Dendritic Cells Genetically Engineered to Express IL-10 Induce Long-Lasting Antigen-Specific Tolerance in Experimental Asthma

Henry, Emmanuelle; Desmet, Christophe; Garzé, Virginie; Fiévez, Laurence; Bedoret, Denis; Heirman, Carlo; Faísca, Pedro; Jaspar, Fabrice; Gosset, Philippe; Jacquet, Alain; Desmecht, Daniël; Thielemans, Kris; Lekeux, Pierre; Moser, Muriel; Bureau, Fabrice

doi:10.4049/jimmunol.181.10.7230

Cited by 78 publications

(73 citation statements)

References 51 publications

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“…Others have reported that IL-10 expression by IL-10-differentiated DCs is required to prevent development of the asthma phenotype in systemically sensitized mice (11) and that IL-10 expression by host cells, presumed to be regulatory T cells, is required for induction of tolerance in asthmatic mice that have been treated with IL-10-lentivirus-transfected DCs (14); the latter authors did not assess tolerization of AHR (14). In addition, we have reported that neutralization of IL-10 prevents DC10-induced regulatory T cells from suppressing effector T cell responses in vitro in our OVA-asthma system (13).…”

Section: Discussionmentioning

confidence: 99%

“…We have further shown that DC10s induce T effector cells from asthmatic animals to alter their phenotype, adapting a bona fide regulatory T cell phenotype (13). Although DCs that are retrovirus transfected to express very high levels of IL-10 can induce a longlasting and robust tolerance (14), significant ethical issues would arise with using such cells clinically. The tolerance induced by regulatory DCs that are differentiated ex vivo with IL-10 is seemingly robust (7,11,13), but we have little information regarding the life span of that tolerance or its durability under allergen rechallenge conditions.…”

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confidence: 99%

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Induction of Prolonged Asthma Tolerance by IL-10–Differentiated Dendritic Cells: Differential Impact on Airway Hyperresponsiveness and the Th2 Immunoinflammatory Response

Nayyar

Dawicki

Huang

et al. 2012

The Journal of Immunology

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IL-10–differentiated dendritic cells (DC10s) can prevent allergen sensitization and reverse the asthma phenotype in mice with established disease. However, little is known about the time-frames over which this tolerance is effective. We report that at 2 wk after i.p. or transtracheal delivery of 1 × 106 OVA-, but not house dust mite- presenting, DC10s to OVA-asthmatic mice, significant diminution of airway hyperresponsiveness (AHR) was first apparent, whereas AHR was abrogated between 3 and 10 wk posttreatment. At 13 wk, AHR returned to pretreatment levels but could again be reversed by DC10 retreatment. The impact of a single DC10 treatment on airway eosinophil and Th2 cytokine responses to recall OVA challenge, and on OVA-specific IgE/IgG1 responses, was substantial at 3 wk posttreatment, but progressively increased thereafter, such that at 8 mo, airway eosinophil and Th2 responses to recall allergen challenge remained ∼85–95% suppressed relative to saline-treated asthmatic mice. Four biweekly DC10 treatments, whether transtracheal or i.p., reduced all asthma parameters to near background by 8 wk, whereas s.c. DC10 treatments did not affect AHR but did reduce the airway Th2 responses (i.v. DC10 had no discernible effects). Repeated challenge of the DC10-treated mice with aerosolized OVA (100 μg/ml) did not reverse tolerance, but treatment with the indoleamine-2,3-dioxygenase antagonist 1-methyltryptophan or neutralizing anti–IL-10R from days 12 to 21 after DC10 therapy partially reversed tolerance (Th2 cytokine responses, but not AHR). These findings indicate that DC10-induced Th2 tolerance in asthmatic animals is long lived, but that DC10s employ distinct mechanisms to affect AHR versus Th2 immunoinflammatory parameters.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Induction of Prolonged Asthma Tolerance by IL-10–Differentiated Dendritic Cells: Differential Impact on Airway Hyperresponsiveness and the Th2 Immunoinflammatory Response

Nayyar

Dawicki

Huang

et al. 2012

The Journal of Immunology

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“…The previous study demonstrated that the granulocyte colony stimulating factor (G-CSF) could promote the generation of regulatory DC in vitro; however, neutralization of IL-10 significantly inhibited this process, suggesting that IL-10 involved in regulatory DC generation (34). BMDC could translate into regulatory DC when genetically engineered to express IL-10, and induce longlasting antigen-specific tolerance with an experimental asthma model (35). Thus, the phenotype and cytokine secretion properties of DC-SOCS1 are similar to those of regulatory DCs.…”

Section: Discussionmentioning

confidence: 99%

Dendritic Cells Transduced with SOCS1 Gene Exhibit Regulatory DC Properties and Prolong Allograft Survival

et al. 2009

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SOCS1 is a key regulator of cytokine signaling and is important for maintaining balance in the immune system. It is thought to participate in negative feedback loops in cytokine signaling and may be an important signal for the regulation of dendritic cell (DC) maturation. However, it remains unclear whether DCs transduced with SOCS1 exhibit characteristics of regulatory DCs and induce allogeneic T-cell hyporesponsiveness. In this study, we constructed adenoviral vector coding SOCS1 (

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“…Lung CD11b lo CD103 + DC have also been shown to express a range of tight junction proteins, leading to the current concept that these cells can interact with bronchial epithelial cells and directly sample the lumen for inhaled allergens (23,24). Regulatory roles have also been described for lung pDC (25), and recent studies have also described populations of regulatory myeloid-origin DC that produce IL-10 and can limit Th2-mediated allergic airway responses (26)(27)(28).…”

Section: Endritic Cells (Dc)mentioning

confidence: 99%

Restricted Aeroallergen Access to Airway Mucosal Dendritic Cells In Vivo Limits Allergen-Specific CD4+ T Cell Proliferation during the Induction of Inhalation Tolerance

Fear

Burchell

Lai

et al. 2011

The Journal of Immunology

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Chronic innocuous aeroallergen exposure attenuates CD4+ T cell-mediated airways hyperresponsiveness in mice; however, the mechanism(s) remain unclear. We examined the role of airway mucosal dendritic cell (AMDC) subsets in this process using a multi-OVA aerosol-induced tolerance model in sensitized BALB/c mice. Aeroallergen capture by both CD11blo and CD11bhi AMDC and the delivery of OVA to airway draining lymph nodes by CD8α− migratory dendritic cells (DC) were decreased in vivo (but not in vitro) when compared with sensitized but nontolerant mice. This was functionally significant, because in vivo proliferation of OVA-specific CD4+ T cells was suppressed in airway draining lymph nodes of tolerized mice and could be restored by intranasal transfer of OVA-pulsed and activated exogenous DC, indicating a deficiency in Ag presentation by endogenous DC arriving from the airway mucosa. Bone marrow-derived DC Ag-presenting function was suppressed in multi-OVA tolerized mice, and allergen availability to airway APC populations was limited after multi-OVA exposure, as indicated by reduced OVA and dextran uptake by airway interstitial macrophages, with diffusion rather than localization of OVA across the airway mucosal surface. These data indicate that inhalation tolerance limits aeroallergen capture by AMDC subsets through a mechanism of bone marrow suppression of DC precursor function coupled with reduced Ag availability in vivo at the airway mucosa, resulting in limited Ag delivery to lymph nodes and hypoproliferation of allergen-specific CD4+ T cells.

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Dendritic Cells Genetically Engineered to Express IL-10 Induce Long-Lasting Antigen-Specific Tolerance in Experimental Asthma

Abstract: ؉ mediastinal lymph node T cells from mice injected with OVA-IL-10-DCs protected OVA-sensitized recipients from airway eosinophilia upon OVA provocation. Our study describes a promising strategy to induce long-lasting Ag-specific tolerance in airway allergy.

Cited by 78 publications

References 51 publications

Induction of Prolonged Asthma Tolerance by IL-10–Differentiated Dendritic Cells: Differential Impact on Airway Hyperresponsiveness and the Th2 Immunoinflammatory Response

Induction of Prolonged Asthma Tolerance by IL-10–Differentiated Dendritic Cells: Differential Impact on Airway Hyperresponsiveness and the Th2 Immunoinflammatory Response

Dendritic Cells Transduced with SOCS1 Gene Exhibit Regulatory DC Properties and Prolong Allograft Survival

Restricted Aeroallergen Access to Airway Mucosal Dendritic Cells In Vivo Limits Allergen-Specific CD4+ T Cell Proliferation during the Induction of Inhalation Tolerance

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