Kinetic Th1/Th2 responses of transgenic mice with bacterial meningitis induced by Haemophilus influenzae

2006 ◽  
Vol 111 (4) ◽  
pp. 253-263 ◽  
Author(s):  
Shyi-Jou Chen ◽  
Mong-Ling Chu ◽  
Chia-Jen Wang ◽  
Ching-Len Liao ◽  
Shie-Liang Hsieh ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Haemophilus Influenzae ◽  
Clinical Symptoms ◽  
Specific Antigen ◽  
Clinical Severity ◽  
Interleukin 4 ◽  
Th2 Cells ◽  
Th1 Cells ◽  
Th2 Response ◽  
Ifn Γ

To investigate the kinetic Th1/Th2 immunopathogenic mechanisms of Haemophilus influenzae meningitis, we established a murine experimental model of meningitis and elucidated the Th1/Th2 immune responses in T1/T2 doubly transgenic mice based on a BALB/c background under the control of the IFN-γ (interferon-γ)/IL-4 (interleukin-4) promoters respectively. NTHi (non-typeable Haemophilus influenzae) meningitis was induced in these mice by inoculation with either a colonized (CNTHi) or invasive (INTHi) strain of NTHi. Mice inoculated with CNTHi displayed a less severe degree of disease in terms of clinical symptoms, mortality rate and brain histopathology. Conversely, INTHi-inoculated mice had more severe clinical symptoms. CNTHi-inoculated mice had a more significant Th1 response in terms of a higher percentage and longer maintenance of Th1 cells, and more production of IFN-γ from strain-specific antigen-stimulated splenocytes than INTHi-inoculated mice. In contrast, INTHi-inoculated mice had a more significant Th2 response. This was due to a significant increase in IL-4-producing CD4+ T-cells (Th2 cells) and more production of IL-4 from strain-specific antigen-stimulated splenocytes accompanied by a rapid decline of Th1 cells in INTHi-inoculated mice. In conclusion, the preferential Th1/Th2 trend in this murine model of NTHi meningitis is correlated with clinical severity as well as isolated characteristics of the pathogens themselves.

scholarly journals Increased Th1 Cells with Disease Resolution of Active Pulmonary Tuberculosis in Non-Atopic Patients

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 724
Author(s):  
Chun-Yu Lo ◽  
Yu-Chen Huang ◽  
Hung-Yu Huang ◽  
Fu-Tsai Chung ◽  
Chang-Wei Lin ◽  
...  
Keyword(s):  
Immunoglobulin E ◽  
Interleukin 4 ◽  
Th2 Cells ◽  
Enzyme Linked Immunosorbent Assay ◽  
Th1 Cells ◽  
T Helper ◽  
Tb Treatment ◽  
Nitrite Production ◽  
Ifn Γ ◽  
The Impact

Type 1 CD4+ T helper (Th1) cells mediate resistance to Mycobacterium tuberculosis (Mtb), and Th2 immunity generates specific immunoglobulin E upon allergen exposure. We investigated the impact of active tuberculosis (TB), atopic status, and anti-TB treatment on the balance between Th1 and Th2 (type 2 CD4+ T helper) immunity. CD4+/interferon (IFN)-γ+ Th1 cells (%Th1) and CD4+/interleukin-4+ Th2 cells (%Th2) in bronchoalveolar lavage (BAL) fluid and peripheral blood mononuclear cells (PBMCs) were measured by flow cytometry. The BAL %Th1 was higher in TB patients at baseline, compared to that in non-TB subjects, and was further increased in TB patients after stimulation with phorbol myristate acetate and ionomycin. The stimulated BAL %Th1 was inversely correlated with the severity score of chest radiography in TB patients. Heat-killed Mtb triggered more IFN-γ and nitrite production, as determined by enzyme-linked immunosorbent assay and the Griess reaction, respectively, from the alveolar macrophages of TB patients than that of non-TB subjects. Non-atopic TB participants had a higher %Th1 in PBMCs, compared to atopic individuals, and their %Th1 decreased after 3-month anti-TB treatment. Th1 response is provoked by active TB infection, is associated with less severe radiographic changes, is reduced in atopic patients with active TB infection, and is attenuated after anti-TB treatment.

scholarly journals Interleukin 21 Is a T Helper (Th) Cell 2 Cytokine that Specifically Inhibits the Differentiation of Naive Th Cells into Interferon γ–producing Th1 Cells

2002 ◽  
Vol 196 (7) ◽  
pp. 969-977 ◽  
Author(s):  
Andrea L. Wurster ◽  
Vikki L. Rodgers ◽  
Abhay R. Satoskar ◽  
Matthew J. Whitters ◽  
Deborah A. Young ◽  
...  
Keyword(s):  
Interferon Γ ◽  
Th2 Cells ◽  
Th1 Cells ◽  
T Helper ◽  
Th2 Response ◽  
Th Cells ◽  
Th Cell ◽  
Ifn Γ

The cytokine potential of developing T helper (Th) cells is directly shaped both positively and negatively by the cytokines expressed by the effector Th cell subsets. Here we find that the recently identified cytokine, interleukin (IL)-21, is preferentially expressed by Th2 cells when compared with Th1 cells generated in vitro and in vivo. Exposure of naive Th precursors to IL-21 inhibits interferon (IFN)-γ production from developing Th1 cells. The repression of IFN-γ production is specific in that the expression of other Th1 and Th2 cytokines is unaffected. IL-21 decreases the IL-12 responsiveness of developing Th cells by specifically reducing both signal transducer and activator of transcription 4 protein and mRNA expression. These results suggest that Th2 cell-derived IL-21 regulates the development of IFN-γ–producing Th1 cells which could serve to amplify a Th2 response.

EpCAM, a human tumor-associated antigen promotes Th2 development and tumor immune evasion

Blood ◽  
2009 ◽  
Vol 113 (15) ◽  
pp. 3494-3502 ◽  
Author(s):  
Alexandra Ziegler ◽  
Regina Heidenreich ◽  
Heidi Braumüller ◽  
Hartwig Wolburg ◽  
Susanne Weidemann ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Evasion ◽  
Immune Therapy ◽  
Human Tumor ◽  
Interleukin 4 ◽  
Th2 Cells ◽  
Th1 Cells ◽  
Tumor Immune Evasion ◽  
Ifn Γ ◽  
Th2 Development

Abstract Experimental tumor vaccination and adoptive T-cell therapies show that interferon-γ (IFN-γ)–producing CD4+ T helper cells (Th1) can be highly effective in tumor prevention and therapy. Unexpectedly, first vaccine trials in humans revealed that tumor immune therapy may not only be protective, but, on the contrary, even promote tumor progression. Here, we analyzed T-cell immune responses to the epithelial cell adhesion molecule (EpCAM), one of the most common tumor-associated antigens (TAA) serving as immune target in colon cancer patients. Th-cell priming against EpCAM inevitably resulted in interleukin-4 (IL-4)–dominated Th2 responses, even under most stringent Th1-inducing conditions. These EpCAM-reactive Th2 cells rather promoted growth of EpCAM-expressing tumors. To analyze the role of IL-4 in tumor immune evasion, we generated EpCAM-reactive Th1 cells from IL-4.ko mice. These Th1 cells provided tumor-specific protection and established highly protective Th1 memory responses, even in naive BALB/c mice. Inhibition of tumor growth by Th1 cells resulted in intra-tumoral expression of cytokines of the IL-12 family and of IFN-γ. Preventing activation-associated death of Th1 cells further increased intratumoral IFN-γ expression and improved therapeutic efficacy. Thus, human TAA may promote tumor immune evasion by strongly favoring Th2 development.

scholarly journals SERPINB10 contributes to asthma by inhibiting the apoptosis of allergenic Th2 cells

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Yuqing Mo ◽  
Ling Ye ◽  
Hui Cai ◽  
Guiping Zhu ◽  
Jian Wang ◽  
...  
Keyword(s):  
T Cells ◽  
Allergic Asthma ◽  
Cd4 T Cells ◽  
Quantitative Polymerase Chain Reaction ◽  
Allergic Inflammation ◽  
Specific Ige ◽  
Th2 Cells ◽  
Th1 Cells ◽  
Th2 Response ◽  
Th1 And Th2

Abstract Background Serine peptidase inhibitor, clade B, member 10 (SERPINB10) contributes to allergic inflammation in asthma. However, its role in the T-helper type 2 (Th2) response of allergic asthma is not known. The goal of this study was to unveil the function of SERPINB10 in the Th2 response of allergic asthma and the mechanism by which SERPINB10 affects the viability of Th2 cells. Methods Th2 cytokines and serum levels of house dust mite (HDM)-specific IgE in bronchoalveolar lavage fluid were examined by ELISA in an HDM-induced asthma model. The number and apoptosis of Th1 and Th2 cells in mouse lungs were measured by flow cytometry. Naïve CD4 T cells from patients with asthma were cultured under appropriate polarizing conditions to generate Th1 and Th2 cells. SERPINB10 expression in polarized Th1 and Th2 cells was quantified by real-time reverse transcription-quantitative polymerase chain reaction. SERPINB10 expression was knocked down in human CD4 T cells with lentivirus. Results Knockdown of SERPINB10 expression significantly diminished HDM-induced Th2 cytokine secretion and level of HDM-specific IgE. After HDM exposure, SERPINB10-knockdown mice had diminished numbers of Th2 cells, but similar numbers of Th1 cells, compared with those in negative-control mice. Th2 cells of SERPINB10-knockdown mice were more susceptible to apoptosis than that of control mice. Stimulating T-cell receptors (TCRs) with anti-CD3 antibody caused upregulation of SERPINB10 expression in polarized Th2 cells, but not polarized Th1 cells. Knockdown of SERPINB10 expression resulted in fewer numbers and greater apoptosis of polarized Th2 cells. Conclusion Our results suggest that SERPINB10 may contribute to allergic inflammation and the Th2 response of asthma by inhibiting the apoptosis of Th2 cells.

scholarly journals Interleukin 18 Acts on Memory T Helper Cells Type 1 to Induce Airway Inflammation and Hyperresponsiveness in a Naive Host Mouse

2004 ◽  
Vol 199 (4) ◽  
pp. 535-545 ◽  
Author(s):  
Takaaki Sugimoto ◽  
Yuriko Ishikawa ◽  
Tomohiro Yoshimoto ◽  
Nobuki Hayashi ◽  
Jiro Fujimoto ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Bronchial Asthma ◽  
Allergic Diseases ◽  
Th2 Cells ◽  
Th1 Cells ◽  
T Helper ◽  
Inflammatory Protein ◽  
Ifn Γ ◽  
Factor Α

Interleukin (IL)-18 was originally regarded to induce T helper cell (Th)1-related cytokines. In general, factors favoring interferon (IFN)-γ production are believed to abolish allergic diseases. Thus, we tested the role of IL-18 in regulation of bronchial asthma. To avoid a background response of host-derived T cells, we administered memory type Th1 or Th2 cells into unsensitized mice and examined their role in induction of bronchial asthma. Administration of antigen (Ag) induced both airway inflammation and airway hyperresponsiveness (AHR) in mice receiving memory Th2 cells. In contrast, the same treatment induced only airway inflammation but not AHR in mice receiving memory Th1 cells. However, these mice developed striking AHR when they were coadministered with IL-18. Furthermore, mice having received IFN-γ–expressing Th1 cells sorted from polarized Th1 cells developed severe airway inflammation and AHR after intranasal administration of Ag and IL-18. Thus, Th1 cells become harmful when they are stimulated with Ag and IL-18. Newly polarized Th1 cells and IFN-γ–expressing Th1 cells, both of which express IL-18 receptor α chain strongly, produce IFN-γ, IL-9, IL-13, granulocyte/macrophage colony-stimulating factor, tumor necrosis factor α, regulated on activation, normal T cell expressed and secreted, and macrophage inflammatory protein 1α upon stimulation with Ag, IL-2, and IL-18 in vitro. Thus, Ag and IL-18 stimulate memory Th1 cells to induce severe airway inflammation and AHR in the naive host.

scholarly journals Regional CNS responses to IFN-γ determine lesion localization patterns during EAE pathogenesis

2008 ◽  
Vol 205 (11) ◽  
pp. 2633-2642 ◽  
Author(s):  
Jason R. Lees ◽  
Paul T. Golumbek ◽  
Julia Sim ◽  
Denise Dorsey ◽  
John H. Russell
Keyword(s):  
Spinal Cord ◽  
T Cells ◽  
Brain Stem ◽  
Clinical Outcomes ◽  
Clinical Symptoms ◽  
Inflammatory Cells ◽  
Th1 Cells ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Ifn Γ

The localization of inflammatory foci within the cerebellum is correlated to severe clinical outcomes in multiple sclerosis (MS). Previous studies of experimental autoimmune encephalomyelitis (EAE), a model of MS, revealed distinct clinical outcomes correlated with the capacity of the animal to produce IFN-γ. Outcomes were linked to localization of inflammatory cells in either the spinal cord (wild type [WT]) or the cerebellum and brain stem (IFN-γ deficient). We demonstrate, using an adoptive transfer system, that the ability of the central nervous system (CNS) to sense pathogenic T cell–produced IFN-γ during EAE initiation determines the sites of CNS pathogenesis. Transfer of WT Th1 cells into IFN-γ receptor–deficient mice results in pathogenic invasion of the brain stem and cerebellum with attendant clinical symptoms, which are identical to the disease observed after transfer of IFN-γ–deficient T cells to WT hosts. Inflammation of the spinal cord associated with classical EAE is abrogated in both IFN-γ–deficient systems. Cotransfer of CNS antigen-specific WT Th1 cells with IFN-γ–deficient T cells is sufficient to restore spinal cord invasion and block cerebellar and brain stem invasion. These data demonstrate that interaction between IFN-γ and host CNS cells during the initiation of EAE can selectively promote or suppress neuroinflammation and pathogenesis.

scholarly journals Requirements for in vivo IFN-γ induction by live microfilariae of the parasitic nematode, Brugia malayi

Parasitology ◽  
2000 ◽  
Vol 120 (6) ◽  
pp. 631-640 ◽  
Author(s):  
R. A. LAWRENCE ◽  
J. E. ALLEN ◽  
C. A. GRAY
Keyword(s):  
Human Disease ◽  
Parasitic Nematode ◽  
Prolonged Exposure ◽  
Brugia Malayi ◽  
Th2 Cells ◽  
Th2 Response ◽  
Antibody Isotypes ◽  
Ifn Γ ◽  
Higher Doses

Lymphatic filariasis caused by the parasitic nematode, Brugia malayi, is a chronic human disease immunologically characterized by stimulation of Th2 cells and reduced antigen-specific T cell responses. Single stage intra-peritoneal infections with infective larvae (L3) or adult nematodes induce Th2 cells, while the microfilarial stage (Mf) stimulates IFN-γ and Mf-specific IgG1, IgG2a, IgG2b, IgG3 and IgM, but not IgE. To investigate whether IFN-γ is elicited by live Mf in their natural site of infection, mice were infected intravenously. Intravenous infection had a striking effect on the response to Mf and high levels of IgE were induced even in the presence of IFN-γ. Indeed IgE levels to Mf increased markedly with the number of immunizations, higher doses of Mf and prolonged exposure to Mf suggesting that under conditions of chronic antigen exposure, typical of human disease, Mf will stimulate high levels of IgE. The ability of Mf-induced IFN-γ to modulate or regulate a pre-existing Th2 response, was investigated by infecting mice initially with adult male worms to induce a Th2 response, followed 14 days later by infection with Mf. Although Mf stimulated IFN-γ in the presence of male adults, the antibody isotypes elicited did not reflect IFN-γ induction and IgG1and IgE dominated the response. Although it cannot be discounted that IFN-γ induction by Mf may act locally as an inflammatory mediator or modulator of Th2 cells, these data suggest that Mf-stimulated IFN-γ does not have a profound effect overall on progression of the Th2-dominated immune response to filarial infection.

Abstract 001: Axl Expression by CD4+ T Lymphocytes Promotes Salt-Dependent Hypertension

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Kristine M Wadosky ◽  
Sri N Batchu ◽  
Angie Hughson ◽  
Kathy Donlon ◽  
Craig N Morrell ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Cd4 T Cells ◽  
White Blood Cells ◽  
Interleukin 4 ◽  
Th2 Cells ◽  
Salt Hypertension ◽  
Ifn Γ

Introduction: Our laboratory has shown that Axl, a receptor tyrosine kinase, is important in both vascular and immune functions during deoxycorticosterone acetate (DOCA)-salt hypertension. We hypothesized that Axl activity specifically in T lymphocytes could explain the dependence of hypertension on Axl. Methods and Results: We did adoptive transfers of either Axl+/+ or Axl-/- CD4+ T cells to RAG1-/- mice that lack mature T cells. Once CD4+ T cell repopulations were confirmed, we induced DOCA-salt hypertension for 6 weeks. Systolic blood pressure (BP, mmHg) increased by 20±5 in Axl+/+RAG-/- mice after DOCA-salt, but Axl-/- RAG-/- mice had increases in BP by only 6+3 after 6 weeks of DOCA-salt. We isolated naïve CD4+ T cells from both Axl+/+ and Axl-/- littermates and primed them under either Th1 or Th2 polarizing conditions in culture. Production of interferon gamma (IFN-γ ng/mL) was significantly decreased (-23%, p<0.05) in Axl-/- (396±23) compared to Axl+/+ (512±42) under Th1-priming. However, Axl had no effect on interleukin 4 (IL-4, ng/mL) production under Th2 polarizing conditions. Intracellular staining of the Th1/Th2 cells with IFN-γ and IL-4 antibodies by flow cytometry confirmed expression of cytokines in culture media. Complete blood counts showed that Axl-/- mice had significantly lower white blood cells due to decreased numbers of lymphocytes (4.5±0.7x10 9 ) compared to Axl+/+ mice (7.8±0.7x10 9 ). We found a higher population of AnnexinV (marker of early apoptosis)-positive peripheral leukocytes in Axl-/- mice (10±1%) compared to Axl+/+ (4±1%) by flow cytometry; while the percentages of dead cells (~10%) were similar between Axl+/+ and Axl-/- mice. Conclusions: Altogether we show that expression of Axl by T cells drives salt-induced hypertension. The mechanism of Axl-dependent effects on T cells occurs via T-cell-dependent expression of the pro-inflammatory cytokine IFN-γ. In addition, Axl plays a role in inhibiting lymphocyte apoptosis in the circulation. Future work will focus on how Axl expression in T cells affects T cell-dependent vascular remodeling during hypertension.

scholarly journals Dynamic Changes of Th1 Cytokines and the Clinical Significance of the IFN-γ/TNF-α Ratio in Acute Brucellosis

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Guang Xu ◽  
Peng Zhang ◽  
Rongjing Dang ◽  
Yanfang Jiang ◽  
Feng Wang ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Clinical Decision Making ◽  
Clinical Symptoms ◽  
Clinical Decision ◽  
Serum Levels ◽  
Post Treatment ◽  
Clinical Severity ◽  
Th1 Cells ◽  
Dynamic Changes ◽  
Necrosis Factor Alpha

Background. T-helper type 1 (Th1) cells and Th1-produced cytokines play essential roles in the immune response to foreign pathogens, such as Brucella spp. The aim of this study was to evaluate the dynamic changes of Th1 cells and Th1-produced cytokines in patients with acute brucellosis and their impact on clinical decision-making. Methods. Fifty-one individuals with acute brucellosis and 17 healthy subjects were enrolled in this study. The brucellosis patients were diagnosed based on clinical symptoms, laboratory tests, and clinical examination. The levels of serum gamma-interferon (IFN-γ) and tumor necrosis factor-alpha (TNF-α), along with the percentage of Th1 cells, were determined by flow cytometry bead arrays (CBA). Results. The frequency of Th1 cells, along with the levels of IFN-γ and TNF-α, was negatively correlated with the clinical parameters. The mean serum levels of IFN-γ and TNF-α and the frequency of Th1 cells were significantly higher in the brucellosis patients in comparison with the healthy subjects (p<0.05). Besides, the cytokine levels were not significantly different between the positive and negative blood culture groups. IFN-γ levels significantly decreased from 6 months to 12 months post treatment (p<0.05). However, the IFN-γ levels remained higher than those of the healthy subjects by 12 months post treatment (p<0.05). The IFN-γ/TNF-α ratio was significantly higher in severe cases than in nonsevere cases (p<0.05). Conclusions. The IFN-γ levels secreted by Th1 cells remain significantly higher than those of healthy subjects more than 12 months after treatment with antibiotics. This finding is different from similar studies. The IFN-γ/TNF-α ratio may be a feasible parameter for assessing clinical severity, yet further longitudinal studies of the immunization and inflammatory reaction of brucellosis are needed in larger patient populations.

scholarly journals Cytokine Production Regulating Th1 and Th2 Cytokines in Hemophagocytic Lymphohistiocytosis

Blood ◽  
1997 ◽  
Vol 89 (11) ◽  
pp. 4100-4103 ◽  
Author(s):  
Yuko Osugi ◽  
Junichi Hara ◽  
Shinichi Tagawa ◽  
Kenji Takai ◽  
Gaku Hosoi ◽  
...  
Keyword(s):  
Acute Phase ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Plasma Concentrations ◽  
Interleukin 2 ◽  
Th1 Cells ◽  
Th2 Response ◽  
Ifn Γ ◽  
Th1 Cytokines ◽  
Th1 And Th2 ◽  
Peak Value

Abstract Hemophagocytic lymphohistiocytosis (HLH) is caused by the hyperactivation of T cells and macrophages. The clinical characteristics associated with this disease result from overproduction of Th1 cytokines including interferon-γ (IFN-γ), interleukin-2 (IL-2), and tumor necrosis factor-α (TNF-α). In this study, we analyzed the production of IL-12 and IL-4, which determine Th1 and Th2 response, respectively, and IL-10, which antagonizes Th1 cytokines, in 11 patients with HLH. IL-12 was detected in plasma in all patients (mean peak value, 30.0 ± 5.0 pg/mL), while IFN-γ was massively produced in nine patients (mean peak value, 79.2 ± 112.0 U/mL). IL-4 was not detected in any of the patients. Plasma IL10 levels were elevated in all patients (mean peak value, 2,698.0 ± 3,535.0 pg/mL). There was a positive correlation between the levels of IFN-γ and IL-10 (P < .01). The plasma concentrations of these cytokines were initially high, before decreasing after the acute phase. However, the decrease in IL-10 levels was slower than that of IFN-γ. Although the concentration of IL-12 was high at the acute phase, in some patients, a peak in the level was delayed until the chronic phase. Thus, in HLH, production of cytokines that promote development of Th1 cells appears to be predominant over that for Th2 cell development. Overproduction of IL-10 was also observed indicating that a mechanism suppressing hyperactivation of Th1 cells and monocytes/macrophages functions in patients with this disease.

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