Constant exposure of the lung to environmental antigens requires the maintenance of immune tolerance to inhaled benign antigens. When lung homeostasis fails, environmental antigens trigger an aberrant immune response that can result in allergic asthma. A key protein in immune tolerance and the development of allergic asthma is transforming growth factor-? (?). Since ? is secreted and bound to the extracellular matrix in a latent form, conversion of this protein to an active form is a critical step in ? signaling. However, the mechanisms that regulate ? activation in vivo are unclear. We recently showed that mice lacking the av?8 integrin on dendritic cells spontaneously develop autoimmunity through defects in ? activation and regulatory T cell induction, but how this process is regulated and the role of av?8 in allergic asthma are unknown. Thus, the long-term objective of this proposal is to elucidate how activation of ? by integrinavp8 is regulated in dendritic cells, and to determine the role of this process in allergic asthma. We plan to achieve this goal with two specific aims that test the hypotheses that (1) av?8-mediated ? activation is differentially regulated in dendritic cell populations and toll-like receptor stimulated dendritic cells and (2) loss of av?8-mediated ? activation on leukocytes results in exacerbated allergic asthma. We will test the first hypothesis by utilizing two bioassays to measure av?8-mediated ? activation in dendritic cell populations and toll-like receptor stimulated dendritic cells. The second hypothesis will be tested by evaluating the responses of mice with a conditional deletion of av?8 integrin on leukocytes in the ovalbumin- and Aspergillus-induced allergic asthma models. The results of these studies should facilitate the development of new therapies for lung diseases by clarifying the mechanisms that maintain lung homeostasis and regulate ? in allergic asthma. Transforming growth factor-p is a protein that maintains lung homeostasis and protects against aberrant immune responses, such as those seen in people with allergic asthma. However, the mechanisms that regulate the activity of this protein are unclear. The experiments in this proposal will provide insight into the regulation of transforming growth factor-? in allergic asthma and could facilitate the development of new treatments for this and other lung diseases.
| Kudo, Makoto; Melton, Andrew C; Chen, Chun et al. (2012) IL-17A produced by ?? T cells drives airway hyper-responsiveness in mice and enhances mouse and human airway smooth muscle contraction. Nat Med 18:547-54 |
| Melton, Andrew C; Bailey-Bucktrout, Samantha L; Travis, Mark A et al. (2010) Expression of ?v?8 integrin on dendritic cells regulates Th17 cell development and experimental autoimmune encephalomyelitis in mice. J Clin Invest 120:4436-44 |
