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Background: Many studies have demonstrated immunologic changes induced by sublingual immunotherapy (SLIT), but the definitive mechanism of action needs further investigation., Objective: To study the immunologic response induced by SLIT in sensitized mice., Methods: Timothy grass (Phleum pratense)-sensitized mice received SLIT for 2, 4, or 6 weeks at 3 different concentrations, including a buffer control. Serum samples and washes of the lungs (bronchoalveolar lavage [BAL]) and the nasal passages (nasal lavage [NAL]) were analyzed for allergen-specific antibodies. T cells were isolated from the spleen and cervical lymph nodes for the analysis of proliferation and cytokine production., Results: Sublingual immunotherapy in sensitized mice resulted in a 30-fold increase in antigen specific IgA levels in BAL and NAL fluid compared with buffer-treated mice, whereas antigen specific IgE was undetectable in BAL and NAL fluid in animals treated with SLIT. Furthermore, IgA levels were proportional to the dose and duration of SLIT. Levels of specific IgA in serum correlated with levels in BAL and NAL fluid. Serum IgA levels were proportional to the duration of allergen exposure to the oral mucosa. Conversely, no changes in serum levels of IgE and IgG were induced by SLIT. Proliferation of T cells was increased in mice treated with SLIT compared with nontreated mice., Conclusion: High levels of IgA in serum and in BAL and NAL fluid of mice treated with SLIT demonstrate that SLIT induces a mucosal, nonallergic response in sensitized mice.