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.

scholarly journals Th2-driven, allergen-induced airway inflammation is reduced after treatment with anti–Tim-3 antibody in vivo

2007 ◽  
Vol 204 (6) ◽  
pp. 1289-1294 ◽  
Author(s):  
Jennifer Kearley ◽  
Sarah J. McMillan ◽  
Clare M. Lloyd
Keyword(s):  
Pulmonary Inflammation ◽  
Allergen Challenge ◽  
Airway Hyperreactivity ◽  
Th2 Cells ◽  
Antibody Treatment ◽  
Th2 Response ◽  
Th2 Cytokine ◽  
Cytokine Levels ◽  
Ifn Γ

T cell immunoglobulin and mucin domain–containing molecule-3 (Tim-3) is a surface molecule that is preferentially expressed on activated Th1 cells in comparison to Th2 cells. Blockade of Tim-3 has been shown to enhance Th1-driven pathology in vivo, suggesting that blockade of Tim-3 may improve the development of Th2-associated responses such as allergy. To examine the effects of Tim-3 blockade on the Th2 response in vivo, we administered anti–Tim-3 antibody during pulmonary inflammation induced by transfer of ovalbumin (OVA)-reactive Th2 cells, and subsequent aerosol challenge with OVA. In this model, anti–Tim-3 antibody treatment before each airway challenge significantly reduced airway hyperreactivity, with a concomitant decrease in eosinophils and Th2 cells in the lung. We examined Th1 and Th2 cytokine levels in the lung after allergen challenge and found that pulmonary expression of the Th2 cytokine IL-5 was significantly reduced, whereas IFN-γ levels were significantly increased by anti–Tim-3 antibody treatment. Thus, blocking Tim-3 function has a beneficial effect during pulmonary inflammation by skewing the Th2 response toward that of a Th1 type, suggesting an important role for Tim-3 in the regulation of allergic disease.

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.

scholarly journals A Signal Transducer and Activator of  Transcription (Stat)4-independent Pathway for the Development of  T Helper Type 1 Cells

1998 ◽  
Vol 188 (6) ◽  
pp. 1191-1196 ◽  
Author(s):  
Mark H. Kaplan ◽  
Andrea L. Wurster ◽  
Michael J. Grusby
Keyword(s):  
Delayed Type Hypersensitivity ◽  
Th2 Cells ◽  
Signal Transducer ◽  
T Helper ◽  
Th1 Cell ◽  
Th Cells ◽  
Th Cell ◽  
Ifn Γ

The differentiation of T helper (Th) cells is regulated by members of the signal transducer and activator of transcription (STAT) family of signaling molecules. We have generated mice lacking both Stat4 and Stat6 to examine the ability of Th cells to develop in the absence of these two transcription factors. Stat4, Stat6−/− lymphocytes fail to differentiate into interleukin (IL)-4–secreting Th2 cells. However, in contrast to Stat4−/− lymphocytes, T cells from Stat4, Stat6−/− mice produce significant amounts of interferon (IFN)-γ when activated in vitro. Although Stat4, Stat6−/− lymphocytes produce less IFN-γ than IL-12–stimulated control lymphocytes, equivalent numbers of IFN-γ–secreting cells can be generated from cultures of Stat4, Stat6−/− lymphocytes activated under neutral conditions and control lymphocytes activated under Th1 cell–promoting conditions. Moreover, Stat4, Stat6−/− mice are able to mount an in vivo Th1 cell–mediated delayed-type hypersensitivity response. These results support a model of Th cell differentiation in which the generation of Th2 cells requires Stat6, whereas a Stat4-independent pathway exists for the development of Th1 cells.

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 Selective Expression and Functions of Interleukin 18 Receptor on T Helper (Th) Type 1 but not Th2 Cells

1998 ◽  
Vol 188 (8) ◽  
pp. 1485-1492 ◽  
Author(s):  
Damo Xu ◽  
Woon Ling Chan ◽  
Bernard P. Leung ◽  
David Hunter ◽  
Kerstin Schulz ◽  
...  
Keyword(s):  
Th2 Cells ◽  
Interleukin 18 ◽  
T Helper ◽  
Th2 Cell ◽  
A Cell ◽  
Ifn Γ

Interleukin (IL)-18 induces interferon (IFN)-γ synthesis and synergizes with IL-12 in T helper type 1 (Th1) but not Th2 cell development. We report here that IL-18 receptor (IL-18R) is selectively expressed on murine Th1 but not Th2 cells. IL-18R mRNA was expressed constitutively and consistently in long-term cultured clones, as well as on newly polarized Th1 but not Th2 cells. IL-18 sustained the expression of IL-12Rβ2 mRNA, indicating that IL-18R transmits signals that maintain Th1 development through the IL-12R complex. In turn, IL-12 upregulated IL-18R mRNA. Antibody against an IL-18R–derived peptide bound Th1 but not Th2 clones. It also labeled polarized Th1 but not Th2 cells derived from naive ovalbumin–T cell antigen receptor-αβ transgenic mice (D011.10). Anti–IL-18R antibody inhibited IL-18– induced IFN-γ production by Th1 clones in vitro. In vivo, anti–IL-18R antibody reduced local inflammation and lipopolysaccharide-induced mortality in mice. This was accompanied by shifting the balance from Th1 to Th2 responses, manifest as decreased IFN-γ and proinflammatory cytokine production and increased IL-4 and IL-5 synthesis. Therefore, these data provide a direct mechanism for the selective effect of IL-18 on Th1 but not Th2 cells. They also show that the synergistic effect of IL-12 and IL-18 on Th1 development may be due to the reciprocal upregulation of their receptors. Furthermore, IL-18R is a cell surface marker distinguishing Th1 from Th2 cells and may be a therapeutic target.

scholarly journals Cooperation between Reactive Oxygen and Nitrogen Intermediates in Killing of Rhodococcus equi by Activated Macrophages

2000 ◽  
Vol 68 (6) ◽  
pp. 3587-3593 ◽  
Author(s):  
Patricia A. Darrah ◽  
Mary K. Hondalus ◽  
Quiping Chen ◽  
Harry Ischiropoulos ◽  
David M. Mosser
Keyword(s):  
Nitric Oxide ◽  
Prolonged Exposure ◽  
Rhodococcus Equi ◽  
Activated Macrophages ◽  
Intracellular Killing ◽  
Oxygen Intermediates ◽  
Bacterial Killing ◽  
Ifn Γ

ABSTRACT Rhodococcus equi is a facultative intracellular bacterium of macrophages which can infect immunocompromised humans and young horses. In the present study, we examine the mechanism of host defense against R. equi by using a murine model. We show that bacterial killing is dependent upon the presence of gamma interferon (IFN-γ), which activates macrophages to produce reactive nitrogen and oxygen intermediates. These two radicals combine to form peroxynitrite (ONOO−), which kills R. equi. Mice deficient in the production of either the high-output nitric oxide pathway (iNOS−/−) or the oxidative burst (gp91 phox−/− ) are more susceptible to lethalR. equi infection and display higher bacterial burdens in their livers, spleens, and lungs than wild-type mice. These in vivo observations, which implicate both nitric oxide (NO) and superoxide (O2 −) in bacterial killing, were reexamined in cell-free radical-generating assays. In these assays, R. equi remains fully viable following prolonged exposure to high concentrations of either nitric oxide or superoxide, indicating that neither compound is sufficient to mediate bacterial killing. In contrast, brief exposure of bacteria to ONOO− efficiently kills virulent R. equi. The intracellular killing of bacteria in vitro by activated macrophages correlated with the production of ONOO− in situ. Inhibition of nitric oxide production by activated macrophages by usingN G-monomethyl-l-arginine blocks their production of ONOO− and weakens their ability to control rhodococcal replication. These studies indicate that peroxynitrite mediates the intracellular killing of R. equiby IFN-γ-activated macrophages.

In vivo effect of the parasite derived peptide GK-1, anti-PD-L1 and GK-1/anti-PD-L1 combination in experimental melanoma. Potential novel treatment pathways.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e21038-e21038 ◽  
Author(s):  
Jesus Vera Aguilera ◽  
Armando Perez-Torres ◽  
Carlos Vera Aguilera ◽  
Matthew Stephen Block ◽  
Narjust Duma ◽  
...  
Keyword(s):  
Immune Cell ◽  
Therapy Group ◽  
Combined Treatment ◽  
Th2 Response ◽  
Treatment Pathways ◽  
Alternative Pathways ◽  
Melanoma Model ◽  
Ifn Γ

e21038 Background: Several studies of advanced melanoma patients suggest that combining therapies that target tumor mechanisms of immune evasion with activation of normal immune cell functionality may provide optimal benefits for patients. The synthetic parasite derived GK1 peptide in combination with anti-PD-L1 showed significant longer survival (34 days) compared to GK1 or Anti-PD-L1 alone (23-27 days) in a murine melanoma model (p < 0.05). This means an increase survival increased in 47.82% in the mice treated with GK-1 + anti-PD-L1, 21.7% treated with GK-1, and 6.08% treated with anti-PD-L1. Methods: To elucidate the potential mechanism by which this combination treatment exerts its anti-melanoma effects, C57BL/6 mice were injected with B16-F10-luc2 cells and separated according to treatments in four groups: control, GK-1, anti-PD-L1 and GK-1/anti-PDL-1.Blood samples were collected at day 0, 14, and at euthanization or end of the experiment and monitored for serum cytokines using mice-specific V-PLEX Pro-inflammatory Panel. Results: On day 14, TNF-α levels in the Anti-PD-L1 and GK-1 therapy group was significantly lower compared to control mice. At sacrifice, the combined treatment group demonstrated significant decrease cytokine production in IL-6 and IL-10. Conclusions: The decreased cytokine levels observed in the GK-1/anti-PD-L1 group may explain the significant improved survival. GK-1 is a Th1 response inductor both in vitro and in vivo as it increases IFN-γ, IL-2 but not IL-4 and IL-10. It is noteworthy that when PD-L1 signaling is reduced in T cells these cells proliferate extensively in vitro and produce increased levels of IFN-γ and IL-17, suggesting an enhanced pro-inflammatory phenotype. It has been established that cytokines of Th2 response such as IL-4 and IL-5 and IL-6, have tumor-promoting activity. The anti-melanoma effect of the GK-1/anti-PD-L1 combination observed in the present study could be mediated by decreasing the pro-tumor Th2 response. These results provide novel alternative pathways and potential targets to enhance the clinical effect of the PD-1/PD-L1 blockade pathway.

Pharmacologic doses of granulocyte colony-stimulating factor affect cytokine production by lymphocytes in vitro and in vivo

Blood ◽  
2000 ◽  
Vol 95 (7) ◽  
pp. 2269-2274 ◽  
Author(s):  
Elaine M. Sloand ◽  
Sonnie Kim ◽  
Jaroslaw P. Maciejewski ◽  
Fritz Van Rhee ◽  
Aniruddho Chaudhuri ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Th2 Cells ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Cd4 Cells ◽  
Ifn Γ ◽  
Stimulating Factor

Peripheral blood stem cell (PBSC) transplantation is successful in improving engraftment without increasing acute graft-versus-host disease (GVHD), despite much larger numbers of T cells in unmanipulated PBSCs than in bone marrow grafts. In mouse models and retrospective human studies, granulocyte colony-stimulating factor (G-CSF) therapy has been associated with less acute GVHD. We studied the effect of G-CSF on interferon (IFN)-γ and IL-4 expression in CD4+lymphocytes. CD4+ cells co-cultivated with G-CSF and stimulated with PHA or CD3 monoclonal antibodies showed significant decreases in IFN-γ and increases in IL-4 expression (n = 13;P < .01). G-CSF appeared to have a direct effect on CD4+ cells independent of monocytes present in the culture because purified CD4+ cells exposed to G-CSF, washed, and cocultivated with untreated monocytes demonstrated similar changes in IFN-γ and IL-4 expression, whereas untreated CD4+ cells cocultured with G-CSF–stimulated monocytes behaved as controls. We then studied peripheral blood mononuclear cells (PBMCs) from G-CSF–mobilized PBSC donors. When their PBMCs were cultured with PHA or CD3 monoclonal antibody, the percent of IFN-γ–expressing cells decreased by a mean of 55% and 42%, respectively, whereas the percent of IL-4–containing cells increased by a mean of 39% and 58%, respectively, following G-CSF stimulation. Increased apoptosis of IFN-γ–producing CD4+ cells was not responsible for the shift in TH1/TH2 subsets. G-CSF-R mRNA was present in both CD4+ and CD8+ cells. These results suggest that G-CSF decreases IFN-γ and increases IL-4 production in vitro and in vivo and likely modulates a balance between TH1 and TH2 cells, an effect that may be important in PBSC transplantation.

scholarly journals Schistosomiasis Decreases Central Nervous System Inflammation and Alters the Progression of Experimental Autoimmune Encephalomyelitis

2003 ◽  
Vol 71 (9) ◽  
pp. 4996-5004 ◽  
Author(s):  
Anne Camille La Flamme ◽  
Kate Ruddenklau ◽  
B. Thomas Bäckström
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Autoimmune Encephalomyelitis ◽  
Th2 Response ◽  
Cns Inflammation ◽  
Necrosis Factor Alpha ◽  
Ifn Γ ◽  
Experimental Autoimmune

ABSTRACT A preestablished infection with the parasitic helminth, Schistosoma mansoni, significantly reduced the incidence and delayed the onset of experimental autoimmune encephalomyelitis (EAE) in C57BL/6J mice immunized with myelin oligodendrocyte glycoprotein (MOG)35-55 peptide. The altered disease progression was not solely due to the induction of a strong Th2 response, since intraperitoneal injection of schistosome eggs did not affect disease development. MOG-specific gamma interferon (IFN-γ), nitric oxide, and tumor necrosis factor alpha production by splenocytes was significantly reduced in schistosome-infected mice compared to uninfected mice. However, similar levels of interleukin-10 (IL-10) were produced in an antigen-specific manner, suggesting that the induction of antigen-specific responses was not inhibited. Analysis of in vivo cytokine production by real-time PCR indicated that IL-12p40, but not IFN-γ, transcript levels were dramatically reduced in the spinal cords of schistosome-infected, MOG-immunized mice. Furthermore, analysis of the cellular composition of the spinal cords and brains revealed that a preestablished infection with S. mansoni decreased central nervous system (CNS) inflammation, particularly of macrophages and CD4 T cells. These results suggest that schistosomiasis may negatively regulate the onset of EAE by downregulating the production of proinflammatory cytokines and altering CNS inflammation.

scholarly journals Interleukin 4–Producing Cd4 T Cells Arise from Different Precursors Depending on the Conditions of Antigen Exposure in Vivo

2000 ◽  
Vol 191 (4) ◽  
pp. 683-694 ◽  
Author(s):  
Gilles Foucras ◽  
Laurent Gapin ◽  
Christiane Coureau ◽  
Jean M. Kanellopoulos ◽  
Jean-Charles Guéry
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Interleukin 4 ◽  
Th2 Cells ◽  
Mouse Strains ◽  
Soluble Antigen ◽  
Th2 Response ◽  
Continuous Administration ◽  
Exposure In Vivo

The precursor origin of T helper (Th) cell subsets in vivo has been difficult to study and remains poorly investigated. We have previously shown that chronic administration of soluble protein antigen induces selective development of antigen-specific CD4 Th2 cells in genetically predisposed mouse strains. To analyze the origin of effector T cells in this model, we designed a competitive polymerase chain reaction–based approach to track public BV-J rearrangement expressed by CD4 T cells specific for hen egg white lysozyme (HEL) in BALB/c mice. We show that public T cell clones are predominantly associated with type 1 or 2 effector Th cells recovered after primary immunization in complete or incomplete Freund's adjuvant, respectively. Conversely, continuous administration of soluble antigen, which induces strong memory Th2 response, is associated with a dose-dependent reduction of public clone size by a mechanism resembling clonal anergy. Thus, soluble HEL–induced Th2 cells do not express the public complementarity determining region 3 motifs characteristic of immunogenic challenge in the presence of adjuvant. These results demonstrate that there are multiple pathways of induction of Th2 responses depending on the condition of antigen exposure in vivo, i.e., clonal immune deviation versus recruitment of a different pool of precursor cells.

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