Down-regulation Of Th2 Responses Research Articles

Crocin Ameliorates Atopic Dermatitis Symptoms by down Regulation of Th2 Response via Blocking of NF-κB/STAT6 Signaling Pathways in Mice

Crocin, a major constituent of Gardenia jasminoides, is a natural colorant carotenoid compound that has been reported to have anti-inflammatory effects. This study investigated the therapeutic effects of crocin on mice with atopic dermatitis induced by Dermatophagoides farinae crude extract, which is a common environmental allergen in house dust that causes atopic dermatitis in humans. Crocin application ameliorated Dermatophagoides farinae crude extract-induced atopic dermatitis symptoms by inhibiting the dermatitis severity score, ear thickness, and serum immunoglobulin E levels in NC/Nga mice. The increases in epidermal thickness and dermal inflammatory cells (eosinophil and mast cells) infiltrations observed on the dorsal back skin of atopic dermatitis control mice were inhibited in a dose-dependent manner by topical application of crocin in atopic dermatitis treatment mice. Crocin inhibited the Dermatophagoides farinae crude extract-induced increase of thymus and activation-regulated chemokines, interleukin (IL)-4, and IL-13 on the dorsal skin of mice. Crocin also inhibited Dermatophagoides farinae crude extract-induced activation of nuclear factor-κB (NF-κB) and signal transducer and activator of transcription (STAT) 6. These results show that crocin ameliorates atopic dermatitis symptoms by down regulation of the Th2 cells-mediated immune response via blocking of NF-κB/STAT6 signaling pathways.

Ovatodiolide suppresses allergic airway inflammation and hyperresponsiveness in a murine model of asthma

Asthma, a complex pulmonary allergic disease, major therapy is applied of drugs to control the disease, but quickly recur after the drugs are stopped. In patients with severe asthma may show steroid resistance and would benefit from the development of novel therapeutic drugs.Ovatodiolide, a unique macrocyclic diterpenoid isolated from Anisomeles indica, showed therapeutic potential for the treatment of allergic asthma. As a model of allergic inflammation, we used ovalbumin (OVA)-immunized mice, which displayed T helper cell type 2 (TH2) cytokine expression in bronchoalveolar lavage fluid (BALF), as well as airway inflammation and hyperresponsiveness (AHR). The results showed that ovatodiolide suppressed TH2 activation, including cell proliferation and production of the TH2 related cytokines, interleukin (IL)-4, IL-5, IL-13, IL-33, eosinophil chemotactic protein (eotaxin), and also reduced airway hyperresponsiveness. In this study, ovatodiolide inhibited allergic asthma through downregulation of TH2 responses in a murine model of asthma.

Application of vitamin E to antagonize SWCNTs-induced exacerbation of allergic asthma

The aggravating effects of zero-dimensional, particle-shaped nanomaterials on allergic asthma have been previously investigated, but similar possible effects of one-dimensional shaped nanomaterials have not been reported. More importantly, there are no available means to counteract the adverse nanomaterial effects to allow for their safe use. In this study, an ovalbumin (OVA)-sensitized rat asthma model was established to investigate whether single walled carbon nanotubes (SWCNTs) aggravate allergic asthma. The results showed that SWCNTs in rats exacerbated OVA-induced allergic asthma and that this exacerbation was counteracted by concurrent administration vitamin E. A mechanism involving the elimination of reactive oxygen species, downregulation of Th2 responses, reduced Ig production, and the relief of allergic asthma symptoms was proposed to explain the antagonistic effects of vitamin E. This work could provide a universal strategy to effectively protect people with allergic asthma from SWCNTs or similar nanomaterial-induced aggravating effects.

Therapeutic effects of a fermented soy product on peanut hypersensitivity is associated with modulation of T‐helper type 1 and T‐helper type 2 responses

ImmuBalance is a koji fungus (Aspergillus oryzae) and lactic acid fermented soybean product. This unique production process is believed to create a food supplement that helps to induce or maintain normal immune response. To assess possible therapeutic effects of ImmuBalance on peanut (PN) hypersensitivity using a murine model of peanut allergy (PNA). PN allergic C3H/HeJ mice were fed standard mouse chow containing 0.5% or 1.0% ImmuBalance (ImmuBalance 2X), radiation-inactivated 1.0% ImmuBalance (I-ImmuBalance 2X), or regular diet chow (sham) for 4 weeks, beginning 10 weeks after the initial PN sensitization, and then challenged with PN. Anaphylactic symptom scores, plasma histamine, serum PN specific-IgE levels and splenocyte cytokine profiles were determined. While 100% of sham-treated PNA mice developed anaphylactic reactions with a median score of 3.3 following PN challenge, only 50% of ImmuBalance, 30% of ImmuBalance 2X and 40% of I-ImmuBalance 2X-treated mice developed allergic reactions with median scores of 1.0, 0.4 and 0.5 respectively, which were significantly less than that in the sham-treated mice (P<0.05). Plasma histamine and PN specific-IgE levels were also significantly less in all treated mice than in sham-treated mice (P<0.05). Furthermore, IL-4, IL-5 and IL-13 production by PN-stimulated splenocytes in vitro from ImmuBalance fed mice were markedly reduced compared with sham-treated mice, whereas IFN-gamma production was moderately increased. TGF-beta and TNF-alpha production were similar. ImmuBalance protects against PN-induced anaphylaxis when administered as a food supplement in this model. Protection was associated with down-regulation of Th2 responses. This supplement may provide a potential novel therapy for PNA.

Changes of soluble CD26 and CD30 levels correlate with response to interferon plus ribavirin therapy in patients with chronic hepatitis C

Clearance of hepatitis C virus (HCV) is attributed to host cellular immune responses, in which T helper cells play a critical role. The purpose of the present paper was therefore to study the serial changes of serum soluble markers released from T helper 1 (Th1) and 2 (Th2) and their correlations with treatment responses in chronic hepatitis C patients receiving interferon-alpha plus ribavirin for 24 weeks. Serum markers (soluble CD26 and CD30 levels) of T helper cells were quantified before and 6 months after combination therapy in 33 chronic hepatitis C patients and in 20 healthy controls. Compared to healthy controls, chronic hepatitis C patients had significantly lower serum soluble CD26 levels before (140.4 +/- 63.9 ng/mL vs 200.6 +/- 60.3 ng/mL, P < 0.0001) and after (115.9 +/- 32.9 ng/mL vs 200.6 +/- 60.3 ng/mL, P < 0.0001) combination therapy. The level was even lower in those with non-sustained virologic response (non-SVR; 139.0 +/- 50.9 ng/mL vs 117.7 +/- 40.3 ng/mL, P = 0.039). In contrast, soluble CD30 levels at 6 months after combination therapy were significantly lower in patients with SVR than those with non-SVR (6.4 +/- 3.5 U/mL vs 10.4 +/- 5.4 U/mL, P = 0.021). Chronic hepatitis C patients have a weak Th1 response as reflected by lower soluble CD26 levels and the levels are even lower in non-sustained responders. In sharp contrast, downregulation of Th2 response with serial changes of soluble CD30 level is associated with successful treatment of HCV infection.

Fyn regulates eosinophil infiltration into the conjunctiva by downregulating the Th2 response

Under certain circumstances, fyn may serve to negatively regulate the differentiation of naïve helper T (Th) cells into Th2 cells. This study aimed to investigate whether fyn negatively regulates the development of experimental immune-mediated blepharoconjunctivitis (EC), in which Th2 cells play an important role in C57BL/6 mice. C57BL/6 background wild-type (WT) or fyn knockout (fyn-/-) mice were subcutaneously immunized with ragweed (RW) adsorbed in aluminum hydroxide. Ten days later the mice were challenged with RW in eye drops, and 24 h after challenge, eyes, blood and spleens were harvested for histology, measurement of serum IgE, and proliferation or cytokine assays, respectively. RW-primed splenocytes from WT and fyn-/- mice were cultured in the presence of RW. Seventy-two hours later, either whole splenocytes or isolated CD4+T cells were transferred into syngeneic WT mice. Four days after the transfer, the recipient mice were challenged with RW and evaluated as described above. Infiltration of eosinophils into the conjunctiva induced by active immunization was significantly increased in fyn-/- mice relative to WT mice. Total serum IgE was also significantly higher in fyn-/- mice than in WT mice. In parallel, a higher level of IL-4 production from splenocytes was induced by concanavalin A stimulation in fyn-/- mice than in WT mice. In contrast to active immunization, transfer of whole splenocytes or separated CD4+T cells derived from WT or fyn-/- mice induced similar levels of eosinophilic infiltration in WT mice. Fyn regulates infiltration of eosinophils into the conjunctiva through downregulation of Th2 responses. This negative regulation is exerted only during the induction phase of EC.

CpG oligodeoxynucleotides can reverse Th2-associated allergic airway responses and alter the B7.1/B7.2 expression in a murine model of asthma.

CpG oligodeoxynucleotides (CpG-ODN) administered during Ag sensitization or before Ag challenge can inhibit allergic pulmonary inflammation and airway hyperreactivity in murine models of asthma. In this study, we investigated whether CpG-ODN can reverse an ongoing allergic pulmonary reaction in a mouse model of asthma. AKR mice were sensitized with conalbumin followed by two intratracheal challenges at weekly intervals. CpG-ODN was administered 24 h after the first Ag challenge. CpG-ODN administration reduced Ag-specific IgE levels, bronchoalveolar lavage fluid eosinophils, mucus production, and airway hyperreactivity. We found that postchallenge CpG-ODN treatment significantly increased IFN-gamma concentrations and decreased IL-13, IL-4, and IL-5 concentrations in bronchoalveolar lavage fluids and spleen cell culture supernatants. Postchallenge CpG-ODN treatment also increased B7.1 mRNA expression and decreased B7.2 mRNA expression in lung tissues. These results suggest that CpG-ODN may have potential for treatment of allergic asthma by suppressing Th2 responses during IgE-dependent allergic airway reactions. The down-regulation of Th2 responses by CPG-ODN may be associated with regulation of the costimulatory factors B7.1 and B7.2.

479 Differential histamine H1 and H2 receptor expression determines up-regulation of Th1 and down-regulation of Th2 responses following histamine stimulation

479 Differential histamine H1 and H2 receptor expression determines up-regulation of Th1 and down-regulation of Th2 responses following histamine stimulation

Down-regulation of Th2 responses by Brucella abortus, a strong Th1 stimulus, correlates with alterations in the B7.2-CD28 pathway.

Down-regulation of the Th2-like response induced by ovalbumin-alum (OVA/alum) immunization by heat-killed Brucella abortus was not reversed by anti-IL-12 antibody treatment or in gamma interferon (IFN-gamma) knockout mice, suggesting that induction of Th1 cytokines was not the only mechanism involved in the B. abortus-mediated inhibition of the Th2 response to OVA/alum. The focus of this study was to determine whether an alternative pathway involves alteration in expression of costimulatory molecules. First we show that the Th2-like response to OVA/alum is dependent on B7.2 interaction with ligand since it can be abrogated by anti-B7.2 treatment. Expression of costimulatory molecules was then studied in mice immunized with OVA/alum in the absence or presence of B. abortus. B7.2, but not B7.1, was up-regulated on mouse non-T and T cells following immunization with B. abortus. Surprisingly, B. abortus induced down-regulation of CD28 and up-regulation of B7.2 on murine CD4(+) and CD8(+) T cells. These effects on T cells were maximal for CD28 and B7.2 at 40 to 48 h and were not dependent on interleukin-12 (IL-12) or IFN-gamma. On the basis of these results, we propose that the IL-12/IFN-gamma-independent inhibition of Th2 responses to OVA/alum is secondary to the effects of B. abortus on expression of costimulatory molecules on T cells. We suggest that down-regulation of CD28 following activation inhibits subsequent differentiation of Th0 into Th2 cells. In addition, decreased expression of CD28 and increased expression of B7.2 on T cells would favor B7.2 interaction with CTLA-4 on T cells, and this could provide a negative signal to developing Th2 cells.

Attenuation of house dust mite Dermatophagoides farinae-induced airway allergic responses in mice by dehydroepiandrosterone is correlated with down-regulation of TH2 response.

Dehydroepiandrosterone (DHEA), an abundant androgen in circulation, has important immunomodulating effects on T-cell differentiation; however, it is not known whether this hormone influences allergic responses. We have established a murine model of airway inflammation induced by house dust mite Dermatophagoides farinae (Der f). Der f challenge of sensitized mice would elicit a pulmonary eosinophilic inflammation. In the present study, we employed this model system to explore the effect of DHEA on allergic responses. Female BALB/c mice were fed with a standard diet incorporated with 1.5% (w/w) of DHEA for 1 week before sensitization and every other day for an additional 2 weeks after sensitization. After intratracheal inoculation of allergen, the Der f-induced airway inflammation, immunoglobulin (Ig)E antibody production, and cytokine expression were compared between control and DHEA-fed mice. In control mice the Der f-induced eosinophilia in bronchoalveolar lavage (BAL) fluids was accompanied by an increase in production of interleukin (IL)-4, IL-5, and interferon IFN-gamma systemically and locally. DHEA supplementation did not affect the body weight of mice. However, in mice that were receiving DHEA, the numbers of eosinophils and lymphocytes in BAL fluids significantly decreased at days 2 and 6 after challenge as compared with control mice. Concomitantly, total IgE antibody concentrations as well as IL-4, IL-5, and IFN-gamma levels in BAL fluids or serum also significantly reduced. Immunocytochemical staining of BAL cells revealed that there were fewer IL-4-, IL-5-, IL-10-, but not IFN-gamma-positive stained cells in DHEA-fed mice than in mice who consumed unsupplemented diet. Reverse transcription-polymerase chain reaction analysis demonstrated DHEA decreased the expression of IL-5 and IL-10 transcripts in BAL cells. Our results showed that administration of DHEA during allergic sensitization could attenuate the subsequent allergic responses elicited by challenge, and that the suppressive effect of DHEA was associated with a down-regulation of TH2 response.