CTLA4Ig Inhibits Airway Eosinophilia and Hyperresponsiveness by Regulating the Development of Th1/Th2 Subsets in a Murine Model of Asthma

Padrid, Philip; Mathur, Mudit; Li, Xiantang; Herrmann, Karin; Qin, Yimin; Cattamanchi, Ashok; Weinstock, Joel V.; Elliott, David E.; Sperling, Anne I.; Bluestone, Jeffrey A.

doi:10.1165/ajrcmb.18.4.3055

Cited by 100 publications

(90 citation statements)

References 38 publications

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“…In addition, recent studies in murine models of allergic asthma (a comparable Th2-induced mucosal hypersensitivity response) suggest an indispensable role for the CTLA-4 signaling pathway in controlling the production of Th2 cytokines, and in the development of airway hyperresponsiveness. As such, inhibition of CD28-B7 interaction ameliorated (11), and even reversed asthmatic manifestations (12), whereas the blockade of CTLA-4 enhanced allergic sensitization (13). In line with these observations, we hypothesized that CTLA-4 is involved in suppressing the induction and progression of sensitization to food proteins.…”

mentioning

confidence: 63%

CTLA-4 Signaling Regulates the Intensity of Hypersensitivity Responses to Food Antigens, but is Not Decisive in the Induction of Sensitization

Wijk¹,

Hoeks²,

Nierkens³

et al. 2005

The Journal of Immunology

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Although food allergy has emerged as a major health problem, the mechanisms that are decisive in the development of sensitization to dietary Ag remain largely unknown. CTLA-4 signaling negatively regulates immune activation, and may play a crucial role in preventing induction and/or progression of sensitization to food Ag. To elucidate the role of CTLA-4 signaling in responses to food allergens, a murine model of peanut allergy was used. During oral exposure to peanut protein extract (PPE) together with the mucosal adjuvant cholera toxin (CT), which induces peanut allergy, CTLA-4 ligation was prevented using a CTLA-4 mAb. Additionally, the effect of inhibition of the CTLA-4 pathway on oral exposure to PPE in the absence of CT, which leads to unresponsiveness to peanut Ag, was explored. During sensitization, anti-CTLA-4 treatment considerably enhanced IgE responses to PPE and the peanut allergens, Ara h 1, Ara h 3, and Ara h 6, resulting in elevated mast cell degranulation upon an oral challenge. Remarkably, antagonizing CTLA-4 during exposure to PPE in the absence of CT resulted in significant induction of Th2 cytokines and an elevation in total serum IgE levels, but failed to induce allergen-specific IgE responses and mast cell degranulation upon a PPE challenge. These results indicate that CTLA-4 signaling is not the crucial factor in preventing sensitization to food allergens, but plays a pivotal role in regulating the intensity of a food allergic sensitization response. Furthermore, these data indicate that a profoundly Th2-biased cytokine environment is insufficient to induce allergic responses against dietary Ag.

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mentioning

confidence: 63%

CTLA-4 Signaling Regulates the Intensity of Hypersensitivity Responses to Food Antigens, but is Not Decisive in the Induction of Sensitization

Wijk¹,

Hoeks²,

Nierkens³

et al. 2005

The Journal of Immunology

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“…However, there are also data to indicate that CD28 signaling promotes Th2 responses (39) and that CD28-B7 blockade is effective in blocking immune responses in Th2-mediated diseases (40)(41)(42)(43)(44). Our data clearly indicate that CTLA4Ig inhibits immune responses in both STAT4 -/-and STAT6 -/-recipients, suggesting that CD28-B7 blockade is effective in blocking the prevailing immune response irrespective of whether it is predominantly Th1 or Th2.…”

Section: Figurementioning

confidence: 99%

The role of CD154-CD40 versus CD28-B7 costimulatory pathways in regulating allogeneic Th1 and Th2 responses in vivo

Kishimoto

Dong²,

Issazadeh³

et al. 2000

J. Clin. Invest.

127

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“…Expression is also apparent on NK cells, where ligation promotes their function [23]. ICOS co-stimulation can induce Th1, Th2 [22,[24][25][26][27] and regulatory cytokines [20,[27][28][29].…”

Section: Introductionmentioning

confidence: 99%

A critical role for ICOS co‐stimulation in immune containment of pulmonary influenza virus infection

et al. 2006

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Lung pathology observed during influenza infection is due to direct damage resulting from viral replication and bystander damage caused by overly exuberant antiviral immune mechanisms. In the absence of universally effective vaccines and antiviral therapies, knowledge of the cellular components required for immune containment of influenza is essential. ICOS is a late co-stimulatory molecule expressed by T cells 12-24 h after activation. We show for the first time that inhibition of ICOS with a monoclonal antibody reduces pulmonary T cell inflammation and associated cytokine expression. Surprisingly however, this reduction in T cells was not accompanied by an alleviation of weight loss and illness. Furthermore, lung viral titres were elevated following anti-ICOS treatment, suggesting that the beneficial outcome of reducing T cell pathology was masked by enhanced virus-induced damage and innate inflammation. This study demonstrates the delicate balance that exists between pathogen burden and pulmonary T cell inflammation during influenza infection and highlights the critical role of ICOS in this response.

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CTLA4Ig Inhibits Airway Eosinophilia and Hyperresponsiveness by Regulating the Development of Th1/Th2 Subsets in a Murine Model of Asthma

Cited by 100 publications

References 38 publications

CTLA-4 Signaling Regulates the Intensity of Hypersensitivity Responses to Food Antigens, but is Not Decisive in the Induction of Sensitization

CTLA-4 Signaling Regulates the Intensity of Hypersensitivity Responses to Food Antigens, but is Not Decisive in the Induction of Sensitization

The role of CD154-CD40 versus CD28-B7 costimulatory pathways in regulating allogeneic Th1 and Th2 responses in vivo

A critical role for ICOS co‐stimulation in immune containment of pulmonary influenza virus infection

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