Modulation of ovalbumin-induced airway inflammation and hyperreactivity by tolerogenic APC.
Allergic asthma is mediated in part by unregulated Th2 inflammation in response to an allergen. Induction of peripheral tolerance by inoculation of Ags into the anterior chamber of the eye (ocular tolerance) before sensitization blocks Th2 responses. Thus, we proposed that induction of ocular tolerance to the allergen might modulate an ongoing allergen-induced Th2 pathogenesis in the lung. We initiated ocular tolerance in previously immunized mice in a classic mouse model of OVA-induced pulmonary allergic inflammation. In the model of ocular tolerance, the need for inoculation of Ag into the anterior chamber can be bypassed by i.v. inoculation of in vitro-generated tolerogenic (TGF-beta2-treated, Ag-pulsed) APC (tol-APC). We observed that with i.v. inoculation, such tolerogenic APC, but not control APC, reduced eosinophil and lymphocyte pulmonary infiltration in experimental mice. Similarly, production of Th2 cytokines (IL-4, -5, and -13), but not IFN-gamma, was reduced. Importantly, airway hyperresponsiveness and mucus production were significantly reduced after treatment with the tol-APC. We also show that in vitro suppression of IL-13 production from OVA-sensitized effector T cells was mediated by CD8+, not CD4+, T regulatory cells. Thus, i.v. inoculation of the tol-APC induced peripheral tolerance that suppressed Th2-mediated pathogenesis in the lungs of presensitized mice. The ability of the tol-APC to induce peripheral tolerance and suppress existing Th2 immune inflammation may lead to novel therapies for pulmonary allergic inflammation and its related pathology.
Zhang-Hoover
Jie
J
Schepens Eye Research Institute, Boston, MA 02114, USA.
Finn
Patricia
P
Stein-Streilein
Joan
J
D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D001249:Asthma / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000032:analysis / Q000276:immunology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015870:Gene Expression; D007108:Immune Tolerance; D007275:Injections, Intravenous; D008168:Lung / Q000276:immunology / Q000473:pathology; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D010047:Ovalbumin / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000276:immunology*
D016207:Cytokines; D010047:Ovalbumin