TNFRSF25 mediated in vivo expansion of regulatory T-cells reduces immunopathology in a chronic model of allergic lung inflammation (55.4)

Abstract

Abstract TNF receptor super family member 25 (TNFR25, DR3) signaling by agonistic antibody (4C12) has been shown to effectively expand CD4+FoxP3+ regulatory T-cells (Treg) in vivo, and prevent acute allergic lung inflammation, a model for asthma. Here we investigate if Treg expansion by TNFR25 stimulation can reduce lung immunopathology associated with chronic allergic lung inflammation. After antigen priming (Ovalbumin/ALUM) and three weeks of antigen aerosol exposure (Ovalbumin in Saline), TNFR25 agonistic antibody given during an aerosol-free period is able to expand Tregs in the peripheral blood and in the lungs as previously reported. After two additional weeks of antigen aerosol exposure, and at a time when TNFR25-expanded Tregs have almost contracted to baseline levels, 4C12 treated animals remained protected from chronic lung immunopathology. Specifically, TNFR25 agonistic antibody treated mice, as compared to IgG treated controls, showed reduced eosinophils in the bronchoalveolar lavage fluid, reduced expression of Th2 cytokines (IL-4, IL-5, IL-13), CCL11 (eotaxin-1), and TNF-a, and reduced mucus production in the bronchial epithelium. These results indicate that TNFR25 mediated expansion of Tregs after established pulmonary inflammation, is able to generate a sustained suppression of chronic lung immunopathology, which may be mediated by antigen-specific Tregs.