Immunomodulatory implications of lymphangiogenesis in allergic airway inflammation

项目总结

Project Summary The lymphatics are mainly recognized for their fluid transport roles, draining liquid and cells from interstitial spaces and peripheral tissues. Indeed, many years of research have revealed ow the lymphatic vasculature pumps fluid and shuttles immune cells to the draining lymph nodes. In chronic inflammatory conditions, such as airway inflammation, increased growth and expansion of lymphatic vessels, or lymphangiogenesis (LAG), has been thought to accommodate for the increased need lymphocyte trafficking1-8. However, recently our lab and others have found that the lymphatics do more than just shuttle immune cells: they play critical roles in modulating immune responses. Indeed, lymphatic endothelial cells (LECs) can take up and present antigen to the adaptive immune system and express costimulatory molecules that can dysfunctionally activate adaptive immune cells9-13. In addition, LAG in tumors has been associated with increased tolerance to tumor antigens as well as metastasis, and acute renal allograft rejection, indicating that LAG also has immunomodulatory ef- fects3,4,14-17. However, what these effects are and whether the lymphatics and LAG contribute to disease per- sistence or resolution is poorly understood. This project seeks to understand these immunological implications in a model system of chronic allergic airway inflammation. We have preliminary data that indicates that the blocking LAG and specifically deleting molecules that allow LEC-immune cell interactions exacerbate the adap- tive immune response. Therefore, my hypothesis is that LECs, particularly in an expanded state, play regulato- ry roles that help shape the adaptive inflammatory response in chronic allergic airway inflammation. To test this hypothesis I will use flow cytometry, histology, qPCR, and protein analysis via ELISA to determine how block- ing LAG alters the immune response in chronic allergic airway inflammation, specifically looking at the effects on regulatory immune cells and the memory response (Aim 1). In addition, I will use fluorescently labeled anti- gens to assess the distribution and uptake of allergens in the lymphatics of the lung and its draining lymph nodes, as well as a novel mouse-model to assess how LEC-immune cell interactions alter the allergic immune response (Aim 2). The results of the proposed project will introduce the role of LECs and LAG in modulating the immune response in chronic allergic airway inflammation. Additionally, this will provide vital knowledge that can inform the development of novel therapies for chronic allergic airway inflammation.