Therapeutic induction of tolerance by IL-10-differentiated dendritic cells in a mouse model of house dust mite-asthma*

Abstract

It has been reported that retrovirally transduced IL-10-expressing dendritic cells can reverse the asthma phenotype in mice, but that i.v. delivery of dendritic cells differentiated with IL-10 alone (DC10) does not. We report herein DC10 can be highly effective therapeutically in experimental asthma. BALB/c mice were sensitized by airway exposure to house dust mite (HDM) without use of adjuvants, then treated with 10⁶ allergen-presenting DC10. We assessed the airway hyperresponsiveness (AHR) to methacholine, circulating levels of IgE and IgG1, and airway recall responses to HDM allergen, including eosinophilia and Th2 cytokines. We also asked whether the DC10 treatments induced tolerance through activation of pulmonary regulatory T cell activities. In vitro, cognate-, but not irrelevant-, allergen-presenting DC10 productively engaged pulmonary Th2-phenotype CD4(+) cells magnetically sorted from HDM-asthmatic mice in Forster (or fluorescence) resonance energy transfer assays. In vivo, treatment of HDM-asthmatic mice with HDM, but not ovalbumin-presenting DC10 abrogated AHR within 4 weeks, and significantly reduced airway eosinophilia, IL-4, IL-5, and IL-13 responses, and circulating HDM-specific IgE and IgG1 levels (each, P ≤ 0.01 versus control mice). CD4(+) CD25(+) Foxp3(+) cells from the lungs of the DC10-treated mice, but not those from asthmatic animals, up-regulated expression of the activated regulatory T cell markers CTLA4 and LAG3, and passive transfer of pulmonary CD4(+) T cells from these mice induced allergen tolerance in HDM-asthmatic recipients. These findings indicate that allergen-presenting DC10 treatments up-regulate T cell regulatory activities and thereby induce allergen-specific tolerance in a relevant model of human asthma.