Local blockade of IL-6R signaling induces lung CD4+ T cell apoptosis in a murine model of asthma via regulatory T cells

Finotto, Susetta; Eigenbrod, Tatjana; Karwot, Roman; Boross, Ildiko; Doganci, Aysefa; Ito, Hiroaki; Nishimoto, Norihiro; Yoshizaki, Kazuyuki; Kishimoto, Tadamitsu; Rose-John, Stefan; Galle, Peter R.; Neurath, Markus F.

doi:10.1093/intimm/dxm037

Cited by 55 publications

(34 citation statements)

References 30 publications

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“…Studies in human patients have demonstrated that reduced T cell apoptosis plays an important role in the pathogenesis of allergic bronchial asthma (Cormican et al 2001;Vignola et al 1999;De Rose et al 2004). These findings are also consistent in murine models of asthma (Jayaraman et al 1999;Tong et al 2006;Finotto et al 2007). In addition, increasing lines of evidence suggest that changes in programmed cell death mechanisms in both mobile and resident cells of the airway may directly contribute to the development and clinical severity of allergy airway inflammation (Vignola et al 2000).…”

Section: Apoptosis Regulation In Allergy Airway Diseasesupporting

confidence: 71%

Allergic Airway Inflammation

Morán¹,

Henríquez²,

Folch³

2012

Allergic Diseases - Highlights in the Clinic, Mechanisms and Treatment

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Section: Apoptosis Regulation In Allergy Airway Diseasesupporting

confidence: 71%

Allergic Airway Inflammation

Morán¹,

Henríquez²,

Folch³

2012

Allergic Diseases - Highlights in the Clinic, Mechanisms and Treatment

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“…19 To confirm this in our model and to determine the extent to which this occurs, we looked at CD44 expression using CD4+ and CD8+ T-cell markers by flow cytometry.…”

Section: T-cell Activation Decreased In High-dose Mr16-1 Mice Comparementioning

confidence: 83%

Interleukin-6 Receptor Signaling Disruption Prevents Cardiac Allograft Deterioration in Mice

Iida¹,

Omoto²,

Kanemitsu³

et al. 2012

Exp Clin Transplant

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Objectives: Interleukin-6, a pleiotropic cytokine that functions in both innate and adaptive immune responses, has been implicated in allograft rejection. We analyzed the efficacy of anti interleukin-6 receptor monoclonal antibody in delaying allograft rejection in a murine model of a heart. Materials and Methods: To investigate the role of interleukin-6 receptor signal transduction in acute and chronic allograft rejection, we blocked interleukin-6 receptor signaling to suppress the alloimmune response in C57BL/6 recipients of BALB/c cardiac allografts. Results: Administration of a high-dose α-interleukin-6 receptor monoclonal antibody prevented the intragraft infiltration of inflammatory cells and lymphocytes and prolonged allograft survival during the peritransplant period. However, all allografts were rejected by 23.5 days after transplant. In contrast, cardiac allograft recipients treated with a cytotoxic T-lymphocyte antigen 4-immunoglobulin plus continued administration of low-dose α-interleukin-6 receptor monoclonal antibody showed long-term graft survival compared with cytotoxic T-lymphocyte antigen 4-immunoglobulin monotherapy. A histologic analysis revealed that graft fibrosis was prevented in cytotoxic T-lymphocyte antigen 4-immunoglobulin plus highdose α-interleukin-6 receptor monoclonal antibody group, but not in the cytotoxic T-lymphocyte antigen 4-immunoglobulin alone group. This suggests that deterioration of graft function associated with chronic rejection could be prevented by blocking interleukin-6 receptor signaling. Conclusions: Disruption of interleukin-6 receptor signaling is an effective strategy for modulating proinflammatory immune responses and preventing chronic rejection.

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“…In that study, anti-TGF-b antibody blocked the inhibitory effects of Tregs on AHR, analogous to our findings. In addition, Treg cells have been shown to induce Th2 cell apoptosis (43) and increased tolerance to inhaled antigen (44), promoting resolution of AHR. Recent work has shown that TGF-b1 induces maturation of naive T cells to a Treg phenotype via expression of the Treg-specific transcription factor Foxp3 (45).…”

Section: Discussionmentioning

confidence: 99%

Transforming Growth Factor-β1 Suppresses Airway Hyperresponsiveness in Allergic Airway Disease

Alcorn¹,

Rinaldi²,

Jaffe³

et al. 2007

Am J Respir Crit Care Med

108

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Rationale: Asthma is characterized by increases in airway resistance, pulmonary remodeling, and lung inflammation. The cytokine transforming growth factor (TGF)-b has been shown to have a central role in asthma pathogenesis and in mouse models of allergic airway disease. Objectives: To determine the contribution of TGF-b to airway hyperresponsiveness (AHR), we examined the time course, source, and isoform specificity of TGF-b production in an in vivo mouse asthma model. To then elucidate the function of TGF-b in AHR, inflammation, and pulmonary fibrosis, we examined the effects of blocking TGF-b signaling with neutralizing antibody. Methods: Mice were sensitized and challenged with ovalbumin (OVA) to establish allergic airway disease. TGF-b activity was neutralized by intranasal administration of monoclonal antibody. Measurements and Main Results: TGF-b1 protein levels were increased in OVA-challenged lungs versus naive controls, and airway epithelial cells were shown to be a likely source of TGF-b1. In addition, TGF-b1 levels were elevated in OVA-exposed IL-5-null mice, which fail to recruit eosinophils into the airways. Neutralization of TGF-b1 with specific antibody had no significant effect on airway inflammation and eosinophilia, although anti-TGF-b1 antibody enhanced OVAinduced AHR and suppressed pulmonary fibrosis. Conclusions: These data show that TGF-b1 is the main TGF-b isoform produced after OVA challenge, with a likely cellular source being the airway epithelium. The effects of blocking TGF-b1 signaling had differential effects on AHR, fibrosis, and inflammation. While TGF-b neutralization may be beneficial to abrogating airway remodeling, it may be detrimental to lung function by increasing AHR.

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Local blockade of IL-6R signaling induces lung CD4+ T cell apoptosis in a murine model of asthma via regulatory T cells

Cited by 55 publications

References 30 publications

Allergic Airway Inflammation

Allergic Airway Inflammation

Interleukin-6 Receptor Signaling Disruption Prevents Cardiac Allograft Deterioration in Mice

Transforming Growth Factor-β1 Suppresses Airway Hyperresponsiveness in Allergic Airway Disease

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