Induction of prolonged asthma tolerance by IL-10-differentiated dendritic cells: differential impact on airway hyperresponsiveness and the Th2 immunoinflammatory response.
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 × 10(6) 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.
Department of Veterinary Microbiology, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5B4, Canada.
Aarti
A
Nayyar
Wojciech
W
Dawicki
Hui
H
Huang
Meiping
M
Lu
Xiaobei
X
Zhang
John R
JR
Gordon
D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D016753:Interleukin-10 / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018418:Th2 Cells / Q000276:immunology* / Q000473:pathology; D013997:Time Factors
C556062:IL10 protein, mouse; D016753:Interleukin-10