Project Summary: The incidence of asthma and allergic rhinitis is rapidly increasing in developed nations. One strategy for treatment of asthma and allergic rhinitis associated with aeroallergen sensitization is allergen-specific subcutaneous immunotherapy (SCIT), which involves a series of subcutaneous injections of allergen extracts. SCIT is a relatively safe and effective method for reducing aeroallergen-induced allergic symptoms, but it has a number of drawbacks, including occasional serious adverse reactions, problems with patient acceptance, and costly, frequent office visits. Therefore, alternative therapies that may result in fewer adverse reactions, increased acceptance by patients, and reduced costs are of interest to clinicians and patients. One alternative therapy that may fit these criteria, allergen-specific sublingual immunotherapy (SLIT), involves the placement of drops of soluble allergen extracts under the patient's tongue. Recent studies suggest that SLIT with high doses of allergen extracts may be safe and effective, but high-dose SLIT still lacks acceptance among most allergists and health care insurers in the U.S.A. Much lower allergen extract doses are used by complementary and alternative medicine (CAM) practitioners in low-dose SLIT, which is even less well accepted. Mechanisms by which high- and/or low-dose SLIT could attenuate allergic responses remain to be elucidated, and little work has been done in animal models to explore potential mechanisms related to SLIT. Therefore, high- and low-dose SLIT will be investigated in a BN rat model of ragweed allergen-induced pulmonary inflammation. The specific aims of this proposal are: (1) to establish ragweed-specific high- and low-dose SLIT models in the BN rat and determine whether high- and/or low-dose SLIT can prevent allergic sensitization in rats (primary prevention) and/or attenuate allergen-induced airway inflammation in previously sensitized rats (therapeutic intervention), and (2) to determine (a) whether functional CD4+ CD25+ regulatory T cells are generated in response to ragweed-specific high- and/or low-dose SLIT in BN rats, (b) whether CD4+ CD25+ regulatory T cells are necessary for efficacious SLIT, and (c) the mechanisms mediating CD4+ CD25+ regulatory T cell function in SLIT. These studies will allow us to investigate whether there is mechanistic support for increased use of high- and/or low-dose SLIT in human patients with asthma and/or allergic rhinitis and provide a basis for translational studies in humans. Relevance: Sublingual immunotherapy is an alternative but increasingly popular treatment for allergic rhinitis (hay fever) and asthma, which involves placing allergen drops under the tongue to reduce allergic responses. To investigate this controversial therapy, these studies will use a novel rat model to compare the efficacy of high vs. low doses of allergen drops and to elucidate mechanisms of sublingual immunotherapy.