and 89.12%) and splenic (95.45% and 95.84%) parasite burden with decrease in spleen weight was observed. AAL and AAS treated mice induced the strongest DTH response, as well as three-fold decrease in IgG1 and two-fold increase in IgG2a levels, as compared to infected controls. Cytometric bead array further affirmed the elicitation of Th1 immune response as indicated by increased levels of IFN-γ, and low levels of Th2 cytokines (IL-4 and IL-10) in serum as well as in culture supernatant of lymphocytes from treated mice. Lymphoproliferative response, IFN-γ producing CD4+ and CD8+ T lymphocytes and nitrite levels were significantly enhanced upon antigen recall in vitro. The co-expression of CD80 and CD86 on macrophages was significantly augmented. CD8+ T cells exhibited CD62Llow and CD44hi phenotype, signifying induction of immunological memory in AAL and AAS treated groups. Serum enzyme markers were in the normal range indicating inertness against nephro- and hepato-toxicity. Conclusions/Significance Our results establish the two-prong antileishmanial efficacy of AAL and AAS for cure against L. donovani that is dependent on both the direct leishmanicidal action as well as switching-on of Th1-biased protective cell-mediated immunity with generation of memory. AAL and AAS could represent adjunct therapies for the treatment

  14. Association of CD30 transcripts with Th1 responses and proinflammatory cytokines in patients with end-stage renal disease.

    PubMed

    Velásquez, Sonia Y; Opelz, Gerhard; Rojas, Mauricio; Süsal, Caner; Alvarez, Cristiam M

    2016-05-01

    High serum sCD30 levels are associated with inflammatory disorders and poor outcome in renal transplantation. The contribution to these phenomena of transcripts and proteins related to CD30-activation and -cleavage is unknown. We assessed in peripheral blood of end-stage renal disease patients (ESRDP) transcripts of CD30-activation proteins CD30 and CD30L, CD30-cleavage proteins ADAM10 and ADAM17, and Th1- and Th2-type immunity-related factors t-bet and GATA3. Additionally, we evaluated the same transcripts and release of sCD30 and 32 cytokines after allogeneic and polyclonal T-cell activation. In peripheral blood, ESRDP showed increased levels of t-bet and GATA3 transcripts compared to healthy controls (HC) (both P<0.01) whereas levels of CD30, CD30L, ADAM10 and ADAM17 transcripts were similar. Polyclonal and allogeneic stimulation induced higher levels of CD30 transcripts in ESRDP than in HC (both P<0.001). Principal component analysis (PCA) in allogeneic cultures of ESRDP identified two correlation clusters, one consisting of sCD30, the Th-1 cytokine IFN-γ, MIP-1α, RANTES, sIL-2Rα, MIP-1β, TNF-β, MDC, GM-CSF and IL-5, and another one consisting of CD30 and t-bet transcripts, IL-13 and proinflammatory proteins IP-10, IL-8, IL-1Rα and MCP-1. Reflecting an activated immune state, ESRDP exhibited after allostimulation upregulation of CD30 transcripts in T cells, which was associated with Th1 and proinflammatory responses. PMID:26970513

  15. Recombinant cardiac myosin fragment induces experimental autoimmune myocarditis via activation of Th1 and Th17 immunity

    PubMed Central

    DANIELS, MELVIN D.; HYLAND, KENNETH V.; WANG, KEGIANG; ENGMAN, DAVID M.

    2009-01-01

    The specificity and function of T helper (Th) immune responses underlying the induction, progression, and resolution of experimental autoimmune myocarditis (EAM) in A/J mice are unclear. Published data suggest involvement of both Th1 and Th2 responses in EAM; however, the previous inability to assess antigen-specific in vivo and in vitro T cell responses in cardiac myosin immunized animals has confounded our understanding of this important model of autoimmune myocarditis. The goal of our study was to develop an alternative model of EAM based on a recombinant fragment of cardiac myosin, in hopes that the recombinant protein will permit measurement of functional T cell responses that is not possible with purified native protein. A/J mice immunized with a recombinant fragment of cardiac myosin spanning amino acids 1074–1646, termed Myo4, developed severe myocarditis characterized by cardiac hypertrophy, massive mononuclear cell infiltration and fibrosis, three weeks post-immunization. The mice also developed an IgG1 dominant humoral immune response specific for both Myo4 and purified cardiac myosin. The in vitro stimulation of splenocytes harvested from Myo4-immunized animals with Myo4 resulted in cellular proliferation with preferential production of the Th1- and Th17-associated cytokines, IFN-γ, IL-17 and IL-6, respectively. Production of IL-4 was negligible by comparison. This study describes a new model of EAM, inducible by immunization with a specific fragment of cardiac myosin, from which antigen-specific analyses reveal an importance for both Th1 and Th17 immunity. PMID:18781477

  16. Cytokine mRNA expression in lung tissue from toxic oil syndrome patients: a TH2 immunological mechanism.

    PubMed

    del Pozo, V; de Andrés, B; Gallardo, S; Cárdaba, B; de Arruda-Chaves, E; Cortegano, M I; Jurado, A; Palomino, P; Oliva, H; Aguilera, B; Posada, M; Lahoz, C

    1997-03-14

    In 1981, an epidemic occurred in Spain, toxic oil syndrome (TOS), in people who consumed rapeseed oil denatured with 2% aniline, and it was one of the largest intoxication epidemics ever recorded. In 1989, a similar disease, eosinophilia-myalgia syndrome (EMS) was reported in the USA and was associated with the ingestion of L-tryptophan. The pathologic findings in TOS showed primary endothelial injury, with cell proliferation and perivascular inflammatory infiltrates. Immunologic mechanisms have presumably been operative in the pathogenesis and perpetuation of TOS. Our previous findings pointed to a T-cell activation during acute phase of the disease. In order to analyze which T-cell subset is involved on TOS, we have developed an mRNA extraction procedure from paraffin-embedded lung tissues in patients with pulmonary involvement. We analyzed mRNA expression from different cytokines (IL-1, IL-2, IL-4, IL-5, IFN-gamma, GM-CSF) and CD25 (interleukin 2 receptor) and CD23 (low affinity IgE receptor), using RT-PCR technique. In lung tissues from these patients a T-cell activation was observed. We found a significant increase in Th1 (P = 0.006) and Th2 (P = 0.003) cytokine profile in TOS patients with respect to controls. The increment in TH2 response with respect to TH1 is significant (P = 0.03) in TOS lung specimens. Non-significant differences were obtained in other cytokines and receptors studied as IL-1, CD25, CD23 and GM-CSF. Data presented in this paper are the first clear evidence that an immunological mechanism is directly implicated in this illness. PMID:9074654

  17. New drugs targeting Th2 lymphocytes in asthma.

    PubMed

    Caramori, Gaetano; Groneberg, David; Ito, Kazuhiro; Casolari, Paolo; Adcock, Ian M; Papi, Alberto

    2008-02-27

    Asthma represents a profound worldwide public health problem. The most effective anti-asthmatic drugs currently available include inhaled beta2-agonists and glucocorticoids and control asthma in about 90-95% of patients. The current asthma therapies are not cures and symptoms return soon after treatment is stopped even after long term therapy. Although glucocorticoids are highly effective in controlling the inflammatory process in asthma, they appear to have little effect on the lower airway remodelling processes that appear to play a role in the pathophysiology of asthma at currently prescribed doses. The development of novel drugs may allow resolution of these changes. In addition, severe glucocorticoid-dependent and resistant asthma presents a great clinical burden and reducing the side-effects of glucocorticoids using novel steroid-sparing agents is needed. Furthermore, the mechanisms involved in the persistence of inflammation are poorly understood and the reasons why some patients have severe life threatening asthma and others have very mild disease are still unknown. Drug development for asthma has been directed at improving currently available drugs and findings new compounds that usually target the Th2-driven airway inflammatory response. Considering the apparently central role of T lymphocytes in the pathogenesis of asthma, drugs targeting disease-inducing Th2 cells are promising therapeutic strategies. However, although animal models of asthma suggest that this is feasible, the translation of these types of studies for the treatment of human asthma remains poor due to the limitations of the models currently used. The myriad of new compounds that are in development directed to modulate Th2 cells recruitment and/or activation will clarify in the near future the relative importance of these cells and their mediators in the complex interactions with the other pro-inflammatory/anti-inflammatory cells and mediators responsible of the different asthmatic

  18. New drugs targeting Th2 lymphocytes in asthma

    PubMed Central

    Caramori, Gaetano; Groneberg, David; Ito, Kazuhiro; Casolari, Paolo; Adcock, Ian M; Papi, Alberto

    2008-01-01

    Asthma represents a profound worldwide public health problem. The most effective anti-asthmatic drugs currently available include inhaled β2-agonists and glucocorticoids and control asthma in about 90-95% of patients. The current asthma therapies are not cures and symptoms return soon after treatment is stopped even after long term therapy. Although glucocorticoids are highly effective in controlling the inflammatory process in asthma, they appear to have little effect on the lower airway remodelling processes that appear to play a role in the pathophysiology of asthma at currently prescribed doses. The development of novel drugs may allow resolution of these changes. In addition, severe glucocorticoid-dependent and resistant asthma presents a great clinical burden and reducing the side-effects of glucocorticoids using novel steroid-sparing agents is needed. Furthermore, the mechanisms involved in the persistence of inflammation are poorly understood and the reasons why some patients have severe life threatening asthma and others have very mild disease are still unknown. Drug development for asthma has been directed at improving currently available drugs and findings new compounds that usually target the Th2-driven airway inflammatory response. Considering the apparently central role of T lymphocytes in the pathogenesis of asthma, drugs targeting disease-inducing Th2 cells are promising therapeutic strategies. However, although animal models of asthma suggest that this is feasible, the translation of these types of studies for the treatment of human asthma remains poor due to the limitations of the models currently used. The myriad of new compounds that are in development directed to modulate Th2 cells recruitment and/or activation will clarify in the near future the relative importance of these cells and their mediators in the complex interactions with the other pro-inflammatory/anti-inflammatory cells and mediators responsible of the different asthmatic

  19. Anti-ulcer treatment during pregnancy induces food allergy in mouse mothers and a Th2-bias in their offspring

    PubMed Central

    Schöll, Isabella; Ackermann, Ute; Özdemir, Cevdet; Blümer, Nicole; Dicke, Tanja; Sel, Serdar; Sel, Sarper; Wegmann, Michael; Szalai, Krisztina; Knittelfelder, Regina; Untersmayr, Eva; Scheiner, Otto; Garn, Holger; Jensen-Jarolim, Erika; Renz, Harald

    2010-01-01

    The treatment of dyspeptic disorders with anti-acids leads to an increased risk of sensitization against food allergens. As these drugs are taken by 30–50% of pregnant women due to reflux and heartburn, we aimed here to investigate the impact of maternal therapy with anti-acids on the immune response in the offspring in a murine model. Codfish extract as model allergen was fed with or without sucralfate, an anti-acid drug, to pregnant BALB/c mice during pregnancy and lactation. These mothers developed a codfish-specific allergic response shown as high IgG1 and IgE antibody levels and positive skin tests. In the next step we analyzed whether this maternal sensitization impacts a subsequent sensitization in the offspring. Indeed, in stimulated splenocytes of these offspring we found a relative Th2-dominance, because the Th1- and T-regulatory cytokines were significantly suppressed. Our data provide evidence that the anti-acid drug sucralfate supports sensitization against food in pregnant mice and favors a Th2-milieu in their offspring. From these results we propose that anti-acid treatment during pregnancy could be responsible for the increasing number of sensitizations against food allergens in young infants. PMID:17227952

  20. Anti-ulcer treatment during pregnancy induces food allergy in mouse mothers and a Th2-bias in their offspring.

    PubMed

    Schöll, Isabella; Ackermann, Ute; Ozdemir, Cevdet; Blümer, Nicole; Dicke, Tanja; Sel, Serdar; Sel, Sarper; Wegmann, Michael; Szalai, Krisztina; Knittelfelder, Regina; Untersmayr, Eva; Scheiner, Otto; Garn, Holger; Jensen-Jarolim, Erika; Renz, Harald

    2007-04-01

    The treatment of dyspeptic disorders with anti-acids leads to an increased risk of sensitization against food allergens. As these drugs are taken by 30-50% of pregnant women due to reflux and heartburn, we aimed here to investigate the impact of maternal therapy with anti-acids on the immune response in the offspring in a murine model. Codfish extract as model allergen was fed with or without sucralfate, an anti-acid drug, to pregnant BALB/c mice during pregnancy and lactation. These mothers developed a codfish-specific allergic response shown as high IgG1 and IgE antibody levels and positive skin tests. In the next step we analyzed whether this maternal sensitization impacts a subsequent sensitization in the offspring. Indeed, in stimulated splenocytes of these offspring we found a relative Th2-dominance, because the Th1- and T-regulatory cytokines were significantly suppressed. Our data provide evidence that the anti-acid drug sucralfate supports sensitization against food in pregnant mice and favors a Th2-milieu in their offspring. From these results we propose that anti-acid treatment during pregnancy could be responsible for the increasing number of sensitizations against food allergens in young infants. PMID:17227952

  1. Th2 Allergic Immune Response to Inhaled Fungal Antigens is Modulated By TLR-4-Independent Bacterial Products

    PubMed Central

    Allard, Jenna B.; Rinaldi, Lisa; Wargo, Matt; Allen, Gilman; Akira, Shizuo; Uematsu, Satoshi; Poynter, Matthew E.; Hogan, Deborah A.; Rincon, Mercedes; Whittaker, Laurie A.

    2009-01-01

    SUMMARY Allergic airway disease is characterized by eosinophilic inflammation, mucus hypersecretion and increased airway resistance. Fungal antigens are ubiquitous within the environment and are well know triggers of allergic disease. Bacterial products are also frequently encountered within the environment and may alter the immune response to certain antigens. The consequence of simultaneous exposure to bacterial and fungal products on the lung adaptive immune response has not been explored. Here we show that oropharyngeal aspiration of fungal lysates (Candida albicans, Aspergillus fumigatus) promotes airway eosinophilia, secretion of Th2 cytokines and mucus cell metaplasia. In contrast, oropharyngeal exposure to bacterial lysates (Pseudomonas aeruginosa) promotes airway inflammation characterized by neutrophils, Th1 cytokine secretion and no mucus production. More importantly, administration of bacterial lysates together with fungal lysates deviates the adaptive immune response to a Th1 type associated with neutrophilia and diminished mucus production. The immunomodulatory effect that bacterial lysates have on the response to fungi is TLR4-independent but MyD88 dependent. Thus, different types of microbial products within the airway can alter the host's adaptive immune response, and potentially impact the development of allergic airway disease to environmental fungal antigens. PMID:19224641

  2. Combination of MIDGE-Th1 DNA vaccines with the cationic lipid SAINT-18: studies on formulation, biodistribution and vector clearance.

    PubMed

    Endmann, Anne; Oswald, Detlef; Riede, Oliver; Talman, Eduard G; Vos, Roelien E; Schroff, Matthias; Kleuss, Christiane; Ruiters, Marcel H J; Juhls, Christiane

    2014-06-01

    We have previously shown that the combination of MIDGE-Th1 DNA vectors with the cationic lipid SAINT-18 increases the immune response to the encoded antigen in mice. Here, we report on experiments to further optimize and characterize this approach. We evaluated different formulations of MIDGE-Th1 vectors with SAINT-18 by assessing their influence on the transfection efficiency in cell culture and on the immune response in mice. We found that high amounts of SAINT-18 in formulations with a w/w ratio MIDGE Th1/SAINT-18 of 1:4.8 are beneficial for cell transfection in vitro. In contrast, the formulation of HBsAg-encoding MIDGE-Th1 DNA vectors with the lowest amount of SAINT-18 (w/w ratio MIDGE Th1/SAINT-18 of 1:0.5) resulted in the highest serum IgG1 and IgG2a levels after intradermal immunization of mice. Consequently, latter formulation was selected for a comparative biodistribution study in rats. Following intradermal administration of both naked and formulated MIDGE-Th1 DNA, the vectors localized primarily at the site of injection. Vector DNA levels decreased substantially over the two months duration of the study. When administered in combination with SAINT-18, the vectors were found in significantly higher amounts in draining lymph nodes in comparison to administration of naked MIDGE-Th1 DNA. We propose that the high immune responses induced by MIDGE-Th1/SAINT-18 lipoplexes are mediated by enhanced transfection of cells in vivo, resulting in stronger antigen expression and presentation. Importantly, the combination of MIDGE-Th1 vectors with SAINT-18 was well tolerated in mice and rats and is expected to be safe in human clinical applications. PMID:24681271

  3. Fatal Leishmaniasis in the Absence of TNF Despite a Strong Th1 Response

    PubMed Central

    Fromm, Phillip D.; Kling, Jessica C.; Remke, Annika; Bogdan, Christian; Körner, Heinrich

    2016-01-01

    Induction of inducible nitric oxide synthase in mononuclear phagocytes by IFN-γ and innate tumor necrosis factor (TNF) provide the basis for an effective immune response to the intracellular parasite Leishmania (L.) major. In previous experiments, we observed a fatal visceral form of leishmaniasis in L. major-infected C57BL/6 TNF-/- mice. To further delineate the protective function of TNF and its receptor requirements, we comparatively assessed L. major-infected C57BL/6 mice that were either deficient for membrane and soluble TNF (Tnf-/-), for soluble TNF alone (memTnfΔ/Δ), or the TNF receptors type 1 (Tnfr1-/-) or type 2 (Tnfr2-/-). We detected locally and systemically increased levels of the cytokine IFN-γ in the absence of the TNF-TNFR1-signaling pathway. An analysis of transcription factors and cytokines revealed that activated Tnf-/- CD4+ T cells displayed a highly active Th1 phenotype with a strong usage of the T cell receptor Vβ5.1/2. From these data we conclude that the fatal outcome of L. major infection in Tnf-/- mice does not result from a skewed or deficient Th1 differentiation. PMID:26834705

  4. Lead effects on development and function of bone marrow-derived dendritic cells promote Th2 immune responses

    SciTech Connect

    Gao Donghong; Mondal, Tapan K.; Lawrence, David A. . E-mail: lawrencd@wadsworth.org

    2007-07-01

    Although lead (Pb) has significant effects on the development and function of macrophages, B cells, and T cells and has been suggested to promote allergic asthma in mice and humans, Pb modulation of bone marrow (BM)-derived dendritic cells (DCs) and the resultant DC effects on Th1 and Th2 development have not been examined. Accordingly, we cultured BM cells with murine granulocyte macrophage-colony stimulating factor (mGM-CSF) {+-} PbCl{sub 2}. At day 10, culture supernatant (SN) and non-adherent cells were harvested for analysis. Additionally, day 10 non-adherent BM-DCs were harvested and recultured with mGM-CSF + LPS {+-} Pb for 2 days. The day 10 Pb exposure significantly inhibited BM-DC generation, based on CD11c expression. Although fewer DCs were generated with Pb, the existing Pb-exposed DCs had significantly greater MHC-II expression than did the non-Pb-exposed DCs. However, these differences diminished upon LPS stimulation. After LPS stimulation, CD80, CD86, CD40, CD54, and MHC-II were all up-regulated on both Pb-DCs and DCs, but Pb-DCs expressed significantly less CD80 than did DCs. The CD86:CD80 ratio suggests a Pb-DC potential for Th2 cell development. After LPS stimulation, IL-6, IL-10, IL-12 (p70), and TNF-{alpha} levels significantly increased with both Pb-DCs and DCs, but Pb-DCs produced significantly less cytokines than did DCs, except for IL-10, which further supports Pb-DC preferential skewing toward type-2 immunity. In vitro studies confirm that Pb-DCs have the ability to polarize antigen-specific T cells to Th2 cells. Pb-DCs also enhanced allogeneic and autologous T cell proliferation in vitro, and in vivo studies suggested that Pb-DCs inhibited Th1 effects on humoral and cell-mediated immunity. The Pb effect was mainly on DCs, rather than on T cells, and Pb's modification of DC function appears to be the main cause of Pb's promotion of type-2-related immunity, which may relate to Pb's enhanced activation of the Erk/MAP kinase pathway.

  5. Herbal medicine Gamgungtang down-regulates autoimmunity through induction of TH2 cytokine production by lymphocytes in experimental thyroiditis model.

    PubMed

    Sa, Eun-Ho; Jin, Un-Ho; Kim, Dong-Soo; Kang, Bong-Seok; Ha, Ki-Tae; Kim, June-Ki; Park, Won-Hwan; Kim, Cheorl-Ho

    2007-02-12

    The crude herbal formulation, Gamgungtang (GGT), has been shown to protect animals against a wide range of spontaneously developing or induced autoimmune diseases. We have previously reported that GGT shows marked down-regulation of several experimental autoimmune diseases. Although very effective at preventing thyroid infiltrates in mice immunized with mouse deglycosylated thyroglobulin and complete Freund's adjuvant and in spontaneous models of thyroiditis, it completely failed to modify experimental autoimmune thyroiditis (EAT) induced in mice immunized with mouse thyroglobulin and lipopolysaccharide. In this study, in an effort to elucidate the mechanisms by which GGT suppresses EAT, and autoimmunity in general, we investigated the in vivo effects of this drug on the Th1/Th2 lymphocyte balance, which is important for the induction or inhibition of autoreactivity. Naive SJL/J mice were treated orally for 5 days with GGT (80 mg/(kg day)). Spleen cells were obtained at various time points during the treatment period and were stimulated in vitro with concanavalin A. Interleukins IL-4, IL-10 and IL-12, transforming growth factor-beta (TGF-beta) and interferon-gamma (IFN-gamma) cytokine production was evaluated at the protein levels of the cytokines in the medium and mRNA expressions. A significant upregulation of IL-4, IL-10 and TGF-beta was observed following treatment with GGT, which peaked at day 5 (IL-10) or day 10 (IL-4). On the other hand, IL-12 and IFN-gamma production were either unchanged or decreased. It seems therefore that GGT induces in vivo a shift towards Th2 lymphocytes which may be one of the mechanisms of down-regulation of the autoimmune reactivity in EAT. Our observations indicate that down-regulation of TH1 cytokines (especially IL-12) and enhancement of Th2 cytokine production may play an important role in the control of T-cell-mediated autoimmunity. These data may contribute to the design of new immunomodulating treatments for a group of

  6. Arctigenin exerts anti-colitis efficacy through inhibiting the differentiation of Th1 and Th17 cells via an mTORC1-dependent pathway.

    PubMed

    Wu, Xin; Dou, Yannong; Yang, Yan; Bian, Difei; Luo, Jinque; Tong, Bei; Xia, Yufeng; Dai, Yue

    2015-08-15

    Arctigenin, the main effective constituent of Arctium lappa L. fruit, has previously been proven to dramatically attenuate dextran sulfate sodium (DSS)-induced colitis in mice, a frequently used animal model of inflammatory bowel disease (IBD). As Th1 and Th17 cells play a crucial role in the pathogenesis of IBD, the present study addressed whether and how arctigenin exerted anti-colitis efficacy by interfering with the differentiation and activation of Th1/Th17 cells. In vitro, arctigenin was shown to markedly inhibit the differentiation of Th17 cells from naïve T cells, and moderately inhibit the differentiation of Th1 cells, which was accompanied by lowered phosphorylation of STAT3 and STAT4, respectively. In contrast, arctigenin was lack of marked effect on the differentiation of either Th2 or regulatory T cells. Furthermore, arctigenin was shown to suppress the mammalian target of rapamycin complex 1 (mTORC1) pathway in T cells as demonstrated by down-regulated phosphorylation of the downstream target genes p70S6K and RPS6, and it functioned independent of two well-known upstream kinases PI3K/AKT and ERK. Arctigenin was also able to inhibit the activity of mTORC1 by dissociating raptor from mTOR. Interestingly, the inhibitory effect of arctigenin on T cell differentiation disappeared under a status of mTORC1 overactivation via knockdown of tuberous sclerosis complex 2 (TSC2, a negative regulator of mTORC1) or pretreatment of leucine (an agonist of mTOR). In DSS-induced mice, the inhibition of Th1/Th17 responses and anti-colitis effect of arctigenin were abrogated by leucine treatment. In conclusion, arctigenin ameliorates colitis through down-regulating the differentiation of Th1 and Th17 cells via mTORC1 pathway. PMID:26074264

  7. Long-lasting complete regression of established mouse tumors by counteracting Th2 inflammation

    PubMed Central

    Dai, Min; Wei, Huafeng; Yip, Yuen Yee; Feng, Qinghua; He, Kecheng; Popov, Viorica; Hellstrom, Ingegerd; Hellstrom, Karl Erik

    2013-01-01

    Mice with intraperitoneal ID8 ovarian carcinoma or subcutaneous SW1 melanoma were injected with monoclonal antibodies (mAbs) to CD137+PD-1+CTLA4 7-15 days following tumor initiation. Survival of mice with ID8 tumors tripled and >40% of mice with SW1 tumors remain healthy >150 days after later treatment and are probably cured. Therapeutic efficacy was associated with a systemic immune response with memory and antigen specificity and required CD4+ cells and involved CD8+ cells and NK cells to a less extent. The 3 mAb combination significantly decreased CD19+ cells at tumor sites, increased IFNγ and TNFα producing CD4+ and CD8+ T cells and mature CD86+ DC, and it increased the ratios of effector CD4+ and CD8+ T cells to CD4+Foxp3+ regulatory T cells and to CD11b+Gr-1+ myeloid suppressor cells. This is consistent with shifting the tumor microenvironment from an immunosuppressive Th2 to an immunostimulatory Th1 type and is further supported by PCR data. Adding an anti-CD19 mAb to the 3 mAb combination in the SW1 model further increased therapeutic efficacy. Data from ongoing experiments show that intratumoral injection of a combination of mAbs to CD137+PD-1+CLA4+CD19 can induce complete regression and dramatically prolong survival also in the TC1 carcinoma and B16 melanoma models, suggesting that the approach has general validity. PMID:23603859

  8. Blockade of CD40 ligand suppresses chronic experimental myasthenia gravis by down-regulation of Th1 differentiation and up-regulation of CTLA-4.

    PubMed

    Im, S H; Barchan, D; Maiti, P K; Fuchs, S; Souroujon, M C

    2001-06-01

    Myasthenia gravis (MG) and experimental autoimmune MG (EAMG) are T cell-dependent Ab-mediated autoimmune disorders, in which the nicotinic acetylcholine receptor (AChR) is the major autoantigen. Th1-type cells and costimulatory factors such as CD40 ligand (CD40L) contribute to disease pathogenesis by producing proinflammatory cytokines and by activating autoreactive B cells. In this study we demonstrate the capacity of CD40L blockade to modulate EAMG, and analyze the mechanism underlying this disease suppression. Anti-CD40L Abs given to rats at the chronic stage of EAMG suppress the clinical progression of the autoimmune process and lead to a decrease in the AChR-specific humoral response and delayed-type hypersensitivity. The cytokine profile of treated rats suggests that the underlying mechanism involves down-regulation of AChR-specific Th1-regulated responses with no significant effect on Th2- and Th3-regulated AChR-specific responses. EAMG suppression is also accompanied by a significant up-regulation of CTLA-4, whereas a series of costimulatory factors remain unchanged. Adoptive transfer of splenocytes from anti-CD40L-treated rats does not protect recipient rats against subsequently induced EAMG. Thus it seems that the suppressed progression of chronic EAMG by anti-CD40L treatment does not induce a switch from Th1 to Th2/Th3 regulation of the AChR-specific immune response and does not induce generation of regulatory cells. The ability of anti-CD40L treatment to suppress ongoing chronic EAMG suggests that blockade of CD40L may serve as a potential approach for the immunotherapy of MG and other Ab-mediated autoimmune diseases. PMID:11359850

  9. The Driving of Immune Response by Th1 Adjuvants in Immunization of Mice with Trypanosoma cruzi marinkellei Elicits a Controversial Infection Control.

    PubMed

    Nascentes, Gabriel Antonio Nogueira; Hernández, César Gómez; Rabelo, Rosiley Aparecida de Souza; Coelho, Raquel Fernandes; Morais, Fabiana Rossetto de; Marques, Tatiane; Batista, Lara Rocha; Meira, Wendell Sérgio Ferreira; Oliveira, Carlo José Freire de; Lages Silva, Eliane; Ramírez, Luis Eduardo

    2016-05-01

    In previous studies, we have demonstrated that inoculation with a Trypanosoma cruzi marinkellei (avirulent RM1 strain) was able to reduce parasitemia in mice challenged with T. cruzi, although it was not able to prevent histopathological lesions. Th1 response stimulation by immunization is necessary for T. cruzi infection control, but the resistance is also dependent on immunoregulatory mechanisms, which can be induced by adjuvants. Thus, we evaluated whether inoculation of T. cruzi marinkellei associated with administration of different adjuvants would be capable of inducing different patterns of immune response to maximize the immune response against T. cruzi (virulent Romildo strain) infection. Two hundred eighty nonisogenic mice were divided into 14 groups according to the immunization scheme and the subsequent challenge with virulent Romildo T. cruzi strain. Nonimmunized groups and animals inoculated without adjuvants were also included. Immune protection was not observed with Th2 adjuvants (incomplete Freund's adjuvant [IFA] and Alum) due to high parasitemia. Th1/Th2-polarizing adjuvants also did not induce immune protection because inulin was unable to maintain survival, and immune-stimulating complexes induced intense inflammatory processes. Animals sensitized with RM1 strain without adjuvants were able to reduce parasitemia, increase survival, and protect against severe histological lesions, followed by adequate cytokine stimulation. Finally, our results demonstrate that the early and balanced IFN-γ production becomes critical to promote protection and that Th1 adjuvant elicited a controversial infection control due to increased histopathological damage. Therefore, the host's immunomodulation remains one of the most important challenges in the research for effective protection against T. cruzi infection. Similarly, the identification of protective antigens in the RM1 strain of T. cruzi marinkellei may contribute to further studies on vaccine development

  10. Aluminium hydroxide adjuvant initiates strong antigen-specific Th2 responses in the absence of IL-4- or IL-13-mediated signaling.

    PubMed

    Brewer, J M; Conacher, M; Hunter, C A; Mohrs, M; Brombacher, F; Alexander, J

    1999-12-15

    Previous studies demonstrate that aluminium hydroxide adjuvant (alum) produces increased Th1 responses in IL-4-deficient mice compared with wild-type animals, although the continued production of IL-5 by spleen cells from these mice also indicates that Th2 responses are induced. In the present study, we demonstrate that alum can induce Th2-associated IL-4 and IL-5 production in the absence of IL-4 signaling in mice deficient in either IL-4Ralpha or Stat6. The Th2 responses observed could not be due to IL-13 as IL-13 responses are also impaired in IL-4Ralpha- and Stat6-deficient mice. We also detected higher levels of IL-4 in IL-4Ralpha gene-deficient, though not Stat6-deficient, mice compared with their wild-type counterparts. The increased levels of IL-4 could be explained by the IL-4R being unavailable to neutralize this cytokine in IL-4Ralpha-deficient mice. While levels of IL-5 production in IL-4Ralpha- or Stat6-deficient mice were similar to IL-4-deficient and wild-type mice, other type 2-associated responses, which are largely or wholly IL-4 dependent, such as the production of IgG1 or IgE Abs, were either reduced or absent. We conclude that alum adjuvants can induce IL-4 production and Th2 responses independently of IL-4 or IL-13, negating the requirement for an early source of IL-4 in the Th2 response induced by this adjuvant. PMID:10586035

  11. Exacerbated Th2-mediated airway inflammation and hyperresponsiveness in autoimmune diabetes-prone NOD mice: a critical role for CD1d-dependent NKT cells.

    PubMed

    Araujo, Luiza M; Lefort, Jean; Nahori, Marie-Anne; Diem, Séverine; Zhu, Ren; Dy, Michel; Leite-de-Moraes, Maria C; Bach, J F; Vargaftig, B Boris; Herbelin, André

    2004-02-01

    The NOD mouse has proved to be a relevant model of insulin-dependent diabetes mellitus, closely resembling the human disease. However, it is unknown whether this strain presents a general biastoward Th1-mediated autoimmunity or remains capable of mounting complete Th2-mediated responses. Here, we show that NOD mice have the capacity to develop a typical Th2-mediated disease, namely experimental allergic asthma. In contrast to what might have been expected, they even developed a stronger Th2-mediated pulmonary inflammatory response than BALB/c mice, a strain that shows a typical Th2 bias in this model. Thus, after allergen sensitization and intra-nasal challenge, the typical features of experimental asthma were exacerbated in NOD mice, including enhanced bronchopulmonary responsiveness, mucus production and eosinophilic inflammation in the lungs as well as specific IgE titers in serum. These hallmarks of allergic asthma were associated with increased IL-4, IL-5, IL-13 and eotaxin production in the lungs, as compared with BALB/c mice. Notwithstanding their quantitative and functional defect in NOD mice, CD1d-dependent NKT cells contribute to aggravate the disease, since in OVA-immunized CD1d(-/-) NOD mice, which are deficient in this particular T cell subset, airway eosinophilia was clearly diminished relative to NOD littermates. This is the first evidence that autoimmune diabetes-prone NOD mice can also give rise to enhanced Th2-mediated responses and might thus provide a useful model for the study of common genetic and cellular components, including NKT cells that contribute to both asthma and type 1 diabetes. PMID:14768037

  12. IL-27 and TGFβ mediated expansion of Th1 and adaptive regulatory T cells expressing IL-10 correlates with bacterial burden and disease severity in pulmonary tuberculosis

    PubMed Central

    Kumar, Nathella P; Moideen, Kadar; Banurekha, Vaithilingam V; Nair, Dina; Sridhar, Rathinam; Nutman, Thomas B; Babu, Subash

    2015-01-01

    CD4+ T cell expression of IL-10 is an important mechanism controlling immunity to tuberculosis (TB). To identify the CD4+ T cell subsets producing IL-10 in human TB, we enumerated the frequencies of IL-10 expressing CD4+ T cell subsets following TB—antigen stimulation of cells from individuals with pulmonary (PTB) and latent TB (LTB). We first demonstrate that TB antigens induce an expansion of IL-10 expressing Th1 (IL-10+, IFNγ+, T-bet+), Th2 (IL-10+, IL-4+, GATA-3+), Th9 (IL-10+, IL-9+, IL-4−), Th17 (IL-10+, IL-17+, IFNγ−), and natural and adaptive regulatory T cells [nTregs; IL-10+, CD4+, CD25+, Foxp3+ and aTregs; IL-10 single+, CD4+, CD25−, Foxp3−] in PTB and LTB individuals, with frequencies being significantly higher in the former. However, only Th1 cells and adaptive Tregs expressing IL-10 exhibit a positive relationship with bacterial burdens and extent of disease in PTB. Finally, we show that IL-27 and TGFβ play an important role in the regulation of IL-10+ Th cell subsets. Thus, active PTB is characterized by an IL-27 and TGFβ mediated expansion of IL-10 expressing CD4+ T cell subsets, with IL-10+ Th1 and IL-10+ aTreg cells playing a potentially pivotal role in the pathogenesis of active disease. PMID:26417443

  13. IL-27 and TGFβ mediated expansion of Th1 and adaptive regulatory T cells expressing IL-10 correlates with bacterial burden and disease severity in pulmonary tuberculosis.

    PubMed

    Kumar, Nathella P; Moideen, Kadar; Banurekha, Vaithilingam V; Nair, Dina; Sridhar, Rathinam; Nutman, Thomas B; Babu, Subash

    2015-09-01

    CD4(+) T cell expression of IL-10 is an important mechanism controlling immunity to tuberculosis (TB). To identify the CD4(+) T cell subsets producing IL-10 in human TB, we enumerated the frequencies of IL-10 expressing CD4(+) T cell subsets following TB-antigen stimulation of cells from individuals with pulmonary (PTB) and latent TB (LTB). We first demonstrate that TB antigens induce an expansion of IL-10 expressing Th1 (IL-10(+), IFNγ(+), T-bet(+)), Th2 (IL-10(+), IL-4(+), GATA-3(+)), Th9 (IL-10(+), IL-9(+), IL-4(-)), Th17 (IL-10(+), IL-17(+), IFNγ(-)), and natural and adaptive regulatory T cells [nTregs; IL-10(+), CD4(+), CD25(+), Foxp3(+) and aTregs; IL-10 single(+), CD4(+), CD25(-), Foxp3(-)] in PTB and LTB individuals, with frequencies being significantly higher in the former. However, only Th1 cells and adaptive Tregs expressing IL-10 exhibit a positive relationship with bacterial burdens and extent of disease in PTB. Finally, we show that IL-27 and TGFβ play an important role in the regulation of IL-10(+) Th cell subsets. Thus, active PTB is characterized by an IL-27 and TGFβ mediated expansion of IL-10 expressing CD4(+) T cell subsets, with IL-10(+) Th1 and IL-10(+) aTreg cells playing a potentially pivotal role in the pathogenesis of active disease. PMID:26417443

  14. Glucocorticoids Induce a TH2 Response In Vitro

    PubMed Central

    Ramírez, Francisco

    1998-01-01

    Purified rat CD4+ T cells were activated in vitro, by the polyclonal mitogen Concanavalin A (Con A) or by mixed lymphocyte reaction (MLR), in the presence or absence of the glucocorticoid dexamethasone (DEX). They were then expanded in IL-2 and subsequently restimulated, this time in the absence of the hormone. The results indicate that the exposure of the cells to DEX in the primary stimulation changed the cytokine synthesis induced by the secondary stimulation. IL-4 production was increased by the pretreatment whereas synthesis of IFN-γ was diminished. Addition of DEX in the second activation suppressed all cytokine production. In brief, the transient presence of glucocorticoids in the culture induces a change in the pattern of cytokine production but the continuous presence causes inhibition of cytokine synthesis. Further studies in which IL-4 was used together with DEX showed that the cytokine potentiated the effect of the hormone. The data here presented suggest that glucocorticoids and the neuroendocrine system may be expected to have long-term immunological effects as well as short-lived immunosuppressive ones. High concentration of glucocorticoids suppress cytokine production but when steroids return to basal levels the immune response is directed in a way that favors Th2-type reactions. Possible implications regarding the immune response to pathogens and autoantigens are discussed. PMID:9814597

  15. Inactivated Parapoxvirus ovis induces a transient increase in the expression of proinflammatory, Th1-related, and autoregulatory cytokines in mice

    PubMed Central

    Anziliero, D.; Weiblen, R.; Kreutz, L.C.; Spilki, F.; Flores, E.F.

    2014-01-01

    The immunostimulatory properties of inactivated Parapoxvirus ovis (iPPVO) have long been investigated in different animal species and experimental settings. In this study, we investigated the effects of iPPVO on cytokine expression in mice after intraperitoneal inoculation. Spleen and sera collected from iPPVO-treated mice at intervals after inoculation were submitted to cytokine mRNA determination by real-time PCR (qPCR), serum protein concentration by ELISA, and interferon (IFN)-α/β activity by bioassay. The spleen of iPPVO-treated animals showed a significant increase in mRNA expression of all cytokines assayed, with different kinetics and magnitude. Proinflammatory cytokines interleukin (IL)-1β, tumor necrosis factor-alpha (TNF-α), and IL-8 mRNA peaked at 24 hours postinoculation (hpi; 5.4-fold increase) and 48 hpi (3- and 10-fold increases), respectively. A 15-fold increase in IFN-γ and 6-fold IL-12 mRNA increase were detected at 48 and 24 hpi, respectively. Increased expression of autoregulatory cytokines (Th2), mainly IL-10 and IL-4, could be detected at later times (72 and 96 hpi) with peaks of 4.7- and 4.9-fold increases, respectively. IFN-I antiviral activity against encephalomyocarditis virus was demonstrated in sera of treated animals between 6 and 12 hpi, with a >90% reduction in the number of plaques. Measurement of serum proteins by ELISA revealed increased levels of IL-1, TNF-α, IL-12, IFN-γ, and IL-10, with kinetics similar to those observed by qPCR, especially for IL-12 and IFN-γ. These data demonstrate that iPPVO induced a transient and complex cytokine response, initially represented by Th1-related cytokines followed by autoregulatory and Th2 cytokines. PMID:24519126

  16. Low-Molecular-Weight Heparin and Unfractionated Heparin Decrease Th-1, 2, and 17 Expressions

    PubMed Central

    Huang, Jing-Ning; Tsai, Ming-Chin; Fang, Shun-Lung; Chang, Margaret Dah-Tsyr; Wu, Yu-Rou; Tsai, Jaw-Ji; Fu, Lin-Shien; Lin, Heng-Kuei; Chen, Yi-Jun; Li, Tsai-Wei

    2014-01-01

    Background We evaluated the effects of T helper cell differentiation in a mite-allergic animal model treated with inhaled heparins of different molecular weight. Method BALB/c mice were divided into four groups: 1. Control, 2. Mite intratracheal (mIT), 3. Inhaled heparin (hIN), 4. Inhaled low-molecular-weight heparin (lmwhIN). Groups 2, 3, and 4 were sensitized twice with Der p allergen subcutaneously on day 1 and day 8. Der p allergen was administered intratracheally on day 15. Groups 3 and 4 were treated with heparin or low-molecular-weight (lmw) heparin intranasally from day 1 to 22. Splenocytes from sacrificed mice stimulated with 16 µg/ml of Der p were cultured for 72 hours. Supernatants of splenocyte were collected to analyze the effect of Interleukin (IL)17-A/F, Interferon(IFN)-γ, IL-4, IL-13, and IL-10. Serum was also collected for Der P-specific IgE level on day 23. Total RNA was extracted from spleen tissue for mRNA expression. Gene expression of Foxp3, IL-10 IFN-γ, GATA3, IL-5, and RORγt were analyzed. Results Both hIN and lmwhIN groups had lower serum IgE level than that of the mIT group (both p<0.0001). Both hIN and lmwhIN groups showed significantly decreased transcripts of GATA-3, IFN-γ, IL-5, and RORγt mRNA in their spleen. Regarding the supernatant of splenocyte culture stimulated with Der p, compared with the mIT group, there were significant decreases in IL-17A/F, IFN-γ, IL-4, IL-13, and IL-10 secretion in inhaled hIN and lmwhIN groups. Conclusions From this balb/c mice study, the analyses of mRNA and cytokines revealed that both intranasal heparin and lmw heparin treatment decreased the expression of Th1, Th2, and Th17 in spleen. The underlying mechanism(s) warrant further studies. PMID:25364825

  17. Exposure to Bisphenol A Prenatally or in Adulthood Promotes TH2 Cytokine Production Associated with Reduction of CD4+CD25+ Regulatory T Cells

    PubMed Central

    Yan, Huimin; Takamoto, Masaya; Sugane, Kazuo

    2008-01-01

    Background Bisphenol A (BPA) is a widespread endocrine-disrupting chemical that can affect humans and animals. Objectives We investigated the effects of adult or prenatal exposure to BPA on T-helper (TH)1/TH2 immune responses and the mechanisms underlying these effects. Methods To evaluate the effects of exposure to BPA in adulthood, male Leishmania major–susceptible BALB/c and –resistant C57BL/6 mice were subcutaneously injected with 0.625, 1.25, 2.5, and 5 μmol BPA 1 week before being infected with L. major. To evaluate prenatal exposure, female mice were given BPA-containing drinking water at concentrations of 1, 10, and 100 nM for 2 weeks, then mated, and given BPA for another week. Male 10-week-old offspring were infected with L. major. Footpad swelling was assessed as a measure of the course of infection. Results Mice exposed to BPA prenatally or in adulthood showed a dose-dependent increase in footpad swelling after being infected with L. major. Exposure to BPA in adulthood significantly promoted antigen-stimulated production of interleukin (IL)-4, IL-10, and IL-13 but not interferon-γ (IFN-γ). However, mice prenatally exposed to BPA showed increased production of not only IL-4 but also IFN-γ. The percentages of CD4+CD25+ cells were decreased in mice exposed to BPA either prenatally or in adulthood. Effects of prenatal BPA exposure were far more pronounced than effects of exposure in adulthood. Conclusion BPA promotes the development of TH2 cells in adulthood and both TH1 and TH2 cells in prenatal stages by reducing the number of regulatory T cells. PMID:18414636

  18. Preventing and curing citrulline-induced autoimmune arthritis in a humanized mouse model using a Th2-polarizing iNKT cell agonist.

    PubMed

    Walker, Kyle M; Rytelewski, Mateusz; Mazzuca, Delfina M; Meilleur, Shannon A; Mannik, Lisa A; Yue, David; Brintnell, William C; Welch, Ian; Cairns, Ewa; Haeryfar, S M Mansour

    2012-07-01

    Invariant natural killer T (iNKT) cells are innate lymphocytes with unique reactivity to glycolipid antigens bound to non-polymorphic CD1d molecules. They are capable of rapidly releasing pro- and/or anti-inflammatory cytokines and constitute attractive targets for immunotherapy of a wide range of diseases including autoimmune disorders. In this study, we have explored the beneficial effects of OCH, a Th2-polarizing glycolipid agonist of iNKT cells, in a humanized mouse model of rheumatoid arthritis (RA) in which citrullinated human proteins are targeted by autoaggressive immune responses in mice expressing an RA susceptibility human leukocyte antigen (HLA) DR4 molecule. We found for the first time that treatment with OCH both prevents and cures citrulline-induced autoimmune arthritis as evidenced by resolved ankle swelling and reversed histopathological changes associated with arthritis. Also importantly, OCH treatment blocked the arthritogenic capacity of citrullinated antigen-experienced splenocytes without compromising their global responsiveness or altering the proportion of splenic naturally occurring CD4(+)CD25(+)FoxP3(+) regulatory T cells. Interestingly, administering the Th1-promoting iNKT cell glycolipid ligand α-C-galactosylceramide into HLA-DR4 transgenic mice increased the incidence of arthritis in these animals and exacerbated their clinical symptoms, strongly suggesting a role for Th1 responses in the pathogenesis of citrulline-induced arthritis. Therefore, our findings indicate a role for Th1-mediated immunopathology in citrulline-induced arthritis and provide the first evidence that iNKT cell manipulation by Th2-skewing glycolipids may be of therapeutic value in this clinically relevant model, a finding that is potentially translatable to human RA. PMID:21912419

  19. Transcription Factors Oct-1 and GATA-3 Cooperatively Regulate Th2 Cytokine Gene Expression via the RHS5 within the Th2 Locus Control Region

    PubMed Central

    Kim, Kiwan; Kim, Najung; Lee, Gap Ryol

    2016-01-01

    The T helper type 2 (Th2) locus control region (LCR) regulates Th2 cell differentiation. Several transcription factors bind to the LCR to modulate the expression of Th2 cytokine genes, but the molecular mechanisms behind Th2 cytokine gene regulation are incompletely understood. Here, we used database analysis and an oligonucleotide competition/electrophoretic mobility shift assays to search for transcription factors binding to RHS5, a DNase I hypersensitive site (DHS) within the Th2 LCR. Consequently, we demonstrated that GATA-binding protein-3 (GATA-3), E26 transformation-specific protein 1 (Ets-1), octamer transcription factor-1 (Oct-1), and Oct-2 selectively associate with RHS5. Furthermore, chromatin immunoprecipitation and luciferase reporter assays showed that Oct-1 and Oct-2 bound within the Il4 promoter region and the Th2 LCR, and that Oct-1 and GATA-3 or Oct-2 synergistically triggered the transactivational activity of the Il4 promoter through RHS5. These results suggest that Oct-1 and GATA-3/Oct-2 direct Th2 cytokine gene expression in a cooperative manner. PMID:26840450

  20. MyD88-dependent expansion of an immature GR-1+CD11b+ population induces T cell suppression and Th2 polarization in sepsis

    PubMed Central

    Delano, Matthew J.; Scumpia, Philip O.; Weinstein, Jason S.; Coco, Dominique; Nagaraj, Srinivas; Kelly-Scumpia, Kindra M.; O'Malley, Kerri A.; Wynn, James L.; Antonenko, Svetlana; Al-Quran, Samer Z.; Swan, Ryan; Chung, Chun-Shiang; Atkinson, Mark A.; Ramphal, Reuben; Gabrilovich, Dmitry I.; Reeves, Wesley H.; Ayala, Alfred; Phillips, Joseph; LaFace, Drake; Heyworth, Paul G.; Clare-Salzler, Michael; Moldawer, Lyle L.

    2007-01-01

    Polymicrobial sepsis alters the adaptive immune response and induces T cell suppression and Th2 immune polarization. We identify a GR-1+CD11b+ population whose numbers dramatically increase and remain elevated in the spleen, lymph nodes, and bone marrow during polymicrobial sepsis. Phenotypically, these cells are heterogeneous, immature, predominantly myeloid progenitors that express interleukin 10 and several other cytokines and chemokines. Splenic GR-1+ cells effectively suppress antigen-specific CD8+ T cell interferon (IFN) γ production but only modestly suppress antigen-specific and nonspecific CD4+ T cell proliferation. GR-1+ cell depletion in vivo prevents both the sepsis-induced augmentation of Th2 cell–dependent and depression of Th1 cell–dependent antibody production. Signaling through MyD88, but not Toll-like receptor 4, TIR domain–containing adaptor-inducing IFN-β, or the IFN-α/β receptor, is required for complete GR-1+CD11b+ expansion. GR-1+CD11b+ cells contribute to sepsis-induced T cell suppression and preferential Th2 polarization. PMID:17548519

  1. Prostaglandin D2 and leukotriene E4 synergize to stimulate diverse TH2 functions and TH2 cell/neutrophil crosstalk

    PubMed Central

    Xue, Luzheng; Fergusson, Joannah; Salimi, Maryam; Panse, Isabel; Ussher, James E.; Hegazy, Ahmed N.; Vinall, Shân L.; Jackson, David G.; Hunter, Michael G.; Pettipher, Roy; Ogg, Graham; Klenerman, Paul

    2015-01-01

    Background Prostaglandin D2 (PGD2) and cysteinyl leukotrienes (cysLTs) are lipid mediators derived from mast cells, which activate TH2 cells. The combination of PGD2 and cysLTs (notably cysteinyl leukotriene E4 [LTE4]) enhances TH2 cytokine production. However, the synergistic interaction of cysLTs with PGD2 in promoting TH2 cell activation is still poorly understood. The receptors for these mediators are drug targets in the treatment of allergic diseases, and hence understanding their interaction is likely to have clinical implications. Objective We aimed to comprehensively define the roles of PGD2, LTE4, and their combination in activating human TH2 cells and how such activation might allow the TH2 cells to engage downstream effectors, such as neutrophils, which contribute to the pathology of allergic responses. Methods The effects of PGD2, LTE4, and their combination on human TH2 cell gene expression were defined by using a microarray, and changes in specific inflammatory pathways were confirmed by means of PCR array, quantitative RT-PCR, ELISA, Luminex, flow cytometry, and functional assays, including analysis of downstream neutrophil activation. Blockade of PGD2 and LTE4 was tested by using TM30089, an antagonist of chemoattractant receptor-homologous molecule expressed on TH2 cells, and montelukast, an antagonist of cysteinyl leukotriene receptor 1. Results PGD2 and LTE4 altered the transcription of a wide range of genes and induced diverse functional responses in TH2 cells, including cell adhesion, migration, and survival and cytokine production. The combination of these lipids synergistically or additively enhanced TH2 responses and, strikingly, induced marked production of diverse nonclassical TH2 inflammatory mediators, including IL-22, IL-8, and GM-CSF, at concentrations sufficient to affect neutrophil activation. Conclusions PGD2 and LTE4 activate TH2 cells through different pathways but act synergistically to promote multiple downstream effector

  2. Intravaginal Chlamydia trachomatis Challenge Infection Elicits TH1 and TH17 Immune Responses in Mice That Promote Pathogen Clearance and Genital Tract Damage.

    PubMed

    Vicetti Miguel, Rodolfo D; Quispe Calla, Nirk E; Pavelko, Stephen D; Cherpes, Thomas L

    2016-01-01

    While ascension of Chlamydia trachomatis into the upper genital tract of women can cause pelvic inflammatory disease and Fallopian tube damage, most infections elicit no symptoms or overt upper genital tract pathology. Consistent with this asymptomatic clinical presentation, genital C. trachomatis infection of women generates robust TH2 immunity. As an animal model that modeled this response would be invaluable for delineating bacterial pathogenesis and human host defenses, herein we explored if pathogen-specific TH2 immunity is similarly elicited by intravaginal (ivag) infection of mice with oculogenital C. trachomatis serovars. Analogous to clinical infection, ascension of primary C. trachomatis infection into the mouse upper genital tract produced no obvious tissue damage. Clearance of ivag challenge infection was mediated by interferon (IFN)-γ-producing CD4+ T cells, while IFN-γ signaling blockade concomitant with a single ivag challenge promoted tissue damage by enhancing Chlamydia-specific TH17 immunity. Likewise, IFN-γ and IL-17 signaling blockade or CD4+ T cell depletion eliminated the genital pathology produced in untreated controls by multiple ivag challenge infections. Conversely, we were unable to detect formation of pathogen-specific TH2 immunity in C. trachomatis-infected mice. Together, our work revealed C. trachomatis infection of mice generates TH1 and TH17 immune responses that promote pathogen clearance and immunopathological tissue damage. Absence of Chlamydia-specific TH2 immunity in these mice newly highlights the need to identify experimental models of C. trachomatis genital infection that more closely recapitulate the human host response. PMID:27606424

  3. Amniotic membrane mesenchymal cells-derived factors skew T cell polarization toward Treg and downregulate Th1 and Th17 cells subsets.

    PubMed

    Pianta, Stefano; Bonassi Signoroni, Patrizia; Muradore, Ivan; Rodrigues, Melissa Francis; Rossi, Daniele; Silini, Antonietta; Parolini, Ornella

    2015-06-01

    We previously demonstrated that cells derived from the mesenchymal layer of the human amniotic membrane (hAMSC) and their conditioned medium (CM-hAMSC) modulate lymphocyte proliferation in a dose-dependent manner. In order to understand the mechanisms involved in immune regulation exerted by hAMSC, we analyzed the effects of CM-hAMSC on T-cell polarization towards Th1, Th2, Th17, and T-regulatory (Treg) subsets. We show that CM-hAMSC equally suppresses the proliferation of both CD4(+) T-helper (Th) and CD8(+) cytotoxic T-lymphocytes. Moreover, we prove that the CM-hAMSC inhibitory ability affects both central (CD45RO(+)CD62L(+)) and effector memory (CD45RO(+)CD62L(-)) subsets. We evaluated the phenotype of CD4(+) cells in the MLR setting and showed that CM-hAMSC significantly reduced the expression of markers associated to the Th1 (T-bet(+)CD119(+)) and Th17 (RORγt(+)CD161(+)) populations, while having no effect on the Th2 population (GATA3(+)CD193(+)/GATA3(+)CD294(+)cells). T-cell subset modulation was substantiated through the analysis of cytokine release for 6 days during co-culture with alloreactive T-cells, whereby we observed a decrease in specific subset-related cytokines, such as a decrease in pro-inflammatory, Th1-related (TNFα, IFNγ, IL-1β), Th2 (IL-5, IL-6), Th9 (IL-9), and Th17 (IL-17A, IL-22). Furthermore, CM-hAMSC significantly induced the Treg compartment, as shown by an induction of proliferating CD4(+)FoxP3(+) cells, and an increase of CD25(+)FoxP3(+) and CD39(+)FoxP3(+) Treg in the CD4(+) population. Induction of Treg cells was corroborated by the increased secretion of TGF-β. Taken together, these data strengthen the findings regarding the immunomodulatory properties of CM-hAMSC derived from human amniotic membrane MSC, and in particular provide insights into their effect on regulation of T cell polarization. PMID:25348066

  4. The lignan niranthin poisons Leishmania donovani topoisomerase IB and favours a Th1 immune response in mice

    PubMed Central

    Chowdhury, Sayan; Mukherjee, Tulika; Mukhopadhyay, Rupkatha; Mukherjee, Budhaditya; Sengupta, Souvik; Chattopadhyay, Sharmila; Jaisankar, Parasuraman; Roy, Syamal; Majumder, Hemanta K

    2012-01-01

    Niranthin, a lignan isolated from the aerial parts of the plant Phyllanthus amarus, exhibits a wide spectrum of pharmacological activities. In the present study, we have shown for the first time that niranthin is a potent anti-leishmanial agent. The compound induces topoisomerase I-mediated DNA–protein adduct formation inside Leishmania cells and triggers apoptosis by activation of cellular nucleases. We also show that niranthin inhibits the relaxation activity of heterodimeric type IB topoisomerase of L. donovani and acts as a non-competitive inhibitor interacting with both subunits of the enzyme. Niranthin interacts with DNA–protein binary complexes and thus stabilizes the ‘cleavable complex’ formation and subsequently inhibits the religation of cleaved strand. The compound inhibits the proliferation of Leishmania amastigotes in infected cultured murine macrophages with limited cytotoxicity to the host cells and is effective against antimony-resistant Leishmania parasites by modulating upregulated P-glycoprotein on host macrophages. Importantly, besides its in vitro efficacy, niranthin treatment leads to a switch from a Th2- to a Th1-type immune response in infected BALB/c mice. The immune response causes production of nitric oxide, which results in almost complete clearance of the liver and splenic parasite burden after intraperitoneal or intramuscular administration of the drug. These findings can be exploited to develop niranthin as a new drug candidate against drug-resistant leishmaniasis. PMID:23027614

  5. IFNγ and IL-12 Restrict Th2 Responses during Helminth/Plasmodium Co-Infection and Promote IFNγ from Th2 Cells

    PubMed Central

    Coomes, Stephanie M.; Pelly, Victoria S.; Kannan, Yashaswini; Okoye, Isobel S.; Czieso, Stephanie; Entwistle, Lewis J.; Perez-Lloret, Jimena; Nikolov, Nikolay; Potocnik, Alexandre J.; Biró, Judit; Langhorne, Jean; Wilson, Mark S.

    2015-01-01

    Parasitic helminths establish chronic infections in mammalian hosts. Helminth/Plasmodium co-infections occur frequently in endemic areas. However, it is unclear whether Plasmodium infections compromise anti-helminth immunity, contributing to the chronicity of infection. Immunity to Plasmodium or helminths requires divergent CD4+ T cell-driven responses, dominated by IFNγ or IL-4, respectively. Recent literature has indicated that Th cells, including Th2 cells, have phenotypic plasticity with the ability to produce non-lineage associated cytokines. Whether such plasticity occurs during co-infection is unclear. In this study, we observed reduced anti-helminth Th2 cell responses and compromised anti-helminth immunity during Heligmosomoides polygyrus and Plasmodium chabaudi co-infection. Using newly established triple cytokine reporter mice (Il4gfpIfngyfpIl17aFP635), we demonstrated that Il4gfp+ Th2 cells purified from in vitro cultures or isolated ex vivo from helminth-infected mice up-regulated IFNγ following adoptive transfer into Rag1–/– mice infected with P. chabaudi. Functionally, Th2 cells that up-regulated IFNγ were transcriptionally re-wired and protected recipient mice from high parasitemia. Mechanistically, TCR stimulation and responsiveness to IL-12 and IFNγ, but not type I IFN, was required for optimal IFNγ production by Th2 cells. Finally, blockade of IL-12 and IFNγ during co-infection partially preserved anti-helminth Th2 responses. In summary, this study demonstrates that Th2 cells retain substantial plasticity with the ability to produce IFNγ during Plasmodium infection. Consequently, co-infection with Plasmodium spp. may contribute to the chronicity of helminth infection by reducing anti-helminth Th2 cells and converting them into IFNγ-secreting cells. PMID:26147567

  6. CpG Oligodeoxynucleotide Inhibits Cockroach-Induced Asthma via Induction of IFN-γ+ Th1 Cells or Foxp3+ Regulatory T Cells in the Lung

    PubMed Central

    Kim, Do-Hyun; Sohn, Jung-Ho; Park, Hong-Jai; Lee, Jae-Hyun

    2016-01-01

    Purpose CpG oligodeoxynucleotide (CpG-ODN), a TLR9 agonist, activates innate immunity and induces Th1 response. Although the immune modulatory effect of CpG-ODN has been extensively studied, its function in cockroach extract-induced allergic asthma has not been studied. Here, we investigated the inhibitory function of CpG-ODN in cockroach extract-induced asthma in mice with different treatment schemes. Methods Scheme 1: BALB/C mice were intra-nasally co-administered by cockroach extract and CpG-ODN twice a week for 3 weeks; Scheme 2: The mice were intra-nasally pre-treated with CpG-ODN at day 0 and cockroach allergen challenge was performed from day 3 as in scheme 1. Scheme 3: Cockroach allergen challenge was performed as in scheme 1 and CpG-ODN was post-treated at day 21. Then, BAL cell count, flow cytometric analysis of alveolar macrophages, regulatory T cells, and lung tissue histology, Th1 and Th2 cytokines, serum IgE, cockroach specific IgE, IgG1/IgG2a ratio, and airway hyper-responsiveness were evaluated. Results Mice with repeated intra-nasal exposure to CpG-ODN showed a dramatic decrease in eosinophilic inflammation, goblet cell hyperplasia, and airway hyper-responsiveness with reduction of IL-13, IL-5, and serum IgE, cockroach specific IgE and IgG1/IgG2a ratio. This inhibitory function might be related to the up-regulation of IL-10 and CD4+Foxp3+ regulatory T cells in the lung. Interestingly, one-time challenge of CpG-ODN either prior or posterior to cockroach extract exposure could modulate airway inflammation and hyper-responsiveness via increase of Th1 response. Conclusions Collectively, our data suggest that CpG-ODN treatment modulates Th2 inflammation in the lung by induction of regulatory T cells or Th1 response in a cockroach-induced asthma model. PMID:26922937

  7. Transcriptional Profiling of Th2 Cells Identifies Pathogenic Features Associated with Asthma.

    PubMed

    Seumois, Grégory; Zapardiel-Gonzalo, Jose; White, Brandie; Singh, Divya; Schulten, Veronique; Dillon, Myles; Hinz, Denize; Broide, David H; Sette, Alessandro; Peters, Bjoern; Vijayanand, Pandurangan

    2016-07-15

    Allergic asthma and rhinitis are two common chronic allergic diseases that affect the lungs and nose, respectively. Both diseases share clinical and pathological features characteristic of excessive allergen-induced type 2 inflammation, orchestrated by memory CD4(+) T cells that produce type 2 cytokines (Th2 cells). However, a large majority of subjects with allergic rhinitis do not develop asthma, suggesting divergence in disease mechanisms. Because Th2 cells play a pathogenic role in both these diseases and are also present in healthy nonallergic subjects, we performed global transcriptional profiling to determine whether there are qualitative differences in Th2 cells from subjects with allergic asthma, rhinitis, and healthy controls. Th2 cells from asthmatic subjects expressed higher levels of several genes that promote their survival as well as alter their metabolic pathways to favor persistence at sites of allergic inflammation. In addition, genes that enhanced Th2 polarization and Th2 cytokine production were also upregulated in asthma. Several genes that oppose T cell activation were downregulated in asthma, suggesting enhanced activation potential of Th2 cells from asthmatic subjects. Many novel genes with poorly defined functions were also differentially expressed in asthma. Thus, our transcriptomic analysis of circulating Th2 cells has identified several molecules that are likely to confer pathogenic features to Th2 cells that are either unique or common to both asthma and rhinitis. PMID:27271570

  8. Interferon Regulatory Factor (IRF)-4 regulates the expression of a subset of Th2 cytokines 1

    PubMed Central

    Ahyi, Ayele-Nati N.; Chang, Hua-Chen; Dent, Alexander L.; Nutt, Stephen L.; Kaplan, Mark H.

    2009-01-01

    Th2 cells can be subdivided into subpopulations depending on the level of a cytokine and the subsets of cytokines they produce. We have recently identified the ETS family transcription factor PU.1 as regulating heterogeneity in Th2 populations. To define additional factors that might contribute to Th2 heterogeneity, we examined the PU.1 interacting protein IFN-regulatory factor (IRF)-4. When Th2 cells are separated based on levels of IL-10 secretion, IRF4 expression segregates into the subset of Th2 cells expressing high levels of IL-10. Infection of total Th2 cells, and IL-10 non-secreting cells, with retrovirus expressing IRF4, resulted in increased IL-4 and IL-10 expression, no change in IL-5 or IL-13 production and decreased Il9 transcription. Transfection of an IRF4-specific siRNA into Th2 cells decreases IL-10 production. IRF4 directly binds the Il10 gene as evidenced by ChIP assay, and regulates Il10 control elements in a reporter assay. IRF4 interacts with PU.1, and in PU.1-deficient T cells there was an increase in IRF4 binding to the Il10 gene, and in the ability of IRF4 to induce IL-10 production compared to wild type cells and Il10 promoter activity in a reporter assay. Further heterogeneity of IRF4 expression was observed in Th2 cells analyzed for expression of multiple Th2 cytokines. Thus, IRF4 promotes the expression of a subset of Th2 cytokines and contributes to Th2 heterogeneity. PMID:19592658

  9. Mitigation of pyrexia by a Th-1-biased IgG subclass response after infection with equine herpesvirus type 1 in horses pre-immunized with inactivated vaccine.

    PubMed

    Bannai, Hiroshi; Tsujimura, Koji; Kondo, Takashi; Nemoto, Manabu; Yamanaka, Takashi; Sugiura, Takeo; Kato, Tomohiro; Maeda, Ken; Matsumura, Tomio

    2012-06-01

    The immunoglobulin G (IgG) subclass response was investigated in horses with or without pyrexia after natural infection with equine herpesvirus type 1 (EHV-1) in the field. All horses were kept at the training centers of the Japan Racing Association and were immunized with an inactivated EHV-1 vaccine before EHV-1 infection. An IgG subclass response dominated by IgGa and IgGb was induced in horses without pyrexia after EHV-1 infection. In contrast, horses that developed pyrexia showed increased IgGc and IgG (T) subclass production in addition to IgGa and IgGb. Although inactivated EHV-1 vaccines are considered to induce a mainly Th-2-biased response, these results indicated that the responses in horses inoculated with inactivated EHV-1 vaccine were not uniform, and that horses with a Th-1-biased response were likely to be protected from pyrexia. PMID:22230983

  10. Memory Th1 Cells Are Protective in Invasive Staphylococcus aureus Infection.

    PubMed

    Brown, Aisling F; Murphy, Alison G; Lalor, Stephen J; Leech, John M; O'Keeffe, Kate M; Mac Aogáin, Micheál; O'Halloran, Dara P; Lacey, Keenan A; Tavakol, Mehri; Hearnden, Claire H; Fitzgerald-Hughes, Deirdre; Humphreys, Hilary; Fennell, Jérôme P; van Wamel, Willem J; Foster, Timothy J; Geoghegan, Joan A; Lavelle, Ed C; Rogers, Thomas R; McLoughlin, Rachel M

    2015-01-01

    Mechanisms of protective immunity to Staphylococcus aureus infection in humans remain elusive. While the importance of cellular immunity has been shown in mice, T cell responses in humans have not been characterised. Using a murine model of recurrent S. aureus peritonitis, we demonstrated that prior exposure to S. aureus enhanced IFNγ responses upon subsequent infection, while adoptive transfer of S. aureus antigen-specific Th1 cells was protective in naïve mice. Translating these findings, we found that S. aureus antigen-specific Th1 cells were also significantly expanded during human S. aureus bloodstream infection (BSI). These Th1 cells were CD45RO+, indicative of a memory phenotype. Thus, exposure to S. aureus induces memory Th1 cells in mice and humans, identifying Th1 cells as potential S. aureus vaccine targets. Consequently, we developed a model vaccine comprising staphylococcal clumping factor A, which we demonstrate to be an effective human T cell antigen, combined with the Th1-driving adjuvant CpG. This novel Th1-inducing vaccine conferred significant protection during S. aureus infection in mice. This study notably advances our understanding of S. aureus cellular immunity, and demonstrates for the first time that a correlate of S. aureus protective immunity identified in mice may be relevant in humans. PMID:26539822

  11. Memory Th1 Cells Are Protective in Invasive Staphylococcus aureus Infection

    PubMed Central

    Lalor, Stephen J.; Leech, John M.; O’Keeffe, Kate M.; Mac Aogáin, Micheál; O’Halloran, Dara P.; Lacey, Keenan A.; Tavakol, Mehri; Hearnden, Claire H.; Fitzgerald-Hughes, Deirdre; Humphreys, Hilary; Fennell, Jérôme P.; van Wamel, Willem J.; Foster, Timothy J.; Geoghegan, Joan A.; Lavelle, Ed C.; Rogers, Thomas R.; McLoughlin, Rachel M.

    2015-01-01

    Mechanisms of protective immunity to Staphylococcus aureus infection in humans remain elusive. While the importance of cellular immunity has been shown in mice, T cell responses in humans have not been characterised. Using a murine model of recurrent S. aureus peritonitis, we demonstrated that prior exposure to S. aureus enhanced IFNγ responses upon subsequent infection, while adoptive transfer of S. aureus antigen-specific Th1 cells was protective in naïve mice. Translating these findings, we found that S. aureus antigen-specific Th1 cells were also significantly expanded during human S. aureus bloodstream infection (BSI). These Th1 cells were CD45RO+, indicative of a memory phenotype. Thus, exposure to S. aureus induces memory Th1 cells in mice and humans, identifying Th1 cells as potential S. aureus vaccine targets. Consequently, we developed a model vaccine comprising staphylococcal clumping factor A, which we demonstrate to be an effective human T cell antigen, combined with the Th1-driving adjuvant CpG. This novel Th1-inducing vaccine conferred significant protection during S. aureus infection in mice. This study notably advances our understanding of S. aureus cellular immunity, and demonstrates for the first time that a correlate of S. aureus protective immunity identified in mice may be relevant in humans. PMID:26539822

  12. The System Overview and Geometric Image Quality of the TH-1 Satellite

    NASA Astrophysics Data System (ADS)

    Wang, Jianrong; Hu, Xin

    2016-06-01

    The Tian-Hui 1 (TH-1) is the first stereo mapping transmission satellite in China, and the primary mission goal of the satellite is for topographic mapping at 1:50,000 scale without Ground Control Points (GCPs). 1st, 2nd and 3rd satellite of TH-1 was launched on August 24, 2010, May 6, 2012 and October 26, 2015. In TH-1 satellite, many payloads are put on a small satellite platform, which has a low cost. The optical camera of TH-1 includes Line-Matrix CCD (LMCCD) camera, high resolution camera and multispectral camera with 60 km ground swath width. To get high geometric accuracy without GCPs, the on-orbit calibration camera parameters and the Equivalent Frame Photo (EFP) Multi-functional bundle adjustment are proposed and realized in ground image processing of TH-1. In order to evaluate the location accuracy of TH-1, some testing fields are established. All GCPs of testing fields are measured by GPS. The GCPs are not participated the EFP Multi-functional bundle adjustment, and are only as Check Points (CPs) to evaluate the location accuracy. The evaluation of 1st satellite is shown: the horizontal accuracy is 10.3 m (RMSE) and the vertical accuracy is 5.7 m (RMSE) without GCPs, which can satisfy for topographic mapping at 1:50,000 scale. The overviews of TH-1 satellite are described in this paper: First, the system overview is introduced, including mission and optical camera of TH-1. Then, the on-orbit calibration camera parameters using LMCCD image and the EFP Multi-functional bundle adjustment are presented. Finally, the location performance is analysed without GCPs and with different number of GCPs. In addition, the products of TH-1 are introduced.

  13. Direct evidence for role of anti-saliva antibodies against salivary gland homogenate of P. argentipes in modulation of protective Th1-immune response against Leishmania donovani.

    PubMed

    Pushpanjali; Thakur, Ajit K; Purkait, Bidyut; Jamal, Fauzia; Singh, Manish K; Ahmed, Ghufran; Bimal, Sanjiva; Kumar, Vijay; Singh, Subhankar K; Keshri, Srikant; Das, Pradeep; Narayan, Shyam

    2016-10-01

    Currently the main concerns regarding control of visceral leishmaniasis (VL) caused by L. donovani are immunosuppression, relating toxicity of anti-leishmanial drug and little development in appropriate vaccine and vector (P. argentipes) control. Reports available from ex-vivo studies reflect significance of vector salivary gland homogenate (SGH) in reverting immunosuppression of infected VL subjects and as such the immunogenic nature of SGH can be a strategy to modulate immune system and anti-leishmanial function to enable immune response to control the disease. Several related studies also identified a better utility of vector anti-saliva antibodies in achieving such effects by an adoptive transfer approach instead of direct stimulation with SGH protein. However, conclusive evidences on VL cases are far beyond satisfactory to suggest role of SGH into modulation of host immune response in VL subjects in India. This study was under taken to make comparison on change in cytokines (TH1 and TH2) response pattern and anti-leishmanial macrophage (Mϕ) function following stimulation of their PBMCS with SGH protein derived from P. argentipes sand fly vector for VL or anti SGH antibodies raised in rabbit. This study reports for the first time that L. donovani sensitized healthy subject demonstrates an up-regulated Interferon-γ (TH1) and down regulate Interleukin-10 (TH2) production following stimulation of their PBMCs by P. argentipes anti-saliva antibodies accompanied with an improvement in anti-leishmanial Mϕ function for nitric oxide (NO) production. Subsequent experiments suggest that P. argentipes based anti-SGH antibodies when used to stimulate LD infected PBMCs in healthy subjects resulted in better clearance of Leishmania amastigotes load compare to SGH protein. Possibly the immunogenic components of anti-saliva an antibody maintains the level of protective cytokine (INF-γ) and seems to restrict the infection by host protection by vector saliva. PMID:27484246

  14. iNKT Cells Are Responsible for the Apoptotic Reduction of Basophils That Mediate Th2 Immune Responses Elicited by Papain in Mice Following γPGA Stimulation

    PubMed Central

    Park, Se-Ho; Hong, Seokmann

    2016-01-01

    Recent studies have demonstrated that Bacillus subtilis-derived poly-gamma glutamic acid (γPGA) treatment suppresses the development of allergic diseases such as atopic dermatitis (AD). Although basophils, an innate immune cell, are known to play critical roles in allergic immune responses and repeated long-term administration of γPGA results in decreased splenic basophils in an AD murine model, the underlying mechanisms by which γPGA regulates basophil frequency remain unclear. To investigate how γPGA modulates basophils, we employed basophil-mediated Th2 induction in vivo model elicited by the allergen papain protease. Repeated injection of γPGA reduced the abundance of basophils and their production of IL4 in mice, consistent with our previous study using NC/Nga AD model mice. The depletion of basophils by a single injection of γPGA was dependent on the TLR4/DC/IL12 axis. CD1d-dependent Vα14 TCR invariant natural killer T (iNKT) cells are known to regulate a variety of immune responses, such as allergy. Because iNKT cell activation is highly sensitive to IL12 produced by DCs, we evaluated whether the effect of γPGA on basophils is mediated by iNKT cell activation. We found that in vivo γPGA treatment did not induce the reduction of basophils in iNKT cell-deficient CD1d KO mice, suggesting the critical role of iNKT cells in γPGA-mediated basophil depletion at the early time points. Furthermore, increased apoptotic basophil reduction triggered by iNKT cells upon γPGA stimulation was mainly attributed to Th1 cytokines such as IFNγ and TNFα, consequently resulting in inhibition of papain-induced Th2 differentiation via diminishing basophil-derived IL4. Taken together, our results clearly demonstrate that γPGA-induced iNKT cell polarization toward the Th1 phenotype induces apoptotic basophil depletion, leading to the suppression of Th2 immune responses. Thus, elucidation of the crosstalk between innate immune cells will contribute to the design and

  15. iNKT Cells Are Responsible for the Apoptotic Reduction of Basophils That Mediate Th2 Immune Responses Elicited by Papain in Mice Following γPGA Stimulation.

    PubMed

    Park, Hyun Jung; Lee, Sung Won; Park, Se-Ho; Hong, Seokmann

    2016-01-01

    Recent studies have demonstrated that Bacillus subtilis-derived poly-gamma glutamic acid (γPGA) treatment suppresses the development of allergic diseases such as atopic dermatitis (AD). Although basophils, an innate immune cell, are known to play critical roles in allergic immune responses and repeated long-term administration of γPGA results in decreased splenic basophils in an AD murine model, the underlying mechanisms by which γPGA regulates basophil frequency remain unclear. To investigate how γPGA modulates basophils, we employed basophil-mediated Th2 induction in vivo model elicited by the allergen papain protease. Repeated injection of γPGA reduced the abundance of basophils and their production of IL4 in mice, consistent with our previous study using NC/Nga AD model mice. The depletion of basophils by a single injection of γPGA was dependent on the TLR4/DC/IL12 axis. CD1d-dependent Vα14 TCR invariant natural killer T (iNKT) cells are known to regulate a variety of immune responses, such as allergy. Because iNKT cell activation is highly sensitive to IL12 produced by DCs, we evaluated whether the effect of γPGA on basophils is mediated by iNKT cell activation. We found that in vivo γPGA treatment did not induce the reduction of basophils in iNKT cell-deficient CD1d KO mice, suggesting the critical role of iNKT cells in γPGA-mediated basophil depletion at the early time points. Furthermore, increased apoptotic basophil reduction triggered by iNKT cells upon γPGA stimulation was mainly attributed to Th1 cytokines such as IFNγ and TNFα, consequently resulting in inhibition of papain-induced Th2 differentiation via diminishing basophil-derived IL4. Taken together, our results clearly demonstrate that γPGA-induced iNKT cell polarization toward the Th1 phenotype induces apoptotic basophil depletion, leading to the suppression of Th2 immune responses. Thus, elucidation of the crosstalk between innate immune cells will contribute to the design and

  16. IL25 elicits a multipotent progenitor cell population that promotes TH2 cytokine responses

    Technology Transfer Automated Retrieval System (TEKTRAN)

    CD4+ T helper 2 (TH2) cells secrete interleukin (IL)4, IL5 and IL13, and are required for immunity to gastrointestinal helminth infections. However, TH2 cells also promote chronic inflammation associated with asthma and allergic disorders. The non-haematopoietic-cell-derived cytokines thymic stromal...

  17. Retnla (Relma/Fizz1) suppresses helminth-induced Th2-Type immunity

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Retnla (Resistin-like molecule alpha/FIZZ1) is induced during Th2 cytokine immune responses. Using Retnla deficient (-/-) mice and three helminth models, we show that Retnla functions as a negative regulator of Th2 responses. Pulmonary granuloma formation induced by the eggs of the helminth parasite...

  18. Molecular events by which dendritic cells promote Th2 immune protection in helmith infection.

    PubMed

    Méndez-Samperio, Patricia

    2016-10-01

    Helminth parasites are a major cause of global infectious diseases, affecting nearly one quarter of the world's population. The common feature of helminth infections is to skew the immune system towards a T-helper 2 (Th2) response that helps to control disease. Dendritic cells (DCs), which are professional antigen-presenting cells, play a critical role for Th2 skewing against helminth parasites. However, the molecular mechanisms by which helminth antigens activate DCs for Th2 polarization have not yet been clearly defined. This review provides a focused update on the major role of DCs for inducing and/or enhancing Th2 immune responses in helminthic infection and will discuss the main signalling-dependent and independent mechanisms by which helminth antigens activate DCs for Th2 skewing. PMID:27348757

  19. Current Views on the Roles of Th1 and Th17 Cells in Experimental Autoimmune Encephalomyelitis

    PubMed Central

    El-behi, Mohamed; Rostami, Abdolmohamad

    2010-01-01

    Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are autoimmune demyelinating diseases of the central nervous system (CNS). Interferon-γ-producing Th1 and interleukin-17-producing Th17 CD4+ T helper (Th) cells mediate disease pathogenesis in EAE and likely in MS as well. However, the relative contribution of each Th subset to autoimmune processes in the CNS remains unclear. Emerging data suggest that both Th1 and Th17 cells contribute to CNS autoimmunity, albeit through different mechanisms. A better understanding of the roles that Th1 and Th17 cells play in autoimmune inflammation will be helpful in developing new therapeutic approaches. In this review, we discuss recent findings on the roles of Th1 and Th17 cells in the pathogenesis of EAE. PMID:20107924

  20. Infection of non-encapsulated species of Trichinella ameliorates experimental autoimmune encephalomyelitis involving suppression of Th17 and Th1 response.

    PubMed

    Wu, Zhiliang; Nagano, Isao; Asano, Kazunobu; Takahashi, Yuzo

    2010-10-01

    Epidemiological and experimental studies have indicated that helminth infections can ameliorate autoimmune diseases. The present study investigated the amelioration effect of the Trichinella pseudospiralis infection on experimental autoimmune encephalomyelitis (EAE), a T-cell-mediated autoimmune disease of central nervous system (CNS), and expression kinetics of Th17 and Th1 cytokine which play a crucial role in the pathogenesis of EAE. The results indicated that the infection of helminth T. pseudospiralis obviously ameliorated clinical severity and greatly delayed the onset of EAE induced by myelin oligodendrocyte glycoprotein (MOG) immunization. Infection caused much lesser inflammatory infiltration and demyilination in the CNS of infected EAE mice than uninfected EAE mice. The reduced infiltration was also suggested by the expressions of the inflammation cytokines, IL-17, IL-6, IL-1β, IFN-γ, and TNF-α, which were high in the spinal cords of the uninfected EAE mice, but was nearly normal or low in the infected EAE mice. The increased production of MOG-induced IL-17 and IFN-γ and the expression of IL-6, IL-1β, TGF-β in splenocytes after restimulation with MOG was inhibited in the infected EAE mice. On the other hand, the greatly induced Th2 response was observed in the splenocytes of the infected EAE mice. The present study showed that T. pseudospiralis infection can suppresses EAE by reducing the inflammatory infiltration in CNS, likely associated with the suppression of Th17 and Th1 responses by the infection. PMID:20661746

  1. Release from Th1-type immune tolerance in spleen and enhanced production of IL-5 in Peyer's patch by cholera toxin B induce the glomerular deposition of IgA.

    PubMed

    Yamanaka, Takahiro; Tamauchi, Hidekazu; Suzuki, Yusuke; Suzuki, Hitoshi; Horikoshi, Satoshi; Terashima, Masazumi; Iwabuchi, Kazuya; Habu, Sonoko; Okumura, Ko; Tomino, Yasuhiko

    2016-04-01

    We examined the pathogenesis of glomerular damage in Th2 type-dependent GATA-3 transgenic (GATA-3 Tg) mice with IgA nephropathy (IgAN). GATA-3 Tg mice were immunized orally using OVA plus cholera toxin B (CTB), and measurement of the serum IgA antibody level and histopathological examination were performed. Marked increases in the serum levels of OVA-specific IgA antibody, IgA and IgG, C3 deposits analogous to those seen in IgAN, and expansion of the matrix in association with mesangial cell proliferation were observed. Furthermore, glomerular IgA deposits were co-localized with mannan-binding lectin (MBL) deposits, which might actually have been abnormal IgA deposits. In GATA-3/TCR-Tg mice that had been orally sensitized with CTB plus OVA and were re-stimulated with OVA in vitro, cultured Peyer's patch cells showed the enhanced production of IL-5 and supernatants from cultures of spleen cells showed a reduction of TGF-β production with a simultaneous increase in IL-2 production and the recovery of IFN-γ formation. The amount of TGF-β produced by the spleen cells was found to be correlated with the amount of IFN-γ and IL-IL-2 produced by the cells. Also, the percentage of regulatory T cells (Treg) in the spleens of mice sensitized with OVA plus CTB was lower than that in mice orally sensitized with OVA alone. These results suggest that the increased production of IL-5 from Peyer's patch cells (PPc) and the restored Th1-type immune response might cause the production of abnormal IgA and might induce the deposition of IgA in glomeruli. PMID:26719095

  2. Plasmids enriched with CpG motifs activate human peripheral blood mononuclear cells in vitro and enhance th-1 immune responses to hepatitis B surface antigen in mice.

    PubMed

    Chen, Zhihui; Cao, Jie; Liao, Xiaoling; Ke, Jinshan; Zhu, Shiying; Zhao, Ping; Qi, Zhongtian

    2011-06-01

    T helper-1 (Th-1)-type immune responses play an important role in viral clearance during infection with hepatitis B virus (HBV). Unmethylated CpG motifs present in bacterial DNA can activate toll-like receptor 9 (TLR9) signals and act as potent adjuvants to induce Th-1-type immune responses. Here, a mini-plasmid with 812 base pairs in length was constructed and used as a vector to prepare a series of plasmids containing 3-21 copies of D-type CpG motifs. In vitro, these CpG-enriched plasmids strongly stimulated proliferation of human peripheral blood mononuclear cells (PBMCs) and enhanced secretion of interferon-γ (IFN-γ) and interleukin-12 (IL-12). The responses of the PBMCs from healthy individuals to the plasmids were stronger than those obtained from HBV-infected individuals. Contrary to the strong Th-2-biased response induced by surface antigen of hepatitis B virus (HBsAg) plus alum adjuvant, immunization of BALB/c mice with HBsAg plus these plasmids induced a strong Th-1-biased response. The plasmids increased the titers of HBsAg-specific total immunoglobulin G (IgG) and IgG(2a). HBsAg-specific IL-2 and IFN-γ production and cytotoxic activity were also enhanced in the presence of the plasmids. The strength of the immune responses positively correlated with the number of CpG motifs in the plasmids. These results indicate that the use of CpG-enriched plasmids as an adjuvant to recombinant HBsAg could provide a promising and cost-effective approach for the development of efficacious therapeutic vaccines against HBV infection. PMID:21668361

  3. The Relationship between the Antitumor Effect of the IL-12 Gene Therapy and the Expression of Th1 Cytokines in an HPV16-Positive Murine Tumor Model

    PubMed Central

    García Paz, Flor; Madrid Marina, Vicente; Morales Ortega, Ausencio; Santander González, Abimelec; Peralta Zaragoza, Oscar; Burguete García, Ana; Torres Poveda, Kirvis; Moreno, José; Alcocer González, Juan; Hernandez Marquez, Eva; Bermúdez Morales, Victor

    2014-01-01

    Objective. The goal of the present study was to investigate the effect of IL-12 expressed in plasmid on the Th1 cytokine profile in an experimental HPV16-positive murine tumor model and the association with the IL-12's antitumor effect. Methods. Mice were injected with BMK-16/myc cells to establish HPV16-positive tumor and then pNGVL3-mIL-12 plasmid; pcDNA3 plasmid or PBS was injected directly into tumor site. The antitumor effect of the treatment was evaluated and the cytokines expression profile in each tumor tissue was analyzed. Results. Treatment with pNGVL3-mIL-12 plasmid had a significant antitumor effect, and a Th2-Th3-type cytokines prolife was detected in the murine tumor model with expression of the cytokines IL-10, IL-4, and TGF-β1. However, after the tumor was treated with three intratumoral injections of plasmid containing IL-12 cDNA, it showed a cytokine profile associated with Th1 with expression of IL-2, IL-12, and IFN-γ cytokines and reduced expression of IL-10, IL-4, and TGF-β1. Conclusions. The treatment with the IL-12 gene in the experimental HPV16-positive tumor model promoted the activation of the cellular immune response via expression of a Th1-type cytokine profile and was associated with the inhibition of tumor growth. Thus, IL-12 treatment represents a novel approach for gene therapy against cervical cancer. PMID:24808638

  4. A recombinant Leishmania antigen that stimulates human peripheral blood mononuclear cells to express a Th1-type cytokine profile and to produce interleukin 12

    PubMed Central

    1995-01-01

    Leishmania braziliensis causes cutaneous and mucosal leishmaniasis in humans. Most patients with cutaneous leishmaniasis heal spontaneously and may therefore have developed protective immunity. There appears to be a mixed cytokine profile associated with active cutaneous or mucosal disease, and a dominant T helper (Th)1-type response associated with healing. Leishmanial antigens that elicit these potent proliferative and cytokine responses from peripheral blood mononuclear cells (PBMC) are now being identified. Herein, we report on the cloning and expression of a L. braziliensis gene homologous to the eukaryotic ribosomal protein eIF4A (LeIF) and patient PBMC responses to rLeIF. Patients with mucosal and self-healing cutaneous disease had significantly higher proliferative responses than those with cutaneous lesions. Whereas the parasite lysate stimulated patient PBMC to produce a mixed Th1/Th2-type cytokine profile, LeIF stimulated the production of interferon gamma (IFN-gamma), interleukin 2 (IL-2), and tumor necrosis factor alpha but not IL-4 or IL-10. Recombinant LeIF (rLeIF) downregulated both IL-10 mRNA in the "resting" PBMC of leishmaniasis patients and LPS-induced IL-10 production by patient PBMC. rLeIF also stimulated the production of IL-12 in cultured PBMC from both patients and uninfected individuals. The production of IFN-gamma by patient PBMC stimulated with either rLeIF or parasite lysate was IL-12 dependent, whereas anti-IFN-gamma monoclonal antibody only partially blocked the LeIF-induced production of IL-12. In vitro production of both IFN-gamma and IL-12 was abrogated by exogenous human recombinant IL-10. Therefore, we have identified a recombinant leishmanial antigen that elicits IL-12 production and Th1-type responses in patients as well as IL-12 production in normal human PBMC. PMID:7699334

  5. Interleukin-6 Induced "Acute" Phenotypic Microenvironment Promotes Th1 Anti-Tumor Immunity in Cryo-Thermal Therapy Revealed By Shotgun and Parallel Reaction Monitoring Proteomics.

    PubMed

    Xue, Ting; Liu, Ping; Zhou, Yong; Liu, Kun; Yang, Li; Moritz, Robert L; Yan, Wei; Xu, Lisa X

    2016-01-01

    Cryo-thermal therapy has been emerged as a promising novel therapeutic strategy for advanced breast cancer, triggering higher incidence of tumor regression and enhanced remission of metastasis than routine treatments. To better understand its anti-tumor mechanism, we utilized a spontaneous metastatic mouse model and quantitative proteomics to compare N-glycoproteome changes in 94 serum samples with and without treatment. We quantified 231 highly confident N-glycosylated proteins using iTRAQ shotgun proteomics. Among them, 53 showed significantly discriminated regulatory patterns over the time course, in which the acute phase response emerged as the most enhanced pathway. The anti-tumor feature of the acute response was further investigated using parallel reaction monitoring target proteomics and flow cytometry on 23 of the 53 significant proteins. We found that cryo-thermal therapy reset the tumor chronic inflammation to an "acute" phenotype, with up-regulation of acute phase proteins including IL-6 as a key regulator. The IL-6 mediated "acute" phenotype transformed IL-4 and Treg-promoting ICOSL expression to Th1-promoting IFN-γ and IL-12 production, augmented complement system activation and CD86(+)MHCII(+) dendritic cells maturation and enhanced the proliferation of Th1 memory cells. In addition, we found an increased production of tumor progression and metastatic inhibitory proteins under such "acute" environment, favoring the anti-metastatic effect. Moreover, cryo-thermal on tumors induced the strongest "acute" response compared to cryo/hyperthermia alone or cryo-thermal on healthy tissues, accompanying by the most pronounced anti-tumor immunological effect. In summary, we demonstrated that cryo-thermal therapy induced, IL-6 mediated "acute" microenvironment shifted the tumor chronic microenvironment from Th2 immunosuppressive and pro-tumorigenic to Th1 immunostimulatory and tumoricidal state. Moreover, the magnitude of "acute" and "danger" signals play a key

  6. TPL-2 Regulates Macrophage Lipid Metabolism and M2 Differentiation to Control TH2-Mediated Immunopathology

    PubMed Central

    Entwistle, Lewis J.; Khoury, Hania; Papoutsopoulou, Stamatia; Mahmood, Radma; Mansour, Nuha R.; Ching-Cheng Huang, Stanley; Pearce, Edward J.; Pedro S. de Carvalho, Luiz; Ley, Steven C.

    2016-01-01

    Persistent TH2 cytokine responses following chronic helminth infections can often lead to the development of tissue pathology and fibrotic scarring. Despite a good understanding of the cellular mechanisms involved in fibrogenesis, there are very few therapeutic options available, highlighting a significant medical need and gap in our understanding of the molecular mechanisms of TH2-mediated immunopathology. In this study, we found that the Map3 kinase, TPL-2 (Map3k8; Cot) regulated TH2-mediated intestinal, hepatic and pulmonary immunopathology following Schistosoma mansoni infection or S. mansoni egg injection. Elevated inflammation, TH2 cell responses and exacerbated fibrosis in Map3k8–/–mice was observed in mice with myeloid cell-specific (LysM) deletion of Map3k8, but not CD4 cell-specific deletion of Map3k8, indicating that TPL-2 regulated myeloid cell function to limit TH2-mediated immunopathology. Transcriptional and metabolic assays of Map3k8–/–M2 macrophages identified that TPL-2 was required for lipolysis, M2 macrophage activation and the expression of a variety of genes involved in immuno-regulatory and pro-fibrotic pathways. Taken together this study identified that TPL-2 regulated TH2-mediated inflammation by supporting lipolysis and M2 macrophage activation, preventing TH2 cell expansion and downstream immunopathology and fibrosis. PMID:27487182

  7. TPL-2 Regulates Macrophage Lipid Metabolism and M2 Differentiation to Control TH2-Mediated Immunopathology.

    PubMed

    Kannan, Yashaswini; Perez-Lloret, Jimena; Li, Yanda; Entwistle, Lewis J; Khoury, Hania; Papoutsopoulou, Stamatia; Mahmood, Radma; Mansour, Nuha R; Ching-Cheng Huang, Stanley; Pearce, Edward J; Pedro S de Carvalho, Luiz; Ley, Steven C; Wilson, Mark S

    2016-08-01

    Persistent TH2 cytokine responses following chronic helminth infections can often lead to the development of tissue pathology and fibrotic scarring. Despite a good understanding of the cellular mechanisms involved in fibrogenesis, there are very few therapeutic options available, highlighting a significant medical need and gap in our understanding of the molecular mechanisms of TH2-mediated immunopathology. In this study, we found that the Map3 kinase, TPL-2 (Map3k8; Cot) regulated TH2-mediated intestinal, hepatic and pulmonary immunopathology following Schistosoma mansoni infection or S. mansoni egg injection. Elevated inflammation, TH2 cell responses and exacerbated fibrosis in Map3k8-/-mice was observed in mice with myeloid cell-specific (LysM) deletion of Map3k8, but not CD4 cell-specific deletion of Map3k8, indicating that TPL-2 regulated myeloid cell function to limit TH2-mediated immunopathology. Transcriptional and metabolic assays of Map3k8-/-M2 macrophages identified that TPL-2 was required for lipolysis, M2 macrophage activation and the expression of a variety of genes involved in immuno-regulatory and pro-fibrotic pathways. Taken together this study identified that TPL-2 regulated TH2-mediated inflammation by supporting lipolysis and M2 macrophage activation, preventing TH2 cell expansion and downstream immunopathology and fibrosis. PMID:27487182

  8. IL-10-Expressing Th2 Cells Contribute to the Elevated Antibody Production in Rheumatoid Arthritis.

    PubMed

    Wang, Jinliang; Ma, Liheng; Yang, Shufeng; Wang, Shaohua; Wei, Xuan; Song, Shuchun

    2016-06-01

    Rheumatoid arthritis (RA) is a common autoimmune disease associated with progressive disability, systemic complications, and early death. Multiple lines of evidence have placed adaptive immune responses in the center of RA pathogenesis. However, the functional roles of T helper cells are insufficiently described. Here, we examined the Th2 cell subsets and their functions in RA patients. A downregulation of IL-4(+) cells in CD4(+) T cells were observed in RA patients, indicating a downregulation of Th2 cells, and these results were confirmed by using and CXCR3 and CCR6 surface markers. We then found that CXCR3(-)CCR6(-) Th2 cells can be separated into IL-4(+) (single positive), IL-10(+) (single positive), and IL-4(+)IL-10(+) (double positive) subsets. Further results showed that CXCR5 only expressed on IL-10+ Th2 cells. The CXCR5(+) and CXCR5(-) Th2 cells each exhibited distinctive features in helping B cell antibody secretion. CXCR5(+) Th2 cells were more potent at stimulating total Ig and IgM secretion, while CXCR5(-) Th2 cells were more potent at stimulating IgE. IL-10 was required for helping B cell total Ig, IgM, and IgE production, while IL-4 was required for total Ig and IgE. The frequencies of IL-10(+) and IL-4(+)IL-10(+) Th2 cells were positively correlated with rheumatoid factor titer in vivo. Together, our study demonstrated distinctive subsets within Th2 cells, each with different impacts on antibody production and RA disease. PMID:26956472

  9. The hair dyes PPD and PTD fail to induce a T(H)2 immune response following repeated topical application in BALB/c mice.

    PubMed

    Rothe, Helga; Sarlo, Katherine; Scheffler, Heike; Goebel, Carsten

    2011-01-01

    1,4-Phenylenediamine (PPD) and the structurally-related 1,4-toluenediamine (PTD) are frequently used oxidative hair dye precursors that can induce a delayed-type hypersensitivity reaction known as contact allergy. Very rare cases of Type 1 (IgE-mediated) allergic responses associated with PPD or PTD have been reported among hair dye users. As part of an effort to determine if repeated dermal exposure to the dyes could induce a T-helper-2 (T(H)2) response, we used a dermal exposure regimen in mice reported to identify a T(H)2 response. Ear swelling was evident at post-final exposure to PPD and PTD, indicating that an immune response was observed. However, cytokine mRNA after repeated topical exposure to these two chemicals showed no shift in the expression toward the typical T(H)2 cytokines interleukin (IL)-4 and IL-10 compared to the T(H)1 cytokine interferon (IFN)-γ. Consistent with these cytokine profiles, no concomitant increase in total serum IgE antibody titer or in B220+IgE+ lymphocytes in lymph nodes and skin application site skin was detected. In contrast, using an identical exposure regimen, animals topically exposed to the known respiratory (Type 1) allergen toluene 2,4-diisocyanate (TDI) showed significant expression of IL-4 and IL-10 mRNA compared to IFN? as well as an increase in total serum IgE and in B220+IgE+ cells in lymph nodes and skin application site. The data generated are consistent with the pattern of adverse reactions to hair dyes seen clinically, which overwhelmingly is of delayed rather than immediate-type hypersensitivity. Although current animal models have a limited ability to detect rare T(H)2 responses to contact allergens, the present study results support the view that exposure to hair dyes is not associated with relevant T(H)2 induction. PMID:21299354

  10. Proinflammatory and Th1 cytokine alterations following ultraviolet radiation enhancement of disease due to influenza infection in mice.

    PubMed

    Ryan, Lisa K; Copeland, Lisa R; Daniels, Mary J; Costa, Elisabeth R; Selgrade, Mary Jane K

    2002-05-01

    Exposure of rodents to immunosuppressive agents such as ozone, dioxin, or ultraviolet radiation (UVR) leads to increased morbidity and mortality following influenza virus infection. However, these adverse effects are not related to the suppression of virus-specific immune responses. Our laboratory showed that UVR increased the morbidity, mortality, and pathogenesis of influenza virus without affecting protective immunity to the virus, as measured by resistance to reinfection, suggesting that UVR and other immunosuppressive pollutants such as dioxin and ozone may exacerbate early responses that contribute to the pathogenesis of a primary viral infection. In the present study, we examined the mechanism of UVR-enhanced mortality in the absence of effects on virus-specific immunity and tested the hypothesis that modulation of cytokine levels was associated with increased deaths and body weight loss. BALB/c mice were exposed to 8.2 kJ/m(2) UVR and were infected 3 days later with a sublethal influenza virus infection (LD(40) of mouse-adapted Hong Kong influenza A/68, H(3)N(2)). Influx of inflammatory cells, proinflammatory cytokines, and cytokines produced by T-helper lymphocytes (Th1 and Th2) were measured in lung homogenates (LH) as well as in bronchoalveolar lavage fluid (BAL). UVR preexposure decreased the influenza-induced lymphocytic influx 5 days after infection, but did not alter macrophage and neutrophil influx into the lung, or increase virus titers significantly. Although interferon (IFN)-gamma, total interleukin (IL)-12, IL-6, and TNF-alpha were altered in mice that received UVR exposure prior to infection, no clear association was made that correlated with the UVR-induced increase in body weight loss and mortality due to influenza infection. PMID:11961220

  11. STAT5-induced lunatic fringe during Th2 development alters delta-like 4-mediated Th2 cytokine production in respiratory syncytial virus-exacerbated airway allergic disease.

    PubMed

    Mukherjee, Sumanta; Rasky, Andrew J; Lundy, Phil A; Kittan, Nicolai A; Kunkel, Steven L; Maillard, Ivan P; Kowalski, Paul E; Kousis, Philaretos C; Guidos, Cynthia J; Lukacs, Nicholas W

    2014-02-01

    Notch activation plays an important role in T cell development and mature T cell differentiation. In this study, we investigated the role of Notch activation in a mouse model of respiratory syncytial virus (RSV)-exacerbated allergic airway disease. During RSV exacerbation, in vivo neutralization of a specific Notch ligand, Delta-like ligand (Dll)-4, significantly decreased airway hyperreactivity, mucus production, and Th2 cytokines. Lunatic Fringe (Lfng), a glycosyltransferase that enhances Notch activation by Dll4, was increased during RSV exacerbation. Lfng loss of function in Th2-skewed cells inhibited Dll4-Notch activation and subsequent IL-4 production. Further knockdown of Lfng in T cells in CD4Cre(+)Lfng(fl/fl) mice showed reduced Th2 response and disease pathology during RSV exacerbation. Finally, we identified STAT5-binding cis-acting regulatory element activation as a critical driver of Lfng transcriptional activation. These data demonstrate that STAT5-dependent amplification of Notch-modifying Lfng augments Th2 response via Dll4 and is critical for amplifying viral exacerbation during allergic airway disease. PMID:24367028

  12. IL-23 signaling enhances Th2 polarization and regulates allergic airway inflammation

    PubMed Central

    Peng, Juan; Yang, Xuexian O.; Chang, Seon Hee; Yang, Jiong; Dong, Chen

    2009-01-01

    IL-23/IL-17 axis is an important regulator in various inflammatory diseases. However, the role of IL-23 in allergic airway inflammation is not well understood. In this study, we show that in an allergen-induced asthma model, mice with transgenic overexpression of IL-23R exhibited increased airway infiltration of eosinophils and Th2 cytokine production, whereas those deficient in IL-23 displayed reduced airway inflammation. In vitro, IL-23-IL-23R signaling promoted GATA-3 expression and enhanced Th2 cytokine expression. Conversely, in the absence of this signal, Th2 cell differentiation was partially inhibited. Therefore, IL-23 signaling may regulate allergic asthma through modulation of Th2 cell differentiation. PMID:19935773

  13. Chronic Helminth Infection Induces Alternatively Activated Macrophages Expressing High Levels of CCR5 with Low Interleukin-12 Production and Th2-Biasing Ability

    PubMed Central

    Rodríguez-Sosa, Miriam; Satoskar, Abhay R.; Calderón, Rodrigo; Gomez-Garcia, Lorena; Saavedra, Rafael; Bojalil, Rafael; Terrazas, Luis I.

    2002-01-01

    Helminth infections induce Th2-type biased immune responses. Although the mechanisms involved in this phenomenon are not yet clearly defined, antigen-presenting cells (APC) could play an important role in this process. Here, we have used peritoneal macrophages (F4/80+) recruited at different times after challenge with Taenia crassiceps as APC and tested their ability to regulate Th1/Th2 differentiation. Macrophages from acute infections produced high levels of interleukin-12 (IL-12) and nitric oxide (NO), paralleled with low levels of IL-6 and prostaglandin E2 (PGE2) and with the ability to induce strong antigen-specific CD4+ T-cell proliferation in response to nonrelated antigens. In contrast, macrophages from chronic infections produced higher levels of IL-6 and PGE2 and had suppressed production of IL-12 and NO, associated with a poor ability to induce antigen-specific proliferation in CD4+ T cells. Failure to induce proliferation was not due to a deficient expression of accessory molecules, since major histocompatibility complex class II, CD40, and B7-2 were up-regulated, together with CD23 and CCR5 as infection progressed. These macrophages from chronic infections were able to bias CD4+ T cells to produce IL-4 but not gamma interferon (IFN-γ), contrary to macrophages from acute infections. Blockade of B7-2 and IL-6 and inhibition of PGE2 failed to restore the proliferative response in CD4+ T cells. Furthermore, studies using STAT6−/− mice revealed that STAT6-mediated signaling was essential for the expansion of these alternatively activated macrophages. These data demonstrate that helminth infections can induce different macrophage populations that have Th2-biasing properties. PMID:12065507

  14. Antigen-pulsed bone marrow derived and pulmonary dendritic cells promote Th2 cell responses and immunopathology in lungs during the pathogenesis of murine mycoplasma pneumonia1

    PubMed Central

    Dobbs, Nicole A.; Zhou, Xia; Pulse, Mark; Hodge, Lisa M.; Schoeb, Trenton R.; Simecka, Jerry W.

    2014-01-01

    Mycoplasmas are a common cause of pneumonia in humans and animals, and attempts to create vaccines have not only failed to generate protective host responses, but exacerbated the disease. Mycoplasma pulmonis causes a chronic inflammatory lung disease resulting from a persistent infection, similar to other mycoplasma respiratory diseases. Using this model, Th1 subsets promote resistance to mycoplasma disease and infection, while Th2 responses contribute to immunopathology. The purpose of these studies was to evaluate the capacity of cytokine differentiated dendritic cells (DC) populations to influence the generation of protective and/or pathologic immune responses during M. pulmonis respiratory disease in BALB/c mice. We hypothesized that intratracheal inoculation of mycoplasma antigen-pulsed bone marrow derived dendritic cells (BMDC) could result in the generation of protective T cell responses during mycoplasma infection. However, intratracheal inoculation (priming) of mice with antigen-pulsed DCs resulted enhanced pathology in the recipient mice when challenged with mycoplasma. Inoculation of immunodeficient SCID mice with antigen-pulsed DCs demonstrated that this effect was dependent on lymphocyte responses. Similar results were observed when mice were primed with antigen-pulsed pulmonary, but not splenic, DCs. Lymphocytes generated in uninfected mice after the transfer of either antigen-pulsed BMDCs or pulmonary DCs were shown to be IL13+ Th2 cells, known to be associated with immunopathology. Thus, resident pulmonary DC most likely promote the development of immunopathology in mycoplasma disease through the generation of mycoplasma-specific Th2 responses. Vaccination strategies that disrupt or bypass this process could potentially result in a more effective vaccination. PMID:24973442

  15. Natural killer cells regulate Th1/Treg and Th17/Treg balance in chlamydial lung infection.

    PubMed

    Li, Jing; Dong, Xiaojing; Zhao, Lei; Wang, Xiao; Wang, Yan; Yang, Xi; Wang, Hong; Zhao, Weiming

    2016-07-01

    Natural killer (NK) cell is an important component in innate immunity, playing a critical role in bridging innate and adaptive immunity by modulating the function of other immune cells including T cells. In this study, we focused on the role of NK cells in regulating Th1/Treg and Th17/Treg balance during chlamydial lung infection. We found that NK cell-depleted mice showed decreased Th1 and Th17 cells, which was correlated with reduced interferon-γ, interleukin (IL)-12, IL-17 and IL-22 production as well as T-bet and receptor-related orphan receptor gamma t expression compared with mice treated with the isotype control antibody. In contrast, NK cell depletion significantly increased Treg in cell number and related transcription factor (Foxp3) expression. The opposite trends of changes of Th1/Th17 and Treg led to significant reduction in the Th1/Treg and Th17/Treg ratios. The data implicate that NK cells play an important role in host defence against chlamydial lung infection, mainly through maintaining Th1/Treg and Th17/Treg balance. PMID:27028780

  16. Effect of Malnutrition on the Expression of Cytokines Involved in Th1 Cell Differentiation

    PubMed Central

    González-Torres, Cristina; González-Martínez, Haydeé; Miliar, Angel; Nájera, Oralia; Graniel, Jaime; Firo, Verónica; Alvarez, Catalina; Bonilla, Edmundo; Rodríguez, Leonor

    2013-01-01

    Malnutrition is a common cause of secondary immune deficiency and has been linked to an increased susceptibility to infection in humans. Malnutrition specifically affects T-cell-mediated immune responses. The aim of this study was to assess in lymphocytes from malnourished children the expression levels of IL-12, IL-18 and IL-21, molecules that induce the differentiation of T cells related to the immunological cellular response (Th1 response) and the production of cytokines related to the immunological cellular response (Th1 cytokines). We found that the expression levels of IL-12, IL-18 and IL-21 were significantly diminished in malnourished children compared to well-nourished children and were coincident with lower plasmatic levels of IL-2 and IFN-γ (Th1 cytokines). In this study, we show for the first time that the gene expression and intracellular production of cytokines responsible for Th1 cell differentiation (IL-12, IL-18 and IL-21) are diminished in malnourished children. As expected, this finding was related to lower plasmatic levels of IL-2 and IFN-γ. The decreased expression of Th1 cytokines observed in this study may contribute to the deterioration of the immunological Type 1 (cellular) response. We hypothesize that the decreased production of IL-12, IL-18 and IL-21 in malnourished children contributes to their inability to eradicate infections. PMID:23429441

  17. The cAMP response element modulator (CREM) regulates TH2 mediated inflammation

    PubMed Central

    Verjans, Eva; Ohl, Kim; Reiss, Lucy K.; van Wijk, Femke; Toncheva, Antonaneta A.; Wiener, Anastasia; Yu, Yin; Rieg, Annette D.; Gaertner, Vincent D.; Roth, Johannes; Knol, Edward; Kabesch, Michael; Wagner, Norbert; Uhlig, Stefan; Martin, Christian; Tenbrock, Klaus

    2015-01-01

    A characteristic feature of allergic diseases is the appearance of a subset of CD4+ cells known as TH2 cells, which is controlled by transcriptional and epigenetic mechanisms. We aimed to analyze the role of CREM, a known transcriptional activator of T cells, with regard to TH2 responses and allergic diseases in men and mice. Here we demonstrate that T cells of asthmatic children and PBMCs of adults with atopy express lower mRNA levels of the transcription factor CREM compared to cells from healthy controls. CREM deficiency in murine T cells results in enhanced TH2 effector cytokines in vitro and in vivo and CREM−/− mice demonstrate stronger airway hyperresponsiveness in an OVA-induced asthma model. Mechanistically, both direct CREM binding to the IL-4 and IL-13 promoter as well as a decreased IL-2 dependent STAT5 activation suppress the TH2 response. Accordingly, mice selectively overexpressing CREMα in T cells display decreased TH2 type cytokines in vivo and in vitro, and are protected in an asthma model. Thus, we provide evidence that CREM is a negative regulator of the TH2 response and determines the outcome of allergic asthma. PMID:26459392

  18. The preventive effects of natural adjuvants, G2 and G2F on tracheal responsiveness and serum IL-4 and IFN-γ (th1/th2 balance) in sensitized guinea pigs

    PubMed Central

    Boskabady, Mohammad Hossein; Neamati, Ali; Hazrati, Saleh Mohaghegh; Khakzad, Mohammad Reza; Moosavi, Shakeeb Hassan; Gholamnezhad, Zahra

    2014-01-01

    OBJECTIVE: The effects of natural adjuvants on lung inflammation and tracheal responsiveness were examined in sensitized guinea pigs. METHODS: The responses of guinea pig tracheal chains and the serum levels of interleukin-4 and interferon-gamma were examined in control pigs and three other groups of guinea pigs: the sensitized group and two other sensitized groups treated with either adjuvant G2 or adjuvant G2F (n = 7 for each group). Sensitization of the animals was achieved by injection and inhalation of ovalbumin. RESULTS: The results showed that sensitized animals had increased tracheal responsiveness and increased serum levels of interleukin-4 and interferon-gamma compared to controls (p<0.05 to p<0.001). Treatments with either G2 or G2F prevented the increase in tracheal responsiveness and serum interleukin-4 (p<0.01 to p<0.001). However, the serum levels of interferon-gamma and the interleukin-4-to-interferon-gamma ratio was increased in the treated groups (p<0.001 for all cases). CONCLUSIONS: These results indicate important preventive effects of two natural adjuvants, particularly G2, on the changes in tracheal responsiveness, serum cytokines and the interleukin-4-to-interferon-gamma ratio (T helper 1/T helper 2 balance) in sensitized guinea pigs. PMID:25029582

  19. Intraperitoneal Administration of Muramyl Dipeptide β-Heptylglycoside to Pregnant and Non-Pregnant Female Mice Modulates Production of Th1/Th2/Th17/Tr1 Cytokines by Splenocytes Ex Vivo.

    PubMed

    Kalyuzhin, O V; Artem'eva, K A; Boltovskaya, M N; Bunyatyan, K A; Inviyayeva, E V; Vinnitskii, L I; Karaulov, A V

    2015-05-01

    Muramyl dipeptide β-heptylglycoside (C7MDP) was administered to non-pregnant CBA female mice and pregnant mice after non-abortion-prone mating (CBA×BALB/c) and mating associated with a high rate of spontaneous abortion (CBA×DBA/2). In non-pregnant females, C7MDP increased the production of IL-2, IL-4, IL-5, IL-6, IL-17, IFNγ, TNFα, and GM-CSF at constant production of IL-1α and IL-10. C7MDP increased the production of IL-10 and IL-17 and suppressed the production of IFNγ on day 8 of gestation in non-abortion-prone mouse couples and stimulated the synthesis of IL-4 and IFNγ, reduced IL-5 production, and slightly increased IL-1α secretion after abortion-prone mating. On day 14 of gestation, C7MDP elevated the yield of IL-2, IL-4, IFNγ, TNFα, and GM-CSF in CBA×BALB/c and CBA×DBA/2 couples and IL-17 in the fi rst variant of mating. PMID:26033590

  20. CYTOKINE-INDUCED ALTERATIONS OF α7 NICOTINIC RECEPTOR IN COLONIC CD4 T CELLS MEDIATE DICHOTOMOUS RESPONSE TO NICOTINE IN MURINE MODELS OF Th1/Th17 VS. Th2-MEDIATED COLITIS

    PubMed Central

    Galitovskiy, Valentin; Qian, Jing; Chernyavsky, Alexander I.; Marchenko, Steve; Gindi, Vivian; Edwards, Robert A.; Grando, Sergei A.

    2014-01-01

    Ulcerative colitis (UC) and Crohn’s disease (CD) are two forms of chronic inflammatory bowel disease. CD4 T cells play a central role in the pathogenesis of both diseases. Smoking affects both UC and CD but with opposite effects, ameliorating UC and worsening CD. We hypothesized that the severity of gut inflammation could be modulated through T-cell nicotinic acetylcholine receptors (nAChRs) and that the exact clinical outcome would depend on the repertoire of nAChRs on CD4 T cells mediating each form of colitis. We measured clinical and immunologic outcomes of treating BALB/c mice with oxazolone- and TNBS-induced colitides by nicotine. Nicotine attenuated oxazolone colitis, which was associated with increased percentage of colonic Tregs and a reduction of Th17 cells. TCR stimulation of naïve CD4+CD62L+ T cells in the presence of nicotine upregulated expression of Foxp3. In marked contrast, nicotine worsened TNBS colitis, and this was associated with increased Th17 cells among colonic CD4 T cells. Nicotine upregulated IL-10 and inhibited IL-17 production, which could be abolished by exogenous IL-12 that also abolished the nicotine-dependent upregulation of Tregs. The dichotomous action of nicotine resulted from the up- and downregulation of anti-inflammatory α7 nAChR on colonic CD4 T cells induced by cytokines characteristic of the inflammatory milieu in oxazolone (IL-4), and TNBS (IL-12) colitis, respectively. These findings help explain the dichotomous effect of smoking in patients with UC and CD, and underscore the potential for nicotinergic drugs in regulating colonic inflammation. PMID:21784975

  1. Accumulation of intraepithelial mast cells with a unique protease phenotype in TH2-high asthma

    PubMed Central

    Dougherty, Ryan H.; Sidhu, Sukhvinder S.; Raman, Kavita; Solon, Margaret; Solberg, Owen D.; Caughey, George H.; Woodruff, Prescott G.; Fahy, John V.

    2010-01-01

    Background Previously, we found that mast cell tryptases and carboxypeptidase A3 (CPA3) are differentially expressed in the airway epithelium in asthmatic subjects. We also found that asthmatic subjects can be divided into 2 subgroups (“TH2 high” and “TH2 low” asthma) based on epithelial cell gene signatures for the activity of TH2 cytokines. Objectives We sought to characterize intraepithelial mast cells (IEMCs) in asthma. Methods We performed gene expression profiling in epithelial brushings and stereology-based quantification of mast cell numbers in endobronchial biopsy specimens from healthy control and asthmatic subjects before and after treatment with inhaled corticosteroids (ICSs). We also performed gene expression and protein quantification studies in cultured airway epithelial cells and mast cells. Results By means of unsupervised clustering, mast cell gene expression in the airway epithelium related closely to the expression of IL-13 signature genes. The levels of expression of mast cell genes correlate positively with lung function improvements with ICSs. IEMC density was 2-fold higher than normal in subjects with TH2-high asthma compared with that seen in subjects with TH2-low asthma or healthy control subjects (P = .015 for both comparisons), and these cells were characterized by expression of tryptases and CPA3 but not chymase. IL-13 induced expression of stem cell factor in cultured airway epithelial cells, and mast cells exposed to conditioned media from IL-13–activated epithelial cells showed downregulation of chymase but no change in tryptase or CPA3 expression. Conclusion IEMC numbers are increased in subjects with TH2-high asthma, have an unusual protease phenotype (tryptase and CPA3 high and chymase low), and predict responsiveness to ICSs. IL-13–stimulated production of stem cell factor by epithelial cells potentially explains mast cell accumulation in TH2-high asthmatic epithelium. PMID:20451039

  2. Contribution of Basophils to Cutaneous Immune Reactions and Th2-Mediated Allergic Responses

    PubMed Central

    Otsuka, Atsushi; Kabashima, Kenji

    2015-01-01

    Basophils are potent effector cells of innate immunity and also play a role in T helper 2 (Th2)-mediated allergic responses. But, although their in vitro functions are well studied, their in vivo functions remain largely unknown. However, several mouse models of basophil depletion have recently been developed and used to investigate basophil functions. For example, in a croton oil-induced model of irritant contact dermatitis in conditionally basophil-depleted transgenic mice, we found that basophils rapidly infiltrate inflamed skin and subsequently induce infiltration of eosinophils. We also showed that basophils induce Th2 skewing upon epicutaneous sensitization with various haptens and peptide antigens. Intriguingly, basophils also promoted Th2 polarization upon protein antigen exposure in the presence of dendritic cells (DCs). The dermal DC subset associated with Th2 skewing was recently identified as CD301b+ DC. Such studies with basophil-deficient mouse models have significantly improved our understanding of the mechanisms involved in human immune-related diseases. In this review, we will focus on the relative contribution of basophils and DCs to Th2-mediated allergic responses. PMID:26284076

  3. A miRNA upregulated in asthma airway T cells promotes TH2 cytokine production

    PubMed Central

    Simpson, Laura J.; Patel, Sana; Bhakta, Nirav R.; Choy, David F.; Brightbill, Hans D.; Ren, Xin; Wang, Yanli; Pua, Heather H.; Baumjohann, Dirk; Montoya, Misty M.; Panduro, Marisella; Remedios, Kelly A.; Huang, Xiaozhu; Fahy, John V.; Arron, Joseph R.; Woodruff, Prescott G.; Ansel., Karl M.

    2014-01-01

    MicroRNAs (miRNAs) exert powerful effects on immune function by tuning networks of target genes that orchestrate cell behavior. We sought to uncover miRNAs and miRNA-regulated pathways that control the TH2 responses that drive pathogenic inflammation in asthma. Profiling miRNA expression in human airway-infiltrating T cells revealed miR-19a elevation in asthma. Modulating miR-19 activity altered TH2 cytokine production in both human and mouse T cells, and TH2 cell responses were markedly impaired in cells lacking the entire miR-17∼92 cluster. miR-19 promotes TH2 cytokine production and amplifies PI(3)K, JAK-STAT, and NF-κB signaling by direct targeting of PTEN, SOCS1, and A20. Thus, miR-19a up regulation in asthma may be an indicator and a cause of increased TH2 cytokine production in the airways. PMID:25362490

  4. Protease-Activated Receptor 2 Is Involved in Th2 Responses against Trichinella spiralis Infection

    PubMed Central

    Park, Mi Kyung; Cho, Min Kyoung; Kang, Shin Ae; Park, Hye-Kyung; Kim, Yun Seong; Kim, Ki Uk; Ahn, Soon Cheol; Kim, Dong-Hee

    2011-01-01

    In order to get a better understanding of the role of protease-activated receptor 2 (PAR2) in type 2 helper T (Th2) cell responses against Trichinella spiralis infection, we analyzed Th2 responses in T. spiralis-infected PAR2 knockout (KO) mice. The levels of the Th2 cell-secreted cytokines, IL-4, IL-5, and IL-13 were markedly reduced in the PAR2 KO mice as compared to the wild type mice following infection with T. spiralis. The serum levels of parasite-specific IgE increased significantly in the wild type mice as the result of T. spiralis infection, but this level was not significantly increased in PAR2 KO mice. The expression level of thymic stromal lymphopoietin, IL-25, and eotaxin gene (the genes were recently known as Th2 response initiators) of mouse intestinal epithelial cells were increased as the result of treatment with T. spiralis excretory-secretory proteins. However, the expression of these chemokine genes was inhibited by protease inhibitor treatments. In conclusion, PAR2 might involve in Th2 responses against T. spiralis infection. PMID:22072823

  5. Foxa2 programs Th2 cell-mediated innate immunity in the developing lung.

    PubMed

    Chen, Gang; Wan, Huajing; Luo, Fengming; Zhang, Liqian; Xu, Yan; Lewkowich, Ian; Wills-Karp, Marsha; Whitsett, Jeffrey A

    2010-06-01

    After birth, the respiratory tract adapts to recurrent exposures to pathogens, allergens, and toxicants by inducing the complex innate and acquired immune systems required for pulmonary homeostasis. In this study, we show that Foxa2, expressed selectively in the respiratory epithelium, plays a critical role in regulating genetic programs influencing Th2 cell-mediated pulmonary inflammation. Deletion of the Foxa2 gene, encoding a winged helix/forkhead box transcription factor that is selectively expressed in respiratory epithelial cells, caused spontaneous pulmonary eosinophilic inflammation and goblet cell metaplasia. Loss of Foxa2 induced the recruitment and activation of myeloid dendritic cells and Th2 cells in the lung, causing increased production of Th2 cytokines and chemokines. Loss of Foxa2-induced expression of genes regulating Th2 cell-mediated inflammation and goblet cell differentiation, including IL-13, IL-4, eotaxins, thymus and activation-regulated chemokine, Il33, Ccl20, and SAM pointed domain-containing Ets transcription factor. Pulmonary inflammation and goblet cell differentiation were abrogated by treatment of neonatal Foxa2(Delta/Delta) mice with mAb against IL-4Ralpha subunit. The respiratory epithelium plays a central role in the regulation of Th2-mediated inflammation and innate immunity in the developing lung in a process regulated by Foxa2. PMID:20483781

  6. AKT isoforms modulate Th1-like Treg generation and function in human autoimmune disease.

    PubMed

    Kitz, Alexandra; de Marcken, Marine; Gautron, Anne-Sophie; Mitrovic, Mitja; Hafler, David A; Dominguez-Villar, Margarita

    2016-08-01

    Foxp3(+) regulatory T cells (Tregs) exhibit plasticity, which dictates their function. Secretion of the inflammatory cytokine IFNγ, together with the acquisition of a T helper 1 (Th1)-like effector phenotype as observed in cancer, infection, and autoimmune diseases, is associated with loss of Treg suppressor function through an unknown mechanism. Here, we describe the signaling events driving the generation of human Th1-Tregs. Using a genome-wide gene expression approach and pathway analysis, we identify the PI3K/AKT/Foxo1/3 signaling cascade as the major pathway involved in IFNγ secretion by human Tregs. Furthermore, we describe the opposing roles of AKT isoforms in Th1-Treg generation ex vivo Finally, we employ multiple sclerosis as an in vivo model with increased but functionally defective Th1-Tregs. We show that the PI3K/AKT/Foxo1/3 pathway is activated in ex vivo-isolated Tregs from untreated relapsing-remitting MS patients and that blockade of the pathway inhibits IFNγ secretion and restores the immune suppressive function of Tregs. These data define a fundamental pathway regulating the function of human Tregs and suggest a novel treatment paradigm for autoimmune diseases. PMID:27312110

  7. Propionibacterium acnes promotes Th17 and Th17/Th1 responses in acne patients.

    PubMed

    Kistowska, Magdalena; Meier, Barbara; Proust, Tatiana; Feldmeyer, Laurence; Cozzio, Antonio; Kuendig, Thomas; Contassot, Emmanuel; French, Lars E

    2015-01-01

    Propionibacterium acnes is a Gram-positive commensal bacterium thought to be involved in the pathogenesis of acne vulgaris. Although the ability of P. acnes in the initiation of pro-inflammatory responses is well documented, little is known about adaptive immune responses to this bacterium. The observation that infiltrating immune cells consist mainly of CD4(+) T cells in the perifollicular space of early acne lesions suggests that helper T cells may be involved in immune responses caused by the intra-follicular colonization of P. acnes. A recent report showing that P. acnes can induce IL-17 production by T cells suggests that acne might be a T helper type 17 (Th17)-mediated disease. In line with this, we show in this work that, in addition to IL-17A, both Th1 and Th17 effector cytokines, transcription factors, and chemokine receptors are strongly upregulated in acne lesions. Furthermore, we found that, in addition to Th17, P. acnes can promote mixed Th17/Th1 responses by inducing the concomitant secretion of IL-17A and IFN-γ from specific CD4(+) T cells in vitro. Finally, we show that both P. acnes-specific Th17 and Th17/Th1 cells can be found in the peripheral blood of patients suffering from acne and, at lower frequencies, in healthy individuals. We therefore identified P. acnes-responding Th17/Th1 cells as, to our knowledge, a previously unreported CD4(+) subpopulation involved in inflammatory acne. PMID:25010142

  8. Instantaneous dynamic change detection based on three-line-array stereoscopic images of TH-1 satellite

    NASA Astrophysics Data System (ADS)

    Zheng, Tuanjie; Cheng, Jiasheng; Li, Heyuan

    2014-05-01

    TH-1 satellite loading three-line array stereoscopic camera, can scanning 3 times from different directions on the same region or target within the time for about 1 minute, conducive to regional monitoring or target instantaneous change monitoring. Based on the time difference of forward, nadir and backward images of the three-line-array camera of TH-1 Satellite, this paper gives a method to get regional dynamic change image by processing of geometric and physical consistency under the principle of photogrammetry, and to construct the model of change detection by the quantitative results of change detection under the improvement and optimization of noise filtering algorithm. The experimental results show that, by using the detection results of forward, nadir and backward images of the three-line -array camera of TH-1 Satellite, moving distance and velocity can be accurately calculated, and quantitative monitoring of topography changes can be achieved, which not only has temporal resolution, but also can't be achieved by other environmental monitoring satellites. It's significant for flood, fire, clouds, or motion detectors. TH-1 satellite is China's first generation of transmission photogrammetry satellite. With the more satellites networking operation, and higher spatial and temporal resolution, The TH satellites will play a greater role in the field of Earth observation. This article merely uses the principles of photogrammetry to consider photography deformation from different directions, and thorough study will aim at shadow and sun elevation angle, to fully realize the monitoring of changes in topography and moving targets.

  9. Salvianolic acid B ameliorates CNS autoimmunity by suppressing Th1 responses.

    PubMed

    Dong, Zhihui; Ma, Dihui; Gong, Ye; Yu, Tingmin; Yao, Gang

    2016-04-21

    Experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS), is a Th1 and Th17 cell-mediated CNS autoimmune disease. Therefore, immune regulation is a key target for therapy. Salvianolic acid B (Sal B) is a major water-soluble bioactive component of the famous traditional Chinese medicine Salvia miltiorrhiza, which is notable for its anti-oxidative and anti-inflammatory effects. Thus Sal B, by impairing Th1 or Th17 responses in EAE/MS, might ameliorate the crippling symptoms. Here we show that the intraperitoneal administration of 30mg/kg Sal B daily for 14 days after the onset of MOG-induced EAE in mice effectively reduced its severity. Additionally, Sal B treatment downgraded the infiltration of inflammatory cells, limited astrogliosis and blocked Th1 responses other than that of Th17. These results indicated that Sal B may serve as an effective therapeutic agent for MS/EAE by inhibiting Th1 cell responses. PMID:26777627

  10. HemoHIM ameliorates the persistent down-regulation of Th1-like immune responses in fractionated γ-irradiated mice by modulating the IL-12p70-STAT4 signaling pathway.

    PubMed

    Park, Hae-Ran; Jo, Sung-Kee; Choi, Nam-Hee; Jung, Uhee

    2012-05-01

    Whole body irradiated mice appear to experience a down-regulation of the helper T (Th)1-like immune response, and maintain a persistent immunological imbalance. In the current study, we evaluated the effect of HemoHIM (an herbal product made from Angelica Radix, Cnidium officinale , and Paeonia japonica cultivated in Korea) to ameliorate the immunological imbalance induce in fractionated γ-irradiated mice. The mice were exposed to γ rays twice a week (0.5 Gy fractions) for a total dose of 5 Gy, and HemoHIM was administrated orally from 1 week before the first irradiation to 1 week before the final analysis. All experiments were performed 4 and 6 months after their first exposure. HemoHIM ameliorated the Th1- and Th2-related immune responses normally occur in irradiated mice with or without dinitrophenylated keyhole limpet hemocyanin immunization. HemoHIM also restored the natural killer cell activities without changing the percentage of natural killer cells in irradiated mice. Furthermore, the administration of HemoHIM prevented the reduction in levels of interleukin-12p70 in irradiated mice. Finally, we found that HemoHIM enhanced the phosphorylation of signal transducer and activator of transcription (STAT) 4 that was reduced in irradiated mice. Our findings suggest that HemoHIM ameliorates the persistent down-regulation of Th1-like immune responses by modulating the IL-12p70/pSTAT4 signaling pathway. PMID:22439601

  11. Inhibition of Th2 cytokine production in T cells by monascin via PPAR-γ activation.

    PubMed

    Hsu, Wei-Hsuan; Lee, Bao-Hong; Hsu, Ya-Wen; Pan, Tzu-Ming

    2013-08-28

    Yellow pigment monascin (MS) is a secondary metabolite isolated from Monascus -fermented products and has numerous physiological activities. However, the potential use of MS for immunomodulation remains unclear. We showed that MS and the synthetic peroxisome proliferator-activated receptor (PPAR)-γ ligand rosiglitazone (RG) significantly inhibited the production of Th2 cytokines, including IL-4, IL-5, and IL-13, in PMA/ionomycin-activated mouse EL-4 T cells. Moreover, we showed that this was due to cellular PPAR-γ translocation. These results indicate that MS and RG promote PPAR-γ-DNA interactions and suggest that the regulatory effects of MS and RG on Th2 cytokine production could be abolished with PPAR-γ antagonist treatment. MS and RG also suppressed Th2 transcription factor translocation (e.g., GATA-3 and nuclear factor of activated T cells) by preventing the phosphorylation of protein kinase C and signal transducer and activator of transcription 6. PMID:23848565

  12. Indigenous enteric eosinophils control DCs to initiate a primary Th2 immune response in vivo

    PubMed Central

    Chu, Derek K.; Jimenez-Saiz, Rodrigo; Verschoor, Christopher P.; Walker, Tina D.; Goncharova, Susanna; Llop-Guevara, Alba; Shen, Pamela; Gordon, Melissa E.; Barra, Nicole G.; Bassett, Jennifer D.; Kong, Joshua; Fattouh, Ramzi; McCoy, Kathy D.; Bowdish, Dawn M.; Erjefält, Jonas S.; Pabst, Oliver; Humbles, Alison A.; Kolbeck, Roland; Waserman, Susan

    2014-01-01

    Eosinophils natively inhabit the small intestine, but a functional role for them there has remained elusive. Here, we show that eosinophil-deficient mice were protected from induction of Th2-mediated peanut food allergy and anaphylaxis, and Th2 priming was restored by reconstitution with il4+/+ or il4−/− eosinophils. Eosinophils controlled CD103+ dendritic cell (DC) activation and migration from the intestine to draining lymph nodes, events necessary for Th2 priming. Eosinophil activation in vitro and in vivo led to degranulation of eosinophil peroxidase, a granule protein whose enzymatic activity promoted DC activation in mice and humans in vitro, and intestinal and extraintestinal mouse DC activation and mobilization to lymph nodes in vivo. Further, eosinophil peroxidase enhanced responses to ovalbumin seen after immunization. Thus, eosinophils can be critical contributors to the intestinal immune system, and granule-mediated shaping of DC responses can promote both intestinal and extraintestinal adaptive immunity. PMID:25071163

  13. Indigenous enteric eosinophils control DCs to initiate a primary Th2 immune response in vivo.

    PubMed

    Chu, Derek K; Jimenez-Saiz, Rodrigo; Verschoor, Christopher P; Walker, Tina D; Goncharova, Susanna; Llop-Guevara, Alba; Shen, Pamela; Gordon, Melissa E; Barra, Nicole G; Bassett, Jennifer D; Kong, Joshua; Fattouh, Ramzi; McCoy, Kathy D; Bowdish, Dawn M; Erjefält, Jonas S; Pabst, Oliver; Humbles, Alison A; Kolbeck, Roland; Waserman, Susan; Jordana, Manel

    2014-07-28

    Eosinophils natively inhabit the small intestine, but a functional role for them there has remained elusive. Here, we show that eosinophil-deficient mice were protected from induction of Th2-mediated peanut food allergy and anaphylaxis, and Th2 priming was restored by reconstitution with il4(+/+) or il4(-/-) eosinophils. Eosinophils controlled CD103(+) dendritic cell (DC) activation and migration from the intestine to draining lymph nodes, events necessary for Th2 priming. Eosinophil activation in vitro and in vivo led to degranulation of eosinophil peroxidase, a granule protein whose enzymatic activity promoted DC activation in mice and humans in vitro, and intestinal and extraintestinal mouse DC activation and mobilization to lymph nodes in vivo. Further, eosinophil peroxidase enhanced responses to ovalbumin seen after immunization. Thus, eosinophils can be critical contributors to the intestinal immune system, and granule-mediated shaping of DC responses can promote both intestinal and extraintestinal adaptive immunity. PMID:25071163

  14. MicroRNA-mediated Th2 bias in methimazole-induced acute liver injury in mice.

    PubMed

    Uematsu, Yasuaki; Akai, Sho; Tochitani, Tomoaki; Oda, Shingo; Yamada, Toru; Yokoi, Tsuyoshi

    2016-09-15

    MicroRNA (miRNA) is a class of small non-coding RNAs containing approximately 20 nucleotides that negatively regulate target gene expression. Little is known about the role of individual miRNAs and their targets in immune- and inflammation-related responses in drug-induced liver injury. In the present study, involvement of miRNAs in the T helper (Th) 2-type immune response was investigated using a methimazole (MTZ)-induced liver injury mouse model. Co-administration of L-buthionine-S,R-sulfoximine and MTZ induced acute hepatocellular necrosis and elevated plasma levels of alanine aminotransferase (ALT) from 4h onward in female Balb/c mice. The hepatic mRNA expression of Th2 promotive factors was significantly increased concomitantly with plasma ALT levels. In contrast, the hepatic mRNA expression of Th2 suppressive factors was significantly decreased during the early phase of liver injury. Comprehensive profiling of hepatic miRNA expression was analyzed before the onset of MTZ-induced liver injury. Using in silico prediction of miRNAs that possibly regulate Th2-related genes and subsequent quantification, we identified up-regulation of expression of miR-29b-1-5p and miR-449a-5p. Among targets of these miRNAs, down-regulation of Th2 suppressive transcription factors, such as SRY-related HMG-box 4 (SOX4) and lymphoid enhancer factor-1 (LEF1), were observed from the early phase of liver injury. In conclusion, negative regulation of the expression of SOX4 by miR-29b-1-5p and that of LEF1 by miR-449a-5p is suggested to play an important role in the development of Th2 bias in MTZ-induced liver injury. PMID:27421576

  15. Oral treatment with zinc sulfate increases the expression of Th1 cytokines mRNA in BALB/c mice infected with Leishmania major.

    PubMed

    Afshari, Mahsa; Riazi-Rad, Farhad; Khaze, Vahid; Bahrami, Fariborz; Ajdary, Soheila; Alimohammadian, Mohammad Hossein

    2016-05-01

    Leishmaniases consist of a group of diseases caused by protozoan parasites of Leishmania genus. The outcome of the disease depends on the immune responses of the host as well as the pathogenicity of the strain of the parasite. In murine models, the inoculation of Leishmania major into resistant mice results in Th1 responses and recovery from the infection. However in the susceptible mice, the same inoculation leads to a profile of Th2 responses. Zinc (Zn) is an essential trace element which is required for the growth and development of the immune responses. In this study, the influence of Zn sulfate on mRNA expression of main cytokines of the immune response was studied in susceptible BALB/c mice infected with L. major. The inoculated mice were divided into 3 groups, namely the untreated (control), the zinc sulfate treated (weeks 2, 4 and 8), and the Glucantime-treated (weeks 4 and 8) mice. During different time points post-infection, the lesion sizes and the parasite burden were measured in all the groups. Moreover, the expression of Ifng, Il4, Il10 and Il12 mRNA levels in the draining lymph nodes of the treated mice were compared to the control mice using real-time PCR. Our data demonstrated significant decreases in lesion sizes and parasite loads in Zn sulfate treated group compared to the untreated group. Moreover, significant fold increases in expression of Ifng transcript were observed in mice treated with Zn sulfate compared to the control. The ratio of Ifng/Il4 mRNA was also higher in Zn sulfate-treated mice compared to Glucantime-treated animals. These results indicate that Zn Sulfate has the ability to induce strong Th1 responses in susceptible BALB/c mice inoculated with L. major. PMID:26896749

  16. Delineating the Role of Histamine-1- and -4-Receptors in a Mouse Model of Th2-Dependent Antigen-Specific Skin Inflammation

    PubMed Central

    Behrens, Barbara; Jirmo, Adan; Behrens, Georg; Hartwig, Christina; Neumann, Detlef; Raap, Ulrike; Bähre, Heike; Herrick, Christina; Dittrich, Anna-Maria

    2014-01-01

    Background Histamine drives pruritus in allergic skin diseases which clinically constitutes a most disruptive symptom. Skin pathology in allergic skin diseases is crucially influenced by different T-helper subsets. However, the contribution of different histamine-receptors to T-helper cell dependent skin pathology has not been definitively answered. Models which can specifically address the functional role of T-helper subsets and the mediators involved are therefore valuable to gain further insights into molecular pathways which contribute to allergic skin disease. They might also be helpful to probe amendable therapeutic interventions such as histamine-receptor antagonism. Objective Establishing an adoptive transfer model for antigen-specific Th cells, we aimed to delineate the role of histamine H1- and H4-receptors in Th2-dependent skin inflammation. Methods In-vitro differentiated and OVA primed Th2 cells were adoptively transferred into congenic recipient mice. In vivo treatment with specific histamine H1- and H4-receptor antagonists was performed to analyze the contribution of these histamine-receptors to Th2-dependent skin pathology in our model. Analysis four days after epicutaneous challenge comprised skin histology, flow cytometric detection of transferred T-helper cells and analysis of antigen-cytokine profiles in skin-draining lymph nodes. Results Use of specific H1- and H4-receptor antagonists revealed a crucial role for H1- and H4-receptors for Th2 migration and cytokine secretion in a Th2-driven model of skin inflammation. While H1- and H4-receptor antagonists both reduced Th2 recruitment to the site of challenge, local cytokine responses in skin-draining lymph nodes were only reduced by the combined application of H1- and H4-receptor antagonists and mast cell counts remained altogether unchanged by either H1R-, H4R- or combined antagonism. Conclusion Our model demonstrates a role for H1- and H4-receptors in Th2 cell infiltration and cytokine

  17. Novel immunostimulators with a thiazolidin-4-one ring promote the immunostimulatory effect of human iNKT cells on the stimulation of Th2-like immune responsiveness via GATA3 activation in vitro.

    PubMed

    Meng, Ming; Li, Chunxiao; Yang, Fei; Chen, Hua; Li, Xiaoliu; Yang, Yongbin; Chen, Dongzhi

    2016-10-01

    Invariant natural killer T cells (iNKTs) are important innate immune cells which get involved in various immune responses in both mice and humans. These immune reactions range from self-tolerance to development of autoimmunity and responses to pathogens and tumor development. In this study, we aimed to explore the effects of the novel immunostimulators (CH1b and CH2b) containing thiazolidin-4-one on the functions of human invariant natural killer T cells (iNKTs). First of all, iNKTs in peripheral blood mononuclear cells were expanded with α-Galactosylceramide (α-Galcer) in vitro. Then, the highly purified iNKTs were isolated from PBMCs using magnetic cells sorting (MACS). Next, we investigated the impacts of CH1b and CH2b on proliferation, cytokines production, cytotoxicity, and the associated signaling pathways in iNKT cells. Finally, we found that CH2b could significantly promote the activated iNKTs proliferation, increase the production of Th2 cytokines, and induce Th0 differentiation into Th2 subset via GATA 3 signaling pathway. Besides, CH2b could markedly enhance the cytotoxic ability of the activated iNKTs. Therefore, we concluded that CH2b, a promising candidate immunostimulator, might be used for the treatment of infections, tumors, autoimmune and allergic diseases, and for the correction of Th1/Th2 balance disorders in future. PMID:27543853

  18. Human CD8+ T-cells recognizing peptides from Mycobacterium tuberculosis (Mtb) presented by HLA-E have an unorthodox Th2-like, multifunctional, Mtb inhibitory phenotype and represent a novel human T-cell subset.

    PubMed

    van Meijgaarden, Krista E; Haks, Mariëlle C; Caccamo, Nadia; Dieli, Francesco; Ottenhoff, Tom H M; Joosten, Simone A

    2015-03-01

    Mycobacterial antigens are not exclusively presented to T-cells by classical HLA-class Ia and HLA-class II molecules, but also through alternative antigen presentation molecules such as CD1a/b/c, MR1 and HLA-E. We recently described mycobacterial peptides that are presented in HLA-E and recognized by CD8+ T-cells. Using T-cell cloning, phenotyping, microbiological, functional and RNA-expression analyses, we report here that these T-cells can exert cytolytic or suppressive functions, inhibit mycobacterial growth, yet express GATA3, produce Th2 cytokines (IL-4,-5,-10,-13) and activate B-cells via IL-4. In TB patients, Mtb specific cells were detectable by peptide-HLA-E tetramers, and IL-4 and IL-13 were produced following peptide stimulation. These results identify a novel human T-cell subset with an unorthodox, multifunctional Th2 like phenotype and cytolytic or regulatory capacities, which is involved in the human immune response to mycobacteria and demonstrable in active TB patients' blood. The results challenge the current dogma that only Th1 cells are able to inhibit Mtb growth and clearly show that Th2 like cells can strongly inhibit outgrowth of Mtb from human macrophages. These insights significantly expand our understanding of the immune response in infectious disease. PMID:25803478

  19. Human CD8+ T-cells Recognizing Peptides from Mycobacterium tuberculosis (Mtb) Presented by HLA-E Have an Unorthodox Th2-like, Multifunctional, Mtb Inhibitory Phenotype and Represent a Novel Human T-cell Subset

    PubMed Central

    van Meijgaarden, Krista E.; Haks, Mariëlle C.; Caccamo, Nadia; Dieli, Francesco; Ottenhoff, Tom H. M.; Joosten, Simone A.

    2015-01-01

    Mycobacterial antigens are not exclusively presented to T-cells by classical HLA-class Ia and HLA-class II molecules, but also through alternative antigen presentation molecules such as CD1a/b/c, MR1 and HLA-E. We recently described mycobacterial peptides that are presented in HLA-E and recognized by CD8+ T-cells. Using T-cell cloning, phenotyping, microbiological, functional and RNA-expression analyses, we report here that these T-cells can exert cytolytic or suppressive functions, inhibit mycobacterial growth, yet express GATA3, produce Th2 cytokines (IL-4,-5,-10,-13) and activate B-cells via IL-4. In TB patients, Mtb specific cells were detectable by peptide-HLA-E tetramers, and IL-4 and IL-13 were produced following peptide stimulation. These results identify a novel human T-cell subset with an unorthodox, multifunctional Th2 like phenotype and cytolytic or regulatory capacities, which is involved in the human immune response to mycobacteria and demonstrable in active TB patients’ blood. The results challenge the current dogma that only Th1 cells are able to inhibit Mtb growth and clearly show that Th2 like cells can strongly inhibit outgrowth of Mtb from human macrophages. These insights significantly expand our understanding of the immune response in infectious disease. PMID:25803478

  20. Starfish, Asterias amurensis and Asterina pectinifera, as potential sources of Th1 immunity-stimulating adjuvants.

    PubMed

    Kawase, Osamu; Goo, Youn-Kyoung; Jujo, Hayato; Nishikawa, Yoshifumi; Xuan, Xuenan

    2011-02-01

    Saponin is the generic name of steroid or triterpene glycosides, and the capacities of some saponins to stimulate both Th1 immune response and production of cytotoxic T cells are useful as vaccine components against intracellular pathogens. Because saponins have been found commonly in starfish, we assessed the potential of starfish, Asterias amurensis and Asterina pectinifera, as adjuvant sources. Crude starfish saponins had hemolytic activities (EC(50)=10 to 100 µg/ml) and thin layer chromatography indicated heterogeneity of their constituents. When starfish saponis were subcutaneously injected into mice with ovalbumin (OVA), OVA-specific IgG, especially IgG2a instead of IgG1 was produced in mouse blood, suggesting starfish saponins stimulated Th1 type immunity and they were potential sources of new adjuvants. PMID:20847539

  1. Analysis of Th1, Th17 and regulatory T cells in tuberculosis case contacts.

    PubMed

    García Jacobo, R E; Serrano, C J; Enciso Moreno, J A; Gaspar Ramírez, O; Trujillo Ochoa, J L; Uresti Rivera, E E; Portales Pérez, D P; González-Amaro, R; García Hernández, M H

    2014-01-01

    We have hypothesized that individuals infected with Mycobacteriumtuberculosis that exhibit different patterns of immune reactivity in serial interferon (IFN)-γ release assays (IGRA's) correspond to different status within the immune spectrum of latent tuberculosis (TB). Accordingly, we analyzed the possible association between the consistent results (negative or positive) in an IGRA test and relevant immune parameters, mainly the levels of Th1 and Th17 lymphocytes and T regulatory (Treg) cells in the peripheral blood of TB case contacts. We found that individuals with a persistently positive IGRA showed increased levels of Th1 and Th17 lymphocytes upon in vitro stimulation with MTB antigens. In addition, a significant increase in the proportion of CD4+CTLA-4+ and CD4+Foxp3+ cells was detected in assays with blood samples from these individuals. Our data support that different immune phenotypes can be identified into the spectrum of latent TB, by combining different parameters of immune reactivity against MTB. PMID:24841855

  2. Th2 cytokine-induced alterations in intestinal smooth muscle function depend on alternatively activated macrophages

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Enteric nematode infection induces a strong Th2 cytokine response and is characterized by increased infiltration of various immune cells including macrophages. The role of these immune cells in host defense against enteric nematode infection, however, remains poorly defined. The present study invest...

  3. Th2 differentiation is necessary for soft tissue fibrosis and lymphatic dysfunction resulting from lymphedema

    PubMed Central

    Avraham, Tomer; Zampell, Jamie C.; Yan, Alan; Elhadad, Sonia; Weitman, Evan S.; Rockson, Stanley G.; Bromberg, Jacqueline; Mehrara, Babak J.

    2013-01-01

    Lymphedema is a dreaded complication of cancer treatment. However, despite the fact that >5 million Americans are affected by this disorder, the development of effective treatments is limited by the fact that the pathology of lymphedema remains unknown. The purpose of these studies was to determine the role of inflammatory responses in lymphedema pathology. Using mouse models of lymphedema, as well as clinical lymphedema specimens, we show that lymphatic stasis results in a CD4+ T-cell inflammation and T-helper 2 (Th2) differentiation. Using mice deficient in T cells or CD4+ cells, we show that this inflammatory response is necessary for the pathological changes of lymphedema, including fibrosis, adipose deposition, and lymphatic dysfunction. Further, we show that inhibition of Th2 differentiation using interleukin-4 (IL-4) or IL-13 blockade prevents initiation and progression of lymphedema by decreasing tissue fibrosis and significantly improving lymphatic function, independent of lymphangiogenic growth factors. We show that CD4+ inflammation is a critical regulator of tissue fibrosis and lymphatic dysfunction in lymphedema and that inhibition of Th2 differentiation markedly improves lymphatic function independent of lymphangiogenic cytokine expression. Notably, preventing and/or reversing the development of pathological tissue changes that occur in lymphedema may be a viable treatment strategy for this disorder.—Avraham, T., Zampell, J. C., Yan, A., Elhadad, S., Weitman, E. S., Rockson, S. G., Bromberg, J., Mehrara, B. J. Th2 differentiation is necessary for soft tissue fibrosis and lymphatic dysfunction resulting from lymphedema. PMID:23193171

  4. Cyclic AMP concentrations in dendritic cells induce and regulate Th2 immunity and allergic asthma

    PubMed Central

    Lee, Jihyung; Kim, Tae Hoon; Murray, Fiona; Li, Xiangli; Choi, Sara S.; Broide, David H.; Corr, Maripat; Lee, Jongdae; Webster, Nicholas J. G.; Insel, Paul A.; Raz, Eyal

    2015-01-01

    The inductive role of dendritic cells (DC) in Th2 differentiation has not been fully defined. We addressed this gap in knowledge by focusing on signaling events mediated by the heterotrimeric GTP binding proteins Gαs, and Gαi, which respectively stimulate and inhibit the activation of adenylyl cyclases and the synthesis of cAMP. We show here that deletion of Gnas, the gene that encodes Gαs in mouse CD11c+ cells (GnasΔCD11c mice), and the accompanying decrease in cAMP provoke Th2 polarization and yields a prominent allergic phenotype, whereas increases in cAMP inhibit these responses. The effects of cAMP on DC can be demonstrated in vitro and in vivo and are mediated via PKA. Certain gene products made by GnasΔCD11c DC affect the Th2 bias. These findings imply that G protein-coupled receptors, the physiological regulators of Gαs and Gαi activation and cAMP formation, act via PKA to regulate Th bias in DC and in turn, Th2-mediated immunopathologies. PMID:25605931

  5. Airway epithelial SPDEF integrates goblet cell differentiation and pulmonary Th2 inflammation.

    PubMed

    Rajavelu, Priya; Chen, Gang; Xu, Yan; Kitzmiller, Joseph A; Korfhagen, Thomas R; Whitsett, Jeffrey A

    2015-05-01

    Epithelial cells that line the conducting airways provide the initial barrier and innate immune responses to the abundant particles, microbes, and allergens that are inhaled throughout life. The transcription factors SPDEF and FOXA3 are both selectively expressed in epithelial cells lining the conducting airways, where they regulate goblet cell differentiation and mucus production. Moreover, these transcription factors are upregulated in chronic lung disorders, including asthma. Here, we show that expression of SPDEF or FOXA3 in airway epithelial cells in neonatal mice caused goblet cell differentiation, spontaneous eosinophilic inflammation, and airway hyperresponsiveness to methacholine. SPDEF expression promoted DC recruitment and activation in association with induction of Il33, Csf2, thymic stromal lymphopoietin (Tslp), and Ccl20 transcripts. Increased Il4, Il13, Ccl17, and Il25 expression was accompanied by recruitment of Th2 lymphocytes, group 2 innate lymphoid cells, and eosinophils to the lung. SPDEF was required for goblet cell differentiation and pulmonary Th2 inflammation in response to house dust mite (HDM) extract, as both were decreased in neonatal and adult Spdef(-/-) mice compared with control animals. Together, our results indicate that SPDEF causes goblet cell differentiation and Th2 inflammation during postnatal development and is required for goblet cell metaplasia and normal Th2 inflammatory responses to HDM aeroallergen. PMID:25866971

  6. CCL5-Mediated Th2 Immune Polarization Promotes Metastasis in Luminal Breast Cancer.

    PubMed

    Zhang, Qianfei; Qin, Jilong; Zhong, Lin; Gong, Lei; Zhang, Bing; Zhang, Yan; Gao, Wei-Qiang

    2015-10-15

    The tumor-promoting chemokine CCL5 has been implicated in malignant transformation of breast epithelial cells, with studies to date focusing mainly on basal-type breast cancers. In this study, we investigated the consequences of CCL5 deletion in the MMTV-PyMT transgenic mouse model of luminal breast cancer. In this model, primary tumor burden and pulmonary metastases were reduced significantly in CCL5-deficient subjects, an effect found to be associated with a deficit of Th2 (IL4⁺CD4⁺ T) cells. Mechanistic investigations revealed that CCL5 activates CCR3, a highly expressed chemokine receptor on CD4⁺ T cells, and also boosts Gfi1 expression to promote the differentiation of Th2 cells, which enhance the prometastatic activity of tumor-associated myeloid cells. Clinically, polarization toward this immunosuppressive Th2 phenotype was also evident in patients with advanced luminal breast cancer. Thus, our findings showed that CCL5/CCR3 signaling promotes metastasis by inducing Th2 polarization of CD4⁺ T cells, with implications for prognosis and immunotherapy of luminal breast cancer. PMID:26249173

  7. A central role for hepatic conventional dendritic cells in supporting Th2 responses during helminth infection

    PubMed Central

    Lundie, Rachel J; Webb, Lauren M; Marley, Angela K; Phythian-Adams, Alexander T; Cook, Peter C; Jackson-Jones, Lucy H; Brown, Sheila; Maizels, Rick M; Boon, Louis; O'Keeffe, Meredith; MacDonald, Andrew S

    2016-01-01

    Dendritic cells (DCs) are the key initiators of T-helper (Th) 2 immune responses against the parasitic helminth Schistosoma mansoni. Although the liver is one of the main sites of antigen deposition during infection with this parasite, it is not yet clear how distinct DC subtypes in this tissue respond to S. mansoni antigens in vivo, or how the liver microenvironment might influence DC function during establishment of the Th2 response. In this study, we show that hepatic DC subsets undergo distinct activation processes in vivo following murine infection with S. mansoni. Conventional DCs (cDCs) from schistosome-infected mice upregulated expression of the costimulatory molecule CD40 and were capable of priming naive CD4+ T cells, whereas plasmacytoid DCs (pDCs) upregulated expression of MHC class II, CD86 and CD40 but were unable to support the expansion of either naive or effector/memory CD4+ T cells. Importantly, in vivo depletion of pDCs revealed that this subset was dispensable for either maintenance or regulation of the hepatic Th2 effector response during acute S. mansoni infection. Our data provides strong evidence that S. mansoni infection favors the establishment of an immunogenic, rather than tolerogenic, liver microenvironment that conditions cDCs to initiate and maintain Th2 immunity in the context of ongoing antigen exposure. PMID:26657145

  8. Suppression of Th1-Mediated Autoimmunity by Embryonic Stem Cell-Derived Dendritic Cells

    PubMed Central

    Ikeda, Tokunori; Hirata, Shinya; Takamatsu, Koutaro; Haruta, Miwa; Tsukamoto, Hirotake; Ito, Takaaki; Uchino, Makoto; Ando, Yukio; Nagafuchi, Seiho; Nishimura, Yasuharu; Senju, Satoru

    2014-01-01

    We herein demonstrate the immune-regulatory effect of embryonic stem cell-derived dendritic cells (ES-DCs) using two models of autoimmune disease, namely non-obese diabetic (NOD) mice and experimental autoimmune encephalomyelitis (EAE). Treatment of pre-diabetic NOD mice with ES-DCs exerted almost complete suppression of diabetes development during the observation period for more than 40 weeks. The prevention of diabetes by ES-DCs was accompanied with significant reduction of insulitis and decreased number of Th1 and Th17 cells in the spleen. Development of EAE was also inhibited by the treatment with ES-DCs, and the therapeutic effect was obtained even if ES-DCs were administrated after the onset of clinical symptoms. Treatment of EAE-induced mice with ES-DCs reduced the infiltration of inflammatory cells into the spinal cord and suppressed the T cell response to the myelin antigen. Importantly, the ES-DC treatment did not affect T cell response to an exogenous antigen. As the mechanisms underlying the reduction of the number of infiltrating Th1 cells, we observed the inhibition of differentiation and proliferation of Th1 cells by ES-DCs. Furthermore, the expression of VLA-4α on Th1 cells was significantly inhibited by ES-DCs. Considering the recent advances in human induced pluripotent stem cell-related technologies, these results suggest a clinical application for pluripotent stem cell-derived dendritic cells as a therapy for T cell-mediated autoimmune diseases. PMID:25522369

  9. Suppression of Th1-mediated autoimmunity by embryonic stem cell-derived dendritic cells.

    PubMed

    Ikeda, Tokunori; Hirata, Shinya; Takamatsu, Koutaro; Haruta, Miwa; Tsukamoto, Hirotake; Ito, Takaaki; Uchino, Makoto; Ando, Yukio; Nagafuchi, Seiho; Nishimura, Yasuharu; Senju, Satoru

    2014-01-01

    We herein demonstrate the immune-regulatory effect of embryonic stem cell-derived dendritic cells (ES-DCs) using two models of autoimmune disease, namely non-obese diabetic (NOD) mice and experimental autoimmune encephalomyelitis (EAE). Treatment of pre-diabetic NOD mice with ES-DCs exerted almost complete suppression of diabetes development during the observation period for more than 40 weeks. The prevention of diabetes by ES-DCs was accompanied with significant reduction of insulitis and decreased number of Th1 and Th17 cells in the spleen. Development of EAE was also inhibited by the treatment with ES-DCs, and the therapeutic effect was obtained even if ES-DCs were administrated after the onset of clinical symptoms. Treatment of EAE-induced mice with ES-DCs reduced the infiltration of inflammatory cells into the spinal cord and suppressed the T cell response to the myelin antigen. Importantly, the ES-DC treatment did not affect T cell response to an exogenous antigen. As the mechanisms underlying the reduction of the number of infiltrating Th1 cells, we observed the inhibition of differentiation and proliferation of Th1 cells by ES-DCs. Furthermore, the expression of VLA-4α on Th1 cells was significantly inhibited by ES-DCs. Considering the recent advances in human induced pluripotent stem cell-related technologies, these results suggest a clinical application for pluripotent stem cell-derived dendritic cells as a therapy for T cell-mediated autoimmune diseases. PMID:25522369

  10. Interleukin-6 Induced “Acute” Phenotypic Microenvironment Promotes Th1 Anti-Tumor Immunity in Cryo-Thermal Therapy Revealed By Shotgun and Parallel Reaction Monitoring Proteomics

    PubMed Central

    Xue, Ting; Liu, Ping; Zhou, Yong; Liu, Kun; Yang, Li; Moritz, Robert L.; Yan, Wei; Xu, Lisa X.

    2016-01-01

    Cryo-thermal therapy has been emerged as a promising novel therapeutic strategy for advanced breast cancer, triggering higher incidence of tumor regression and enhanced remission of metastasis than routine treatments. To better understand its anti-tumor mechanism, we utilized a spontaneous metastatic mouse model and quantitative proteomics to compare N-glycoproteome changes in 94 serum samples with and without treatment. We quantified 231 highly confident N-glycosylated proteins using iTRAQ shotgun proteomics. Among them, 53 showed significantly discriminated regulatory patterns over the time course, in which the acute phase response emerged as the most enhanced pathway. The anti-tumor feature of the acute response was further investigated using parallel reaction monitoring target proteomics and flow cytometry on 23 of the 53 significant proteins. We found that cryo-thermal therapy reset the tumor chronic inflammation to an “acute” phenotype, with up-regulation of acute phase proteins including IL-6 as a key regulator. The IL-6 mediated “acute” phenotype transformed IL-4 and Treg-promoting ICOSL expression to Th1-promoting IFN-γ and IL-12 production, augmented complement system activation and CD86+MHCII+ dendritic cells maturation and enhanced the proliferation of Th1 memory cells. In addition, we found an increased production of tumor progression and metastatic inhibitory proteins under such “acute” environment, favoring the anti-metastatic effect. Moreover, cryo-thermal on tumors induced the strongest “acute” response compared to cryo/hyperthermia alone or cryo-thermal on healthy tissues, accompanying by the most pronounced anti-tumor immunological effect. In summary, we demonstrated that cryo-thermal therapy induced, IL-6 mediated “acute” microenvironment shifted the tumor chronic microenvironment from Th2 immunosuppressive and pro-tumorigenic to Th1 immunostimulatory and tumoricidal state. Moreover, the magnitude of “acute” and

  11. Th1 and Th17 Cells in Tuberculosis: Protection, Pathology, and Biomarkers

    PubMed Central

    Lyadova, I. V.; Panteleev, A. V.

    2015-01-01

    The outcome of Mycobacterium tuberculosis (Mtb) infection ranges from a complete pathogen clearance through asymptomatic latent infection (LTBI) to active tuberculosis (TB) disease. It is now understood that LTBI and active TB represent a continuous spectrum of states with different degrees of pathogen “activity,” host pathology, and immune reactivity. Therefore, it is important to differentiate LTBI and active TB and identify active TB stages. CD4+ T cells play critical role during Mtb infection by mediating protection, contributing to inflammation, and regulating immune response. Th1 and Th17 cells are the main effector CD4+ T cells during TB. Th1 cells have been shown to contribute to TB protection by secreting IFN-γ and activating antimycobacterial action in macrophages. Th17 induce neutrophilic inflammation, mediate tissue damage, and thus have been implicated in TB pathology. In recent years new findings have accumulated that alter our view on the role of Th1 and Th17 cells during Mtb infection. This review discusses these new results and how they can be implemented for TB diagnosis and monitoring. PMID:26640327

  12. Rudimentary TCR signaling triggers default IL-10 secretion by human Th1 cells.

    PubMed

    Burrows, G G; Chou, Y K; Wang, C; Chang, J W; Finn, T P; Culbertson, N E; Kim, J; Bourdette, D N; Lewinsohn, D A; Lewinsohn, D M; Ikeda, M; Yoshioka, T; Allen, C N; Offner, H; Vandenbark, A A

    2001-10-15

    Understanding the process of inducing T cell activation has been hampered by the complex interactions between APC and inflammatory Th1 cells. To dissociate Ag-specific signaling through the TCR from costimulatory signaling, rTCR ligands (RTL) containing the alpha1 and beta1 domains of HLA-DR2b (DRA*0101:DRB1*1501) covalently linked with either the myelin basic protein peptide 85-99 (RTL303) or CABL-b3a2 (RTL311) peptides were constructed to provide a minimal ligand for peptide-specific TCRs. When incubated with peptide-specific Th1 cell clones in the absence of APC or costimulatory molecules, only the cognate RTL induced partial activation through the TCR. This partial activation included rapid TCR zeta-chain phosphorylation, calcium mobilization, and reduced extracellular signal-related kinase activity, as well as IL-10 production, but not proliferation or other obvious phenotypic changes. On restimulation with APC/peptide, the RTL-pretreated Th1 clones had reduced proliferation and secreted less IFN-gamma; IL-10 production persisted. These findings reveal for the first time the rudimentary signaling pattern delivered by initial engagement of the external TCR interface, which is further supplemented by coactivation molecules. Activation with RTLs provides a novel strategy for generating autoantigen-specific bystander suppression useful for treatment of complex autoimmune diseases. PMID:11591763

  13. Thermophysical and anion diffusion properties of (Ux,Th1−x)O2

    PubMed Central

    Cooper, Michael W. D.; Murphy, Samuel T.; Fossati, Paul C. M.; Rushton, Michael J. D.; Grimes, Robin W.

    2014-01-01

    Using molecular dynamics, the thermophysical properties of the (Ux,Th1−x)O2 system have been investigated between 300 and 3600 K. The thermal dependence of lattice parameter, linear thermal expansion coefficient, enthalpy and specific heat at constant pressure is explained in terms of defect formation and diffusivity on the oxygen sublattice. Vegard's law is approximately observed for solid solution thermal expansion below 2000 K. Different deviations from Vegard's law above this temperature occur owing to the different temperatures at which the solid solutions undergo the superionic transition (2500–3300 K). Similarly, a spike in the specific heat, associated with the superionic transition, occurs at lower temperatures in solid solutions that have a high U content. Correspondingly, oxygen diffusivity is higher in pure UO2 than in pure ThO2. Furthermore, at temperatures below the superionic transition, oxygen mobility is notably higher in solid solutions than in the end members. Enhanced diffusivity is promoted by lower oxygen-defect enthalpies in (Ux,Th1−x)O2 solid solutions. Unlike in UO2 and ThO2, there is considerable variety of oxygen vacancy and oxygen interstitial sites in solid solutions generating a wide range of property values. Trends in the defect enthalpies are discussed in terms of composition and the lattice parameter of (Ux,Th1−x)O2. PMID:25383028

  14. The role of Th1 and Th17 cells in glomerulonephritis

    PubMed Central

    Azadegan-Dehkordi, Fatemeh; Bagheri, Nader; Shirzad, Hedayatollah; Rafieian-Kopaei, Mahmoud

    2015-01-01

    Context: T helper (Th) cells as an important part of the immune is responsible for elimination of invading pathogens. But, if Th cell responses are not regulated effectively, the autoimmune diseases might develop. The Th17 subset usually produces interleukin-17A which in experimental models of organ-specific autoimmune inflammation is very important. Evidence Acquisitions: Directory of open access journals (DOAJ), Google Scholar, Embase, Scopus, PubMed and Web of Science have been searched. Results: Fifty-six articles were found and searched. In the present review article, we tried to summarize the recently published data about characteristics and role of Th1 and Th17 cells and discuss in detail, the potential role of these T helpers immune responses in renal inflammation and renal injury, focusing on glomerulonephritis. Published papers in animal and human studies indicated that autoimmune diseases such as rheumatoid arthritis and multiple sclerosis, classically believed to be Th1-mediated, are mainly derived from a Th17 immune response. Identification of the Th17 subgroup has explained seemingly paradoxical observations and improved our understanding of immune-mediated inflammatory responses. Conclusions: Secretion of IL-17A, as well as IL-17F, IL-21, IL-22, suggests that Th17 subset may play a crucial role as a pleiotropic pro-inflammatory Th subset. There is experimental evidence to support the notion that Th1 and Th17 cells contribute to kidney injury in renal inflammatory diseases like glomerulonephritis. PMID:25964886

  15. Thermophysical and anion diffusion properties of (U x ,Th1-x )O2.

    PubMed

    Cooper, Michael W D; Murphy, Samuel T; Fossati, Paul C M; Rushton, Michael J D; Grimes, Robin W

    2014-11-01

    Using molecular dynamics, the thermophysical properties of the (U x ,Th1-x )O2 system have been investigated between 300 and 3600 K. The thermal dependence of lattice parameter, linear thermal expansion coefficient, enthalpy and specific heat at constant pressure is explained in terms of defect formation and diffusivity on the oxygen sublattice. Vegard's law is approximately observed for solid solution thermal expansion below 2000 K. Different deviations from Vegard's law above this temperature occur owing to the different temperatures at which the solid solutions undergo the superionic transition (2500-3300 K). Similarly, a spike in the specific heat, associated with the superionic transition, occurs at lower temperatures in solid solutions that have a high U content. Correspondingly, oxygen diffusivity is higher in pure UO2 than in pure ThO2. Furthermore, at temperatures below the superionic transition, oxygen mobility is notably higher in solid solutions than in the end members. Enhanced diffusivity is promoted by lower oxygen-defect enthalpies in (U x ,Th1-x )O2 solid solutions. Unlike in UO2 and ThO2, there is considerable variety of oxygen vacancy and oxygen interstitial sites in solid solutions generating a wide range of property values. Trends in the defect enthalpies are discussed in terms of composition and the lattice parameter of (U x ,Th1-x )O2. PMID:25383028

  16. Free fatty acids sensitize dendritic cells to amplify TH1/TH17-immune responses.

    PubMed

    Stelzner, Kristin; Herbert, Diana; Popkova, Yulia; Lorz, Axel; Schiller, Jürgen; Gericke, Martin; Klöting, Nora; Blüher, Matthias; Franz, Sandra; Simon, Jan C; Saalbach, Anja

    2016-08-01

    Obesity is associated with body fat gain and impaired glucose metabolism. Here, we identified both body fat gain in obesity and impaired glucose metabolism as two independent risk factors for increased serum levels of free fatty acids (FFAs). Since obesity is associated with increased and/or delayed resolution of inflammation observed in various chronic inflammatory diseases such as psoriasis, we investigated the impact of FFAs on human monocyte-derived and mouse bone marrow-derived dendritic cell (DCs) functions relevant for the pathogenesis of chronic inflammation. FFAs such as palmitic acid (PA) and oleic acid (OA) did not affect the pro-inflammatory immune response of DCs. In contrast, PA and OA sensitize DCs resulting in augmented secretion of TH1/TH17-instructive cytokines upon pro-inflammatory stimulation. Interestingly, obesity in mice worsened a TH1/TH17-driven psoriasis-like skin inflammation. Strong correlation of the amount of total FFA, PA, and OA in serum with the severity of skin inflammation points to a critical role of FFA in obesity-mediated exacerbation of skin inflammation. Our data suggest that increased levels of FFAs might be a predisposing factor promoting a TH1/TH17-mediated inflammation such as psoriasis in response to an inflammatory danger signal. PMID:27214608

  17. Prostaglandin D2 pathway upregulation: Relation to asthma severity, control, and TH2 inflammation

    PubMed Central

    Fajt, Merritt L.; Gelhaus, Stacy L.; Freeman, Bruce; Uvalle, Crystal E.; Trudeau, John B.; Holguin, Fernando; Wenzel, Sally E.

    2013-01-01

    Background Bronchoalveolar lavage (BAL) fluid prostaglandin D2 (PGD2) levels are increased in patients with severe, poorly controlled asthma in association with epithelial mast cells (MCs). PGD2, which is generated by hematopoietic prostaglandin D synthase (HPGDS), acts on 3 G protein–coupled receptors, including chemoattractant receptor–homologous molecule expressed on TH2 lymphocytes (CRTH2) and PGD2 receptor 1 (DP1). However, much remains to be understood regarding the presence and activation of these pathway elements in asthmatic patients. Objective We sought to compare the expression and activation of PGD2 pathway elements in bronchoscopically obtained samples from healthy control subjects and asthmatic patients across a range of disease severity and control, as well as in relation to TH2 pathway elements. Methods Epithelial cells and BAL fluid were evaluated for HPGDS (quantitative real-time PCR/immunohistochemistry [IHC]) and PGD2 (ELISA/liquid chromatography mass spectrometry) in relation to levels of MC proteases. Expression of the 2 inflammatory cell receptors DP1 and CRTH2 was evaluated on luminal cells. These PGD2 pathway markers were then compared with asthma severity, level of control, and markers of TH2 inflammation (blood eosinophils and fraction of exhaled nitric oxide). Results Confirming previous results, BAL fluid PGD2 levels were highest in patients with severe asthma (overall P = .0001). Epithelial cell compartment HPGDS mRNA and IHC values differed among groups (P = .008 and P < .0001, respectively) and correlated with MC protease mRNA. CRTH2 mRNA and IHC values were highest in patients with severe asthma (P = .001 and P = .0001, respectively). Asthma exacerbations, poor asthma control, and TH2 inflammatory markers were associated with higher PGD2, HPGDS, and CRTH2 levels. Conclusion The current study identifies coordinated upregulation of the PGD2 pathway in patients with severe, poorly controlled, TH2-high asthma despite corticosteroid

  18. Th2 polarization by Der p 1--pulsed monocyte-derived dendritic cells is due to the allergic status of the donors.

    PubMed

    Hammad, H; Charbonnier, A S; Duez, C; Jacquet, A; Stewart, G A; Tonnel, A B; Pestel, J

    2001-08-15

    The polarization of the immune response toward a Th2 or a Th1 profile can be mediated by dendritic cells (DCs) following antigen presentation and interaction with T cells. Costimulatory molecules such as CD80 and CD86 expressed by DCs, the polarizing cytokine environment during DC--T-cell interaction, and also the nature of the antigen are critical in the orientation of the immune response. In this study, the effect of the cysteine protease Der p 1, one of the major allergens of the house dust mite Dermatophagoides pteronyssinus, on these different parameters was evaluated comparatively on monocyte-derived DCs obtained from healthy donors, from pollen-sensitive patients, or from patients sensitive to Dermatophagoides pteronyssinus. Results showed that Der p 1 induced an increase in CD86 expression only on DCs from house dust mite--sensitive patients. This was also associated with a higher capacity to induce T-cell proliferation, a rapid increase in the production of proinflammatory cytokines, tumor necrosis factor--alpha and interleukin (IL)-1 beta, and the type 2 cytokine IL-10. No changes in the release of IL-12 p70 were induced by Der p 1. Finally, purified T cells from house dust mite-sensitive patients stimulated by autologous Der p 1--pulsed DCs preferentially produced IL-4 rather than interferon-gamma. These effects were abolished in the presence of the inactive precursor of Der p 1 (ProDer p 1). Taken together, these data suggest that DCs from house dust mite--sensitive patients, in contrast to DCs from healthy donors and from pollen-sensitive patients, exposed to Der p 1 play a pivotal role in the enhancement of the Th2 response associated with the allergic reaction developed in response to house dust mite exposure. (Blood. 2001;98:1135-1141) PMID:11493462

  19. The bioactivity of teleost IL-6: IL-6 protein in orange-spotted grouper (Epinephelus coioides) induces Th2 cell differentiation pathway and antibody production.

    PubMed

    Chen, Hsin-Hung; Lin, Han-Tso; Foung, Yi-Fan; Han-You Lin, John

    2012-10-01

    Interleukin 6 (IL-6) is a protein secreted by T cells and macrophages and plays an important role in immune response. IL-6 regulates the proliferation and differentiation of T cells, and elicits immunoglobulin production in B cells. In this study, the cDNA il-6 (gil-6) sequence of the orange spotted grouper (Epinephelus coioides) was obtained. The deduced IL-6 (gIL-6) protein comprised 223 amino acids, the sequence shared approximately 30% similarity with mammalian IL-6, and between 47% and 69% similarity with other available teleost IL-6. The protein comprises the signal peptide, the IL-6 family signature, and conserved amino acid residues found in IL-6 sequences of other teleost. In order to understand the bioactivity and influence of gIL-6 on humoral immune response, recombinant gIL-6 (rgIL-6) synthesized by prokaryotes was injected into orange spotted groupers, and the immune-related gene expression at various times in various organs was observed. Our results revealed that the Th1 specific transcription factor t-bet was down-regulated and Th2 specific transcription factors gata3, and c-maf were up-regulated in immune organs, following IL-6 stimulation. Additionally, higher levels of igm mRNA and translated protein were detected in rgIL-6 stimulated fish. These results indicate that IL-6 in groupers regulates the differentiation of naїve T helper cells into Th2 cells and elicits the production of antibodies. PMID:22858412

  20. Decidual stromal cell-derived IL-33 contributes to Th2 bias and inhibits decidual NK cell cytotoxicity through NF-κB signaling in human early pregnancy.

    PubMed

    Hu, Wen-Ting; Huang, Li-Li; Li, Ming-Qing; Jin, Li-Ping; Li, Da-Jin; Zhu, Xiao-Yong

    2015-06-01

    Decidual stromal cells (DSCs) are an important component of decidual tissues where they are in strict proximity with immune cells. Although previous research has indicated that DSCs participate in the regulation of immune cells during pregnancy, the crosstalk between DSCs and decidual NK cells (dNKs) has not been fully elucidated. The aim of this study was to ascertain the effect of DSC-derived IL-33 on dNK function and explore the underlying mechanism. Flow cytometry showed a considerable increase in ST2 expression on dNKs compared with peripheral NKs (pNKs). Subsequent research found that perforin production, granzyme A production, and the cytolytic activity of dNKs were impaired by DSC media. Furthermore, the addition of DSC media induced an increase in Th2 cytokine production (IL-4, IL-13, and IL-10) with a concomitant decrease in Th1 cytokine expression (TNF-α) of dNKs. However, IFN-γ, another member of the Th1 cytokine family that is thought to be necessary during early gestation increased after IL-33 stimulation. DSC media sharply inhibited the expression of major activating receptors (NKp30, NKG2D) while up-regulating the levels of inhibitory receptor (KIR2DL1) on dNKs. The biological effect of DSC media on dNKs was abrogated by the administration of sST2. Moreover, Western blot analysis suggested that the NF-κB pathway was involved in the IL-33-induced changes in the phenotype and function of dNKs, which was further confirmed by pharmacological inhibition with the NF-κB inhibitor BAY 11-7082. Our results suggest that the crosstalk between DSCs and dNKs might play a crucial role in maintaining successful pregnancy. PMID:25712540

  1. LFA-1/ICAM-1 Ligation in Human T Cells Promotes Th1 Polarization through a GSK3β Signaling-Dependent Notch Pathway.

    PubMed

    Verma, Navin K; Fazil, M H U Turabe; Ong, Seow Theng; Chalasani, Madhavi Latha S; Low, Jian Hui; Kottaiswamy, Amuthavalli; P, Praseetha; Kizhakeyil, Atish; Kumar, Sunil; Panda, Aditya K; Freeley, Michael; Smith, Sinead M; Boehm, Bernhard O; Kelleher, Dermot

    2016-07-01

    In this study, we report that the integrin LFA-1 cross-linking with its ligand ICAM-1 in human PBMCs or CD4(+) T cells promotes Th1 polarization by upregulating IFN-γ secretion and T-bet expression. LFA-1 stimulation in PBMCs, CD4(+) T cells, or the T cell line HuT78 activates the Notch pathway by nuclear translocation of cleaved Notch1 intracellular domain (NICD) and upregulation of target molecules Hey1 and Hes1. Blocking LFA-1 by a neutralizing Ab or specific inhibition of Notch1 by a γ-secretase inhibitor substantially inhibits LFA-1/ICAM-1-mediated activation of Notch signaling. We further demonstrate that the Notch pathway activation is dependent on LFA-1/ICAM-1-induced inactivation of glycogen synthase kinase 3β (GSK3β), which is mediated via Akt and ERK. Furthermore, in silico analysis in combination with coimmunoprecipitation assays show an interaction between NICD and GSK3β. Thus, there exists a molecular cross-talk between LFA-1 and Notch1 through the Akt/ERK-GSK3β signaling axis that ultimately enhances T cell differentiation toward Th1. Although clinical use of LFA-1 antagonists is limited by toxicity related to immunosuppression, these findings support the concept that Notch inhibitors could be attractive for prevention or treatment of Th1-related immunologic disorders and have implications at the level of local inflammatory responses. PMID:27206767

  2. American tegumentary leishmaniasis: mRNA expression for Th1 and Treg mediators are predominant in patients with recent active disease.

    PubMed

    Souza, Marina A; Almeida, Thays M; Castro, Maria Carolina A B; Oliveira-Mendes, Andresa P; Almeida, Amanda F; Oliveira, Beatriz C; Rocha, Lucas F; Medeiros, Angela C R; Brito, Maria E F; Dessein, Alain J J; Pereira, Valéria R A

    2016-02-01

    Besides the Th1×Th2 paradigm, Treg and Th17 cytokines may play a role in the response to American tegumentary leishmaniasis. Considering the sensitivity and accuracy of qPCR and the lack of studies using this approach, we evaluated mRNA expression for IFN-γ, TNF-α, IL-4, IL-10, IL-6, IL-17A, IL-22, TGF-β, Foxp3 and RORC in peripheral blood mononuclear cells (PBMC) from patients with active disease, after stimulation with L. (V.) braziliensis soluble or insoluble fractions. Our results show that the antigens promoted specific mRNA expression related to the immune response in patients with ATL, and the insoluble fraction seems to stimulate the immune response in a higher intensity. The pro-inflammatory response was also fueled by IFN-γ and TNF-α, probably due to the active disease. IL-4, in certain way, seems to regulate this response along with IL-10 that may be produced by Treg cells, which are supposedly present in the patients' samples due the evidenced expression of Foxp3, in the presence of AgIns. In contrast, down-regulated RORC suggests that the significant levels of IL-6 expressed in response to AgSol were not able to induce an expressive Th17 profile along with TGF-β, which might have predominantly contributed to the development of a regulatory profile in the active disease. PMID:26572279

  3. Monocyte derived IL 10 and PGE2 are associated with the absence of Th 1 cells and in vitro T cell suppression in lepromatous leprosy.

    PubMed

    Misra, N; Selvakumar, M; Singh, S; Bharadwaj, M; Ramesh, V; Misra, R S; Nath, I

    1995-12-01

    Our previous studies had shown that the clinicopathological spectrum in leprosy was associated with discrete T cell subsets in circulation, with tuberculoid patients having antigen-induced Th 1, whereas lepromatous leprosy patients with antigen-specific T cell anergy possessed Th 2 cells. The present study shows that infected monocytes from lepromatous but not tuberculoid leprosy patients released soluble factors (MoF(s)) containing IL-10 and PGE2 which inhibited M. leprae induced in vitro lymphoproliferation of previously sensitised healthy or tuberculoid leprosy subjects. A strong negative correlation was observed between adherent cell derived IL-10 and IL-2 at the level of both the product and cytokine mRNA. Moreover, anti-IL-10 antibodies and indomethacin partially reversed the suppressor effects of MoF(s). Taken together these studies indicate that infected monocytes contribute to the development of T cell anergy by releasing factors that affect regulatory cytokines and T cell subset differentiation in lepromatous leprosy. PMID:8719110

  4. Microbiota-Independent Ameliorative Effects of Antibiotics on Spontaneous Th2-Associated Pathology of the Small Intestine

    PubMed Central

    Han, Daehee; Walsh, Matthew C.; Kim, Kwang Soon; Hong, Sung-Wook; Lee, Junyoung; Yi, Jaeu; Rivas, Gloriany; Surh, Charles D.; Choi, Yongwon

    2015-01-01

    We have previously generated a mouse model of spontaneous Th2-associated disease of the small intestine called TRAF6ΔDC, in which dendritic cell (DC)-intrinsic expression of the signaling mediator TRAF6 is ablated. Interestingly, broad-spectrum antibiotic treatment ameliorates TRAF6ΔDC disease, implying a role for commensal microbiota in disease development. However, the relationship between the drug effects and commensal microbiota status remains to be formally demonstrated. To directly assess this relationship, we have now generated TRAF6ΔDC bone marrow chimera mice under germ-free (GF) conditions lacking commensal microbiota, and found, unexpectedly, that Th2-associated disease is actually exacerbated in GF TRAF6ΔDC mice compared to specific pathogen-free (SPF) TRAF6ΔDC mice. At the same time, broad-spectrum antibiotic treatment of GF TRAF6ΔDC mice has an ameliorative effect similar to that observed in antibiotics-treated SPF TRAF6ΔDC mice, implying a commensal microbiota-independent effect of broad-spectrum antibiotic treatment. We further found that treatment of GF TRAF6ΔDC mice with broad-spectrum antibiotics increases Foxp3+ Treg populations in lymphoid organs and the small intestine, pointing to a possible mechanism by which treatment may directly exert an immunomodulatory effect. To investigate links between the exacerbated phenotype of the small intestines of GF TRAF6ΔDC mice and local microbiota, we performed microbiotic profiling of the luminal contents specifically within the small intestines of diseased TRAF6ΔDC mice, and, when compared to co-housed control mice, found significantly increased total bacterial content characterized by specific increases in Firmicutes Lactobacillus species. These data suggest a protective effect of Firmicutes Lactobacillus against the spontaneous Th2-related inflammation of the small intestine of the TRAF6ΔDC model, and may represent a potential mechanism for related disease phenotypes. PMID:25689829

  5. Phenotypic and genotypic association of epithelial IL1RL1 to human TH2-like asthma

    PubMed Central

    Traister, Russell S.; Uvalle, Crystal E.; Hawkins, Gregory A.; Meyers, Deborah A.; Bleecker, Eugene R.; Wenzel, Sally E.

    2014-01-01

    Background Severe asthma remains poorly characterized, although it likely consists of at least 1 phenotype with features of TH2-like inflammation. IL1RL1, encoding both the IL-33 receptor, ST2L, and decoy receptor, sST2, has been genetically associated with asthma, though the mechanism for susceptibility remains unknown. Objective Given previous data supporting a role for IL1RL1 in TH2 inflammation, we hypothesized that ST2L expression might be increased in TH2-like asthma and that expression levels would be associated with single nucleotide polymorphisms in IL1RL1, possibly explaining its genetic relationship with asthma. We also sought to evaluate the regulation of ST2L and sST2 in vitro. Methods Endobronchial brushings and biopsies were obtained and expression of ST2L compared by severity levels, as well as by TH2-like biomarkers. Subjects were genotyped and the relationship of dichotomous expression of ST2L and sST2 to single nucleotide polymorphisms in IL1RL1 were determined. Epithelial cells were grown in air-liquid interface culture, and ST2L and sST2 responses to IFN-γ and IL-13 were evaluated. Results ST2L expression was increased in severe asthma (P = .02) and associated with multiple indicators of TH2-like inflammation, including blood eosinophils (P = .001), exhaled nitric oxide (P = .003), and epithelial CLCA1 (P < .0001) and eotaxin-3 (P = .001) mRNA expression. Multiple single nucleotide polymorphisms in IL1RL1 were found in relation to dichotomous expression of both ST2L and sST2. sST2 expression was associated with IFN-γ expression in bronchoalveolar lavage, while inducing its expression in vitro in primary human epithelial cells. Conclusion Both pathologic and genetic approaches support a role for IL1RL1 in severe asthma, as well as TH2-lke asthma, suggesting that targeting this pathway may have therapeutic benefits. PMID:25091434

  6. Th2 type inflammation promotes the gradual progression of HPV-infected cervical cells to cervical carcinoma

    PubMed Central

    Feng, Qinghua; Wei, Huafeng; Morihara, Janice; Stern, Joshua; Yu, Mujun; Kiviat, Nancy; Hellstrom, Ingegerd; Hellstrom, Karl Erik

    2012-01-01

    Objectives To investigate the role of immunological parameters in tumorigenesis of cervical cancer in women infected with high risk human papillomavirus (hr-HPV), and determine whether key findings with human material can be recapitulated in the mouse TC1 carcinoma model which expresses hr-HPV epitopes. Methods Epithelial and lymphoid cells in cervical tissues were analyzed by immunohistochemistry and serum IL10 levels were determined by ELISA. Tumor draining lymph nodes were analyzed in the mouse TC1 model by flow cytometry. Results The mucosa was infiltrated by CD20+ and CD138+ cells already at cervical intraepithelial neoplasia 1 (CIN1) and infiltration increased in cervical intraepithelial neoplasia 3 (CIN3)/carcinoma in situ (CIS) and invasive cervical cancer (ICC), where it strongly correlated with infiltration by CD32B+ and FoxP3+ lymphocytes. GATA3+ and T-bet+ lymphoid cells were increased in ICC compared to normal, and expression in epithelial cells of the Th2 inflammation-promoting cytokine TSLP and of IDO1 was higher in CIN3/CIS and ICC. As a corollary, serum levels of IL10 were higher in women with CIN3/CIS or ICC than in normals. Finally we demonstrated in the mouse TC1 carcinoma, which expresses hr-HPV epitopes, an increase of cells expressing B cell or plasma cell markers or Fc receptors in tumor-draining than distal lymph nodes or spleen. Conclusions hr-HPV initiates a local Th2 inflammation at an early stage, involving antibody forming cells, and fosters an immunosuppressive microenvironment that aids tumor progression. PMID:22828962

  7. TGF-β converts Th1 cells into Th17 cells through stimulation of Runx1 expression

    PubMed Central

    Liu, Hou-Pu; T. Cao, Anthony; Feng, Ting; Li, Qingjie; Zhang, Wenbo; Yao, Suxia; Dann, Sara M.; Elson, Charles O.; Cong, Yingzi

    2015-01-01

    Differentiated CD4+ T cells preserve plasticity under various conditions. However, the stability of Th1 cells is unclear, as is whether Th1 cells can convert into Th17 cells and thereby contribute to the generation of IFN-γ+IL-17+CD4+ T cells, the number of which correlates with severity of colitis. We investigated whether IFN-γ+Th1 cells can convert into Th17 cells under intestinal inflammation and the mechanisms involved. IFN-γThy1.1+ Th1 cells were generated by culturing naïve CD4+ T cells from IFN-γThy1.1 CBir1 TCR-Tg reporter mice, whose TCR is specific for an immunodominant microbiota antigen, CBir1 flagellin, under Th1 polarizing conditions. IFN-γThy1.1+ Th1 cells induced colitis in Rag−/− mice after adoptive transfer and converted into IL-17+Th17, but not Foxp3+Treg cells in the inflamed intestines. TGF-β and IL-6, but not IL-1β and IL-23, regulated Th1 conversion into Th17 cells. TGF-β induction of transcriptional factor Runx1 is crucial for the conversion, since silencing Runx1 by siRNA inhibited Th1 conversion into Th17 cells. Furthermore, TGF-β enhanced histone H3K9 acetylation but inhibited H3K9 trimethylation of Runx1- and RORγt-binding sites on il-17 or rorc genes in Th1 cells. We conclude that Th1 cells convert into Th17 cells under inflammatory conditions in intestines, which is possibly mediated by TGF-β induction of Runx1. PMID:25605286

  8. GENERAL ARRANGEMENT AND OUTLINE. T.H. 2.5 PUMPING PLANT. TEXAS HILL ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    GENERAL ARRANGEMENT AND OUTLINE. T.H. 2.5 PUMPING PLANT. TEXAS HILL CANAL - STA. 132+00. TEXAS HILL CANAL AND DISTRIBUTION SYSTEM. United States Department of Interior, Bureau of Reclamation; Gila Project, Arizona, Wellton-Mohawk Division. Drawing No. 50-D-3187, dated January 10, 1955, Denver, Colorado - Wellton-Mohawk Irrigation System, Relift Station, Texas Hill Canal 2.5, Northern Terminus of Avenue 51 East, approximately .5 mile south of Union Pacific Railroad, Wellton, Yuma County, AZ

  9. LOCATION PLAN. T.H. 2.5 PUMPING PLANT. TEXAS HILL CANAL ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    LOCATION PLAN. T.H. 2.5 PUMPING PLANT. TEXAS HILL CANAL - STA. 132+00. TEXAS HILL CANAL AND DISTRIBUTION SYSTEM. United States Department of Interior, Bureau of Reclamation; Gila Project, Arizona, Wellton-Mohawk Division. Drawing No. 50-D-3186, dated January 25, 1955, Denver, Colorado - Wellton-Mohawk Irrigation System, Relift Station, Texas Hill Canal 2.5, Northern Terminus of Avenue 51 East, approximately .5 mile south of Union Pacific Railroad, Wellton, Yuma County, AZ

  10. Differential Activation of Airway Eosinophils Induces IL-13 Mediated Allergic Th2 Pulmonary Responses in Mice

    PubMed Central

    Jacobsen, EA; Doyle, AD; Colbert, DC; Zellner, KR; Protheroe, CA; LeSuer, WE; Lee, NA.; Lee, JJ

    2015-01-01

    Background Eosinophils are hallmark cells of allergic Th2 respiratory inflammation. However, the relative importance of eosinophil activation and the induction of effector functions such as the expression of IL-13 to allergic Th2 pulmonary disease remain to be defined. Methods Wild type or cytokine deficient (IL-13−/− or IL-4−/−) eosinophils treated with cytokines (GM-CSF, IL-4, IL-33) were adoptively transferred into eosinophil-deficient recipient mice subjected to allergen provocation using established models of respiratory inflammation. Allergen-induced pulmonary changes were assessed. Results In contrast to the transfer of untreated blood eosinophils to the lungs of recipient eosinophildeficient mice, which induced no immune/inflammatory changes either in the lung or lung draining lymph nodes (LDLNs), pretreatment of blood eosinophils with GM-CSF prior to transfer elicited trafficking of these eosinophils to LDLNs. In turn, these LDLN eosinophils elicited the accumulation of dendritic cells and CD4+ T cells to these same LDLNs without inducing pulmonary inflammation. However, exposure of eosinophils to GM-CSF, IL-4 and IL-33 prior to transfer induced not only immune events in the LDLN, but also allergen-mediated increases in airway Th2 cytokine/chemokine levels, the subsequent accumulation of CD4+ T cells as well as alternatively activated (M2) macrophages, and the induction of pulmonary histopathologies. Significantly, this allergic respiratory inflammation was dependent on eosinophil-derived IL-13 whereas IL-4 expression by eosinophils had no significant role. Conclusion The data demonstrate the differential activation of eosinophils as a function of cytokine exposure and suggest that eosinophil-specific IL-13 expression by activated cells is a necessary component of the subsequent allergic Th2 pulmonary pathologies. PMID:26009788

  11. Early immunological response to German cockroach frass exposure induces a Th2/Th17 environment.

    PubMed

    Page, Kristen; Zhou, Ping; Ledford, John R; Day, Scottie B; Lutfi, Riad; Dienger, Krista; Lewkowich, Ian P

    2011-01-01

    Cockroach exposure is a major risk factor for the development of asthma; however, the early immune events induced by cockroach leading to the Th2 response are not fully understood. Exposure of naïve mice to German cockroach (GC) feces (frass) was sufficient to induce dendritic cell (DC) recruiting and activating chemokines C-C motif ligand 20, granulocyte macrophage colony-stimulating factor, granulocyte colony-stimulating factor and macrophage inflammatory protein-1α into the airways. This corresponded with an increase in myeloid DCs (mDCs) in the airways as well as increased expression of CD80 and CD86 on the mDCs. Plasmacytoid DCs in the lung were unchanged. Levels of IL-5, IL-17A and IL-6 cytokines in whole lung cultures were significantly increased 18 h following GC frass exposure demonstrating the early development of a mixed Th2/Th17 response. In addition, GC frass stimulated the production of IL-23, IL-6 and IL-12p70 from bone marrow-derived mDCs. Adoptive transfer of GC frass-pulsed mDCs induced airway reactivity, airway inflammation as well as eosinophilia and induced a strong Th2/Th17 response in the lung. MyD88-deficient bone marrow-derived mDCs did not respond to GC frass treatment, suggesting a functional Toll-like receptor pathway was important to induce the Th2/Th17 response. Together, our data show that GC frass activated the innate immune response to augment DC recruitment and activation of mDCs which promoted robust T cell-skewing cytokines and ultimately drive the development of airway inflammation. PMID:21051864

  12. The chicken TH1 response: potential therapeutic applications of ChIFN-γ.

    PubMed

    Guo, Pengju; Thomas, Jesse D; Bruce, Matthew P; Hinton, Tracey M; Bean, Andrew G D; Lowenthal, John W

    2013-11-01

    The outcomes of viral infections are costly in terms of human and animal health and welfare worldwide. The observed increase in the virulence of some viruses and failure of many vaccines to stop these infections has lead to the apparent need to develop new anti-viral strategies. One approach to dealing with viral infection may be to employ the therapeutic administration of recombinant cytokines to act as 'immune boosters' to assist in augmenting the host response to virus. With this in mind, a greater understanding of the immune response, particularly cell mediated T-helper-1 (TH1) type responses, is imperative to the development of new anti-viral and vaccination strategies. Following the release of the chicken genome, a number of TH1-type cytokines have been identified, including chicken interleukin-12 (ChIL-12), ChIL-18 and interferon-γ ChIFN-γ), highlighting the nature of the TH1-type response in this non-mammalian vertebrate. To date a detailed analysis of the in vivo biological function of these cytokines has been somewhat hampered by access to large scale production techniques. This review describes the role of TH-1 cytokines in immune responses to viruses and explores their potential use in enhancing anti-viral treatment strategies in chickens. Furthermore, this review focuses on the example of ChIFN-γ treatment of Chicken Anemia Virus (CAV) infection. CAV causes amongst other things thymocyte depletion and thymus atrophy, as well as immunosuppression in chickens. However, due to vaccination, clinical disease appears less often, nevertheless, the subclinical form of the disease is often associated with secondary complicating infections due to an immunocompromised state. Since CAV-induced immunosuppression can cause a marked decrease in the immune response against other pathogens, understanding this aspect of the disease is critically important, as well as providing insights into developing new control approaches. With increasing emphasis on developing

  13. The histamine H4 receptor mediates inflammation and pruritus in Th2-dependent dermal inflammation.

    PubMed

    Cowden, Jeffery M; Zhang, Mai; Dunford, Paul J; Thurmond, Robin L

    2010-04-01

    The role of histamine H(4) receptor (H(4)R) was investigated in a T-helper type 2 (Th2)-cell-mediated mouse skin inflammation model that mimics several of the features of atopic dermatitis. Treatment with two specific H(4)R antagonists before challenge with FITC led to a significant reduction in ear edema, inflammation, mast cell, and eosinophil infiltration. This was accompanied by a reduction in the levels of several cytokines and chemokines in the ear tissue. Upon ex vivo antigen stimulation of lymph nodes, H(4)R antagonism reduced lymphocyte proliferation and IL-4, IL-5, and IL-17 levels. One explanation for this finding is that lymph nodes from animals dosed with the H(4)R antagonist, JNJ 7777120, contained a lower number of FITC-positive dendritic cells. The effect of H(4)R antagonism on dendritic cell migration in vivo may be an indirect result of the reduction in tissue cytokines and chemokines or a direct effect on chemotaxis. In addition to anti-inflammatory effects, JNJ 7777120 also significantly inhibited the pruritus shown in the model. Therefore, the dual effects of H(4)R antagonists on pruritus and Th2-cell-mediated inflammation point to their therapeutic potential for the treatment of Th2-mediated skin disorders, including atopic dermatitis. PMID:19907432

  14. TLR4 genotype and environmental LPS mediate RSV bronchiolitis through Th2 polarization

    PubMed Central

    Caballero, Mauricio T.; Serra, M. Elina; Acosta, Patricio L.; Marzec, Jacqui; Gibbons, Luz; Salim, Maximiliano; Rodriguez, Andrea; Reynaldi, Andrea; Garcia, Alejandro; Bado, Daniela; Buchholz, Ursula J.; Hijano, Diego R.; Coviello, Silvina; Newcomb, Dawn; Bellabarba, Miguel; Ferolla, Fausto M.; Libster, Romina; Berenstein, Ada; Siniawaski, Susana; Blumetti, Valeria; Echavarria, Marcela; Pinto, Leonardo; Lawrence, Andrea; Ossorio, M. Fabiana; Grosman, Arnoldo; Mateu, Cecilia G.; Bayle, Carola; Dericco, Alejandra; Pellegrini, Mariana; Igarza, Ignacio; Repetto, Horacio A.; Grimaldi, Luciano Alva; Gudapati, Prathyusha; Polack, Norberto R.; Althabe, Fernando; Shi, Min; Ferrero, Fernando; Bergel, Eduardo; Stein, Renato T.; Peebles, R. Stokes; Boothby, Mark; Kleeberger, Steven R.; Polack, Fernando P.

    2015-01-01

    While 30%–70% of RSV-infected infants develop bronchiolitis, 2% require hospitalization. It is not clear why disease severity differs among healthy, full-term infants; however, virus titers, inflammation, and Th2 bias are proposed explanations. While TLR4 is associated with these disease phenotypes, the role of this receptor in respiratory syncytial virus (RSV) pathogenesis is controversial. Here, we evaluated the interaction between TLR4 and environmental factors in RSV disease and defined the immune mediators associated with severe illness. Two independent populations of infants with RSV bronchiolitis revealed that the severity of RSV infection is determined by the TLR4 genotype of the individual and by environmental exposure to LPS. RSV-infected infants with severe disease exhibited a high GATA3/T-bet ratio, which manifested as a high IL-4/IFN-γ ratio in respiratory secretions. The IL-4/IFN-γ ratio present in infants with severe RSV is indicative of Th2 polarization. Murine models of RSV infection confirmed that LPS exposure, Tlr4 genotype, and Th2 polarization influence disease phenotypes. Together, the results of this study identify environmental and genetic factors that influence RSV pathogenesis and reveal that a high IL-4/IFN-γ ratio is associated with severe disease. Moreover, these molecules should be explored as potential targets for therapeutic intervention. PMID:25555213

  15. Treatment of allergic asthma: Modulation of Th2 cells and their responses

    PubMed Central

    2011-01-01

    Atopic asthma is a chronic inflammatory pulmonary disease characterised by recurrent episodes of wheezy, laboured breathing with an underlying Th2 cell-mediated inflammatory response in the airways. It is currently treated and, more or less, controlled depending on severity, with bronchodilators e.g. long-acting beta agonists and long-acting muscarinic antagonists or anti-inflammatory drugs such as corticosteroids (inhaled or oral), leukotriene modifiers, theophyline and anti-IgE therapy. Unfortunately, none of these treatments are curative and some asthmatic patients do not respond to intense anti-inflammatory therapies. Additionally, the use of long-term oral steroids has many undesired side effects. For this reason, novel and more effective drugs are needed. In this review, we focus on the CD4+ Th2 cells and their products as targets for the development of new drugs to add to the current armamentarium as adjuncts or as potential stand-alone treatments for allergic asthma. We argue that in early disease, the reduction or elimination of allergen-specific Th2 cells will reduce the consequences of repeated allergic inflammatory responses such as lung remodelling without causing generalised immunosuppression. PMID:21867534

  16. T(H)2 cytokines modulate the IL-9R expression on human neutrophils.

    PubMed

    Dragon, Stéphane; Takhar, Manrit Kaur; Shan, Lianyu; Hayglass, Kent T; Simons, F Estelle; Gounni, Abdelilah S

    2009-06-26

    Interleukin (IL)-9 is associated with key pathological features of asthma such as airway hyperresponsiveness, bronchoconstriction and mucus production. Inflammatory responses mediated by IL-9 rely on the expression of the IL-9R which has been reported on lung epithelial cells, T lymphocytes and recently on airway granulocyte infiltrates. In this study, we assessed the regulatory and constitutive cell surface expression of the IL-9Ralpha in unfractionated and purified human neutrophils from atopic asthmatics, atopic non-asthmatics and healthy normal controls. We demonstrate that T(H)2 cytokines (IL-4 or IL-13) and granulocyte macrophage-colony stimulating factor (GM-CSF) up-regulated mRNA and cell surface expression levels of the IL-9Ralpha in primary human and HL-60 differentiated neutrophils. Pharmacological inhibition of NF-kappaB did not affect T(H)2-mediated IL-9Ralpha expression in human neutrophils although IFN-gamma and IL-10 down-regulated IL-9Ralpha expression when co-incubated with IL-4, IL-13 or GM-CSF. Collectively, our results reveal a regulatory function for IFN-gamma and IL-10 on modulating the inducible IL-9Ralpha expression levels on peripheral blood neutrophils by T(H)2 cytokines. PMID:19401191

  17. Increased susceptibility to Strongyloides venezuelensis in mice due to Mycobacterium bovis co-infection which modulates production of Th2 cytokines.

    PubMed

    Carmo, A M; Vicentini, M A; Dias, A T; Alves, L L; Alves, C C S; Brandi, J S; De Paula, M L; Fernandes, A; Barsante, M M; Souza, M A; Teixeira, H C; Negrão-Corrêa, D; Ferreira, A P

    2009-09-01

    An estimated quarter of the world's population possesses an infection caused by gastrointestinal nematodes, which induce a Th2 type immune response. Concomitant infection of nematodes with Mycobacterium tuberculosis, which induces a predominantly Th1 type response, is very frequent in tropical and subtropical regions. This study examined immune responses of BALB/c mice infected with Strongyloides venezuelensis and then co-infected with Mycobacterium bovis. The number of worms in the intestine, eggs in feces, cytokine production in lungs and intestine and the expression of CD80, CD86, CTLA-4 and CD28 cell markers on pulmonary cells were analysed. Our results indicate that co-infected mice had an increased parasite burden, which correlates with elevated IFN-gamma and IL-10 cytokine production and decreased IL-4 and IL-13. Moreover, decreased expression of CD80 and increased expression of CTLA-4 were observed in co-infected mice. Our data point out that susceptibility to Strongyloides venezuelensis infection is increased by Mycobacterium bovis co-infection, resulting in higher parasite survival. PMID:19660155

  18. Decreased B and T lymphocyte attenuator in Behcet's disease may trigger abnormal Th17 and Th1 immune responses.

    PubMed

    Ye, Zi; Deng, Bolin; Wang, Chaokui; Zhang, Dike; Kijlstra, Aize; Yang, Peizeng

    2016-01-01

    Behcet's disease (BD) is a chronic, systemic and recurrent inflammatory disease associated with hyperactive Th17 and Th1 immune responses. Recent studies have shown that B and T lymphocyte attenuator (BTLA) negatively regulates the immune response. In this study, we investigated whether BTLA activation could be exploited to inhibit the development of abnormal immune responses in BD patients. BTLA expression in PBMCs and CD4(+) T cells was significantly decreased in active BD patients. Decreased BTLA level was associated with increased Th17 and Th1 responses. Activation of BTLA inhibited the abnormal Th17 and Th1 responses and IL-22 expression in both patients and controls. Addition of an agonistic anti-BTLA antibody remarkably inhibited DC-induced Th17 and Th1 cell responses, resulted in decreased production of the Th17 and Th1-related cytokines IL-1beta, IL-6, IL-23 and IL-12p70 and reduced CD40 expression in DCs. In conclusion, decreased BTLA expression in ocular BD may lead to inappropriate control of the Th17 and Th1 immune responses and DC functions. Therefore, BTLA may be involved in the development and recurrence of this disease. Agonistic agents of BTLA may represent a potential therapeutic approach for the treatment of BD and other inflammatory diseases mediated by abnormal Th17 and Th1 immune responses. PMID:26841832

  19. The Role of Neutrophils in the Induction of Specific Th1 and Th17 during Vaccination against Tuberculosis

    PubMed Central

    Trentini, Monalisa M.; de Oliveira, Fábio M.; Kipnis, André; Junqueira-Kipnis, Ana P.

    2016-01-01

    Mycobacterium tuberculosis causes tuberculosis (TB), a disease that killed more than 1.5 million people worldwide in 2014, and the Bacillus Calmette Guérin (BCG) vaccine is the only currently available vaccine against TB. However, it does not protect adults. Th1 and Th17 cells are crucial for TB control, as well as the neutrophils that are directly involved in DC trafficking to the draining lymph nodes and the activation of T lymphocytes during infection. Although several studies have shown the importance of neutrophils during M. tuberculosis infection, none have shown its role in the development of a specific response to a vaccine. The vaccine mc2-CMX was shown to protect mice against M. tuberculosis challenge, mainly due to specific Th1 and Th17 cells. This study evaluated the importance of neutrophils in the generation of the Th1- and Th17-specific responses elicited by this vaccine. The vaccine injection induced a neutrophil rich lesion with a necrotic central area. The IL-17 KO mice did not generate vaccine-specific Th1 cells. The vaccinated IL-22 KO mice exhibited Th1- and Th17-specific responses. Neutrophil depletion during vaccination abrogated the induction of Th1-specific responses and prohibited the bacterial load reduction observed in the vaccinated animals. The results show, for the first time, the role of neutrophils in the generation of specific Th1 and Th17 cells in response to a tuberculosis vaccine. PMID:27375607

  20. Th1 Versus Th17: Are T Cell Cytokines Relevant in Multiple Sclerosis?

    PubMed Central

    Yang, Yuhong; Racke, Michael K.

    2010-01-01

    Our understanding of the pathophysiology of multiple sclerosis (MS) has evolved significantly over the past two decades as the fields of immunology and neurobiology provide new avenues of exploration into the cause and mechanism of the disease. It has been known for decades that T cells have different cytokine phenotypes, yet the cytokine phenotype of pathogenic T cells in MS is still an area of debate. In EAE, it appears that IFNγ and IL-17, produced by Th1 and Th17 cells respectively, are not the critical factor that determines T cell encephalitogenicity. However, there are molecules such as IL-23, T-bet and STAT4, that appear to be critical, yet it is unclear whether all these molecules contribute to a common, yet undefined pathway, or act in a synergistic manner which culminates in encephalitogenicity has still to be determined. Therefore, the focus of research on effector T cells in MS should focus on pathways upstream of the cytokines that define Th1 and Th17 cells, since downstream products, such as IFNγ and IL-17, probably are not critical determinants of whether an effector T cells is capable of trafficking to the CNS and inducing inflammatory demyelination. PMID:20600875

  1. Curcumin relieves TPA-induced Th1 inflammation in K14-VEGF transgenic mice.

    PubMed

    Sun, Jun; Zhao, Yi; Jin, Hairong; Hu, Jinhong

    2015-04-01

    Curcumin has been confirmed to have anti-inflammatory properties in addition to the ability to decrease the expression of pro-inflammatory cytokines in keratinocytes. It was suggested that the interleukin-23 (IL-23)/IL-17A cytokine axis played a critical role in the pathogenesis of 12-O-tetradecanoyl phorbol 12-myristate 13-acetate (TPA)-induced K14-VEGF transgenic psoriasis-like mice model. Here, we report that topical use of a curcumin gel formulation inhibited TPA-induced Th1 inflammation in K14-VEGF transgenic mice ears but not Th17 inflammation as expected. Real-time PCR showed that mRNA levels of IL-23, IL-17A, IL-22, IL-6 and TNFα cytokines failed to increase after TPA-induction in K14-VEGF transgenic mice ear skin; but the mRNA level of IFNγ increased significantly at the same time. Furthermore, TPA-induction up-regulated the TCRγδ protein but failed to impact the CCR6 protein, which means that the proliferation of γδ T cells is incapable of IL-17A production. We find that curcumin is capable of relieving TPA-induced inflammation by directly down-regulating IFNγ production. In conclusion, curcumin inhibits TPA-induced Th1 inflammation in K14-VEGF transgenic mice which has not been previously described. PMID:25682767

  2. Epigenetic silencing of Th1 type chemokines shapes tumor immunity and immunotherapy

    PubMed Central

    Peng, Dongjun; Kryczek, Ilona; Nagarsheth, Nisha; Zhao, Lili; Wei, Shuang; Wang, Weimin; Sun, Yuqing; Zhao, Ende; Vatan, Linda; Szeliga, Wojciech; Kotarski, Jan; Tarkowski, Rafał; Dou, Yali; Cho, Kathleen; Hensley-Alford, Sharon; Munkarah, Adnan; Liu, Rebecca; Zou, Weiping

    2015-01-01

    Summary Epigenetic silencing including histone modifications and DNA methylation is an important tumorigenic mechanism1 However, its role in cancer immunopathology and immunotherapy is poorly understood. Using ovarian cancers as our model, we found that enhancer of zeste homolog 2 (EZH2)-mediated histone H3 lysine 27 trimethylation (H3K27me3) and DNA methyltransferase (DNMT) 1-mediated DNA methylation repress the tumor production of Th1-type chemokines CXCL9 and CXCL10, and subsequently determine effector T cell trafficking to the tumor microenvironment. Treatment with epigenetic modulators removes the repression and increases effector T cell tumor infiltration, slows down tumor progression, and improves therapeutic efficacy of PD-L1 (B7-H1) checkpoint blockade2–4 and adoptive T cell transfusion5 in tumor bearing mice. Moreover, tumor EZH2 and DNMT1 are negatively associated with tumor infiltrating CD8+ T cells and patient outcome. Thus, epigenetic silencing of Th1-type chemokine is a novel tumor immune evasion mechanism. Selective epigenetic reprogramming alters T cell landscape6 in cancer and may enhance clinical efficacy of cancer therapy. PMID:26503055

  3. Complement Regulates Nutrient Influx and Metabolic Reprogramming during Th1 Cell Responses

    PubMed Central

    Kolev, Martin; Dimeloe, Sarah; Le Friec, Gaelle; Navarini, Alexander; Arbore, Giuseppina; Povoleri, Giovanni A.; Fischer, Marco; Belle, Réka; Loeliger, Jordan; Develioglu, Leyla; Bantug, Glenn R.; Watson, Julie; Couzi, Lionel; Afzali, Behdad; Lavender, Paul; Hess, Christoph; Kemper, Claudia

    2015-01-01

    Summary Expansion and acquisition of Th1 cell effector function requires metabolic reprogramming; however, the signals instructing these adaptations remain poorly defined. Here we found that in activated human T cells, autocrine stimulation of the complement receptor CD46, and specifically its intracellular domain CYT-1, was required for induction of the amino acid (AA) transporter LAT1 and enhanced expression of the glucose transporter GLUT1. Furthermore, CD46 activation simultaneously drove expression of LAMTOR5, which mediated assembly of the AA-sensing Ragulator-Rag-mTORC1 complex and increased glycolysis and oxidative phosphorylation (OXPHOS), required for cytokine production. T cells from CD46-deficient patients, characterized by defective Th1 cell induction, failed to upregulate the molecular components of this metabolic program as well as glycolysis and OXPHOS, but IFN-γ production could be reinstated by retrovirus-mediated CD46-CYT-1 expression. These data establish a critical link between the complement system and immunometabolic adaptations driving human CD4+ T cell effector function. PMID:26084023

  4. Salmonella as a Model for Non-Cognate Th1 Cell Stimulation

    PubMed Central

    O’Donnell, Hope; McSorley, Stephen J.

    2014-01-01

    Salmonella has been a model pathogen for examining CD4 T cell activation and effector functions for many years due to the strength of the Th1 cell response observed during Salmonella infections, the relative ease of use of Salmonella, the availability of Salmonella-specific T cell reagents, and the well-characterized nature of the model system, the pathogen, and the immune response elicited. Herein, we discuss the use of Salmonella as a model pathogen to explore the complex interaction of T cells with their inflammatory environment. In particular, we address the issue of bystander activation of naïve T cells and non-cognate stimulation of activated and memory T cells. Further, we compare and contrast our current knowledge of these non-cognate responses in CD8 versus CD4 T cells. Finally, we make a case for Salmonella as a particularly appropriate model pathogen in the study of non-cognate CD4 T cell responses based on the strength of the Th1 response during infection, the requirement for CD4 T cells in bacterial clearance, and the well-characterized inflammatory response to conserved molecular patterns induced by Salmonella infection. PMID:25540644

  5. Eriocalyxin B ameliorates experimental autoimmune encephalomyelitis by suppressing Th1 and Th17 cells

    PubMed Central

    Lu, Ying; Chen, Bing; Song, Jun-Hong; Zhen, Tao; Wang, Bai-Yan; Li, Xin; Liu, Ping; Yang, Xin; Zhang, Qun-Ling; Xi, Xiao-Dong; Chen, Sheng-Di; Zuo, Jian-Ping; Chen, Zhu; Chen, Sai-Juan

    2013-01-01

    Eriocalyxin B (EriB), a diterpenoid isolated from Isodon eriocalyx, was previously reported to have antitumor effects via multiple pathways, and these pathways are related to immune responses. In this study, we demonstrated that EriB was efficacious in experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. Treatment with EriB led to amelioration of EAE, which correlated with reduced spinal cord inflammation and demyelination. EriB treatment abolished encephalitogenic T-cell responses to myelin oligodendrocyte glycoprotein in an adoptive transfer EAE model. The underlying mechanism of EriB-induced effects involved inhibition of T helper (Th) 1 and Th17 cell differentiation through Janus Kinase/Signal Transducer and Activator Of Transcription and Nuclear factor-κB signaling pathways as well as elevation of reactive oxygen species. These findings indicate that EriB exerts potent antiinflammatory effects through selective modulation of pathogenic Th1 and Th17 cells by targeting critical signaling pathways. The study provides insights into the role of EriB as a unique therapeutic agent for the treatment of autoimmune diseases. PMID:23345445

  6. Elevated Ratio of Th17 Cell-Derived Th1 Cells (CD161+Th1 Cells) to CD161+Th17 Cells in Peripheral Blood of Early-Onset Rheumatoid Arthritis Patients

    PubMed Central

    Kotake, Shigeru; Nanke, Yuki; Yago, Toru; Kawamoto, Manabu; Kobashigawa, Tsuyoshi; Yamanaka, Hisashi

    2016-01-01

    Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by the destruction of articular cartilage and bone with elevated levels of proinflammatory cytokines. It has been reported that IL-17 and Th17 cells play important roles in the pathogenesis of RA. Recently, plasticity in helper T cells has been demonstrated; Th17 cells can convert to Th1 cells. It remains to be elucidated whether this conversion occurs in the early phase of RA. Here, we tried to identify Th17 cells, Th1 cells, and Th17 cell-derived Th1 cells (CD161+Th1 cells) in the peripheral blood of early-onset RA patients. We also evaluated the effect of methotrexate on the ratio of Th17 cells in early-onset RA patients. The ratio of Th17 cell-derived Th1 cells to CD161+Th17 cells was elevated in the peripheral blood of early-onset RA patients. In addition, MTX reduced the ratio of Th17 cells but not Th1 cells. These findings suggest that IL-17 and Th17 play important roles in the early phase of RA; thus, anti-IL-17 antibodies should be administered to patients with RA in the early phase. PMID:27123445

  7. Enhancement of adaptive immunity to Neisseria gonorrhoeae by local intravaginal administration of microencapsulated interleukin 12.

    PubMed

    Liu, Yingru; Egilmez, Nejat K; Russell, Michael W

    2013-12-01

    Gonorrhea remains one of the most frequent infectious diseases, and Neisseria gonorrhoeae is emerging as resistant to most available antibiotics, yet it does not induce a state of specific protective immunity against reinfection. Our recent studies have demonstrated that N. gonorrhoeae proactively suppresses host T-helper (Th) 1/Th2-mediated adaptive immune responses, which can be manipulated to generate protective immunity. Here we show that intravaginally administered interleukin 12 (IL-12) encapsulated in sustained-release polymer microspheres significantly enhanced both Th1 and humoral immune responses in a mouse model of genital gonococcal infection. Treatment of mice with IL-12 microspheres during gonococcal challenge led to faster clearance of infection and induced resistance to reinfection, with the generation of gonococcus-specific circulating immunoglobulin G and vaginal immunoglobulin A and G antibodies. These results suggest that local administration of microencapsulated IL-12 can serve as a novel therapeutic and prophylactic strategy against gonorrhea, with implications for the development of an effective vaccine. PMID:24048962

  8. IL-25/IL-33–responsive TH2 cells characterize nasal polyps with a default TH17 signature in nasal mucosa

    PubMed Central

    Lam, Emily P.S.; Kariyawasam, Harsha H.; Rana, Batika M.J.; Durham, Stephen R.; McKenzie, Andrew N.J.; Powell, Nicholas; Orban, Nara; Lennartz-Walker, Melissa; Hopkins, Claire; Ying, Sun; Rimmer, Joanne; Lund, Valerie J.; Cousins, David J.; Till, Stephen J.

    2016-01-01

    Background Chronic rhinosinusitis with nasal polyposis (CRSwNP) in Western countries is characterized by eosinophilia, IgE production, and TH2 cytokine expression. Type 2 innate lymphoid cells from polyps produce IL-5 and IL-13 in response to IL-25 and IL-33, although the relevance of this axis to local mucosal T-cell responses is unknown. Objective We sought to investigate the role of the IL-25/IL-33 axis in local mucosal T-cell responses in patients with CRSwNP. Methods Polyp tissue and blood were obtained from patients undergoing nasal polypectomy. Control nasal biopsy specimens and blood were obtained from healthy volunteers. Tissue was cultured in a short-term explant model. T-cell surface phenotype/intracellular cytokines were assessed by means of flow cytometry. T-cell receptor variable β-chain analysis was performed with the immunoSEQ assay. Microarrays were performed for gene expression analysis. Results IL-25 receptor (IL-17RB)–expressing TH2 effector cells were identified in nasal polyp tissue but not the healthy nasal mucosa or periphery. IL-17RB+CD4+ polyp–derived TH2 cells coexpressed ST2 (IL-33 receptor) and responded to IL-25 and IL-33 with enhanced IL-5 and IL-13 production. Within IL-17RB+CD4+ T cells, several identical T-cell receptor variable β-chain complementarity-determining region 3 sequences were identified in different subjects, suggesting clonal expansion driven by a common antigen. Abundant IL-17–producing T cells were observed in both healthy nasal mucosal and polyp populations, with TH17-related genes the most overexpressed compared with peripheral blood T cells. Conclusion IL-25 and IL-33 can interact locally with IL-17RB+ST2+ polyp T cells to augment TH2 responses in patients with CRSwNP. A local TH17 response might be important in healthy nasal mucosal immune homeostasis. PMID:26684290

  9. Thermodynamic properties of CexTh1-xO2 solid solution from first-principles calculations

    SciTech Connect

    Xiao, Haiyan Y.; Zhang, Yanwen; Weber, William J.

    2012-11-02

    A systematic study based on first-principles calculations along with a quasi-harmonic approximation has been conducted to calculate the thermodynamic properties of the CexTh1xO2 solid solution. The predicted density, thermal expansion coefficients, heat capacity and thermal conductivity for the CexTh1xO2 solid solution all agree well with the available experimental data. The thermal expansion coefficient for ThO2 increases with CeO2 substitution, and complete substitution shows the highest expansion coefficient. On the other hand, the mixed CexTh1xO2 (0 < x < 1) solid solution generally exhibits lower heat capacity and thermal conductivity than the ThO2 and CeO2 end members. Our calculations indicate a strong effect of Ce concentration on the thermodynamic properties of the CexTh1xO2 solid solution.

  10. Induction of a Th1 immune response and suppression of IgE via immunotherapy with a recombinant hybrid molecule encapsulated in liposome-protamine-DNA nanoparticles in a model of experimental allergy.

    PubMed

    Nouri, Hamid Reza; Varasteh, Abdolreza; Jaafari, Mahmoud Reza; Davies, Janet M; Sankian, Mojtaba

    2015-07-01

    Liposome-protamine-DNA nanoparticles (LPD) are safe, effective, and non-toxic adjuvants that induce Th1-like immune responses. We hypothesized that encapsulation of allergens into liposomes could be an appropriate option for immunotherapy. The present study evaluated the immunotherapeutic potential of a recombinant hybrid molecule (rHM) encapsulated in LPD nanoparticles in a murine model of Chenopodium album allergy. BALB/c mice were sensitized with the allergen in alum, and the immunotherapy procedure was performed by subcutaneous injections of LPD-rHM, rHM, or empty LPD at weekly intervals. Sensitized mice developed a Th2-biased immune response characterized by strong specific IgG1 and IgE production, IL-4, and the transcription factor GATA3 in spleen cell cultures. Treatment with the LPD-rHM resulted in a reduction in IgE and a marked increase in IgG2a. The LPD-rHM induced allergen-specific responses with relatively high interferon-gamma production, as well as expression of the transcription factor T-bet in stimulated splenocytes. In addition, lymphoproliferative responses were higher in the LPD-rHM-treated mice than in the other groups. Removal of the nanoparticles from the rHM resulted in a decrease in the allergen's immunogenicity. These results indicate that the rHM complexed with LPD nanoparticles has a marked suppressive effect on the allergic response and caused a shift toward a Th1 pathway. PMID:25957889

  11. Parallel algorithms of relative radiometric correction for images of TH-1 satellite

    NASA Astrophysics Data System (ADS)

    Wang, Xiang; Zhang, Tingtao; Cheng, Jiasheng; Yang, Tao

    2014-05-01

    The first generation of transitive stereo-metric satellites in China, TH-1 Satellite, is able to gain stereo images of three-line-array with resolution of 5 meters, multispectral images of 10 meters, and panchromatic high resolution images of 2 meters. The procedure between level 0 and level 1A of high resolution images is so called relative radiometric correction (RRC for short). The processing algorithm of high resolution images, with large volumes of data, is complicated and time consuming. In order to bring up the processing speed, people in industry commonly apply parallel processing techniques based on CPU or GPU. This article firstly introduces the whole process and each step of the algorithm - that is in application - of RRC for high resolution images in level 0; secondly, the theory and characteristics of MPI (Message Passing Interface) and OpenMP (Open Multi-Processing) parallel programming techniques is briefly described, as well as the superiority for parallel technique in image processing field; thirdly, aiming at each step of the algorithm in application and based on MPI+OpenMP hybrid paradigm, the parallelizability and the strategies of parallelism for three processing steps: Radiometric Correction, Splicing Pieces of TDICCD (Time Delay Integration Charge-Coupled Device) and Gray Level Adjustment among pieces of TDICCD are deeply discussed, and furthermore, deducts the theoretical acceleration rates of each step and the one of whole procedure, according to the processing styles and independence of calculation; for the step Splicing Pieces of TDICCD, two different strategies of parallelism are proposed, which are to be chosen with consideration of hardware capabilities; finally, series of experiments are carried out to verify the parallel algorithms by applying 2-meter panchromatic high resolution images of TH-1 Satellite, and the experimental results are analyzed. Strictly on the basis of former parallel algorithms, the programs in the experiments

  12. Intratracheal myriocin enhances allergen‐induced Th2 inflammation and airway hyper‐responsiveness

    PubMed Central

    Edukulla, Ramakrishna; Rehn, Kira Lee; Liu, Bo; McAlees, Jaclyn W.; Hershey, Gurjit K.; Wang, Yui Hsi; Lewkowich, Ian

    2016-01-01

    Introduction Ceramide is the central substrate of sphingolipid metabolism and plays a key role in cellular signal transduction pathways, regulating apoptosis, differentiation, and chemotaxis. Alterations in airway ceramide levels are observed in multiple pulmonary diseases and recent human genetic association studies have linked dysregulation of sphingolipid regulatory genes with asthma pathogenesis. Methods Utilizing myriocin, a potent inhibitor of sphingolipid synthesis, we evaluated the immune regulatory role of de novo ceramide generation in vitro and in vivo. Intratracheal myriocin was administered alone or during house dust mite sensitization (HDM) of BALB/C mice and airway hyper‐responsiveness (AHR) was evaluated by invasive plethysmography followed by bronchial lavage (BAL) cytology and cytokine quantification. Results Myriocin inhibits and HDM exposure activates de novo ceramide synthesis in bone marrow‐derived dendritic cells. Mice receiving intratracheal myriocin developed a mild airway neutrophilic infiltrate without inducing a significant increase in AHR. CXCL1 was elevated in the BAL fluid of myriocin‐treated mice while the neutrophilic chemotactic factors anaphylatoxin C5a, leukotriene B4, and IL‐17 were unaffected. HDM treatment combined with myriocin led to a dramatic enhancement of AHR (63% increase over HDM alone, p < 0.001) and increased granulocyte pulmonary infiltrates versus HDM or myriocin alone. Elevated Th2 T cell counts and Th2 cytokines/chemokines (IL5, IL13, CCL17) were observed in mice treated with combined HDM/myriocin compared to HDM alone. Myriocin‐treated pulmonary CD11c+ cells stimulated with HDM secreted significantly more CXCL1 than cells stimulated with HDM alone while HDM stimulated airway epithelial cells showed no change in CXCL1 secretion following myriocin treatment. Conclusions Intratracheal myriocin, likely acting via ceramide synthesis inhibition, enhances allergen‐induced airway inflammation

  13. Sampling and analysis of the inactive waste tanks TH-2, WC-1, and WC-15

    SciTech Connect

    Autrey, J.W.; Keller, J.M.; Griest, W.H.; Botts, J.L.; Schenley, R.L.; Sipe, M.A.

    1992-02-01

    Thirty-eight inactive liquid low-level radioactive waste tanks are currently managed by the Environmental Restoration Program of Oak Ridge National Laboratory. The contents of these tanks are to be characterized in preparation for future corrective actions and remediation activities as part of compliance with the pending Federal Facility Agreement for the Oak Ridge Reservation. Twenty-nine of these tanks were sampled and analyzed in 1989. Three of the tanks (TH-2, WC-1, and