The epithelium of the lung is one of the largest interfaces between the body and the environment and it is exposed daily to approximately 11,000 liters of air that is contaminated with bacteria, viruses, pathogens and allergens. The pulmonary host defense system must ignore harmless antigens but respond appropriately to harmful pathogens. One of local host defense system is pulmonary surfactant. Recent studies have identified two of the surfactant proteins, SP-A and SP-D, as members of the collectin family of collagen-like lectins that function in host defense. The overall hypothesis to be tested in this proposal is that SP-A and SP-D interact with cells of both the adaptive and innate immune systems to coordinately maximize defense against inhaled allergens and pathogens while minimizing potentially harmful inflammatory consequences of an over exuberant immune response. Our findings that SP-A and SP-D have cell specific effects suggest that they modulate cellular response in a context specific manner. We propose to pursue three specific aims.
Aim 1 will define the roles of SP-A and SP-D and their receptors in regulating antigen uptake, intracellular targeting, and antigen presentation by bone marrow derived dendritic cells and mast cells. Blocking antibodies and receptor null mice will be used to test the hypothesis that dendritic and mast cell specific responses are modulated by different collectin receptors that target pathogens to different intracellular processing pathways for presentation via MHCI and MHCII.
Aim 2 will define the mechanism by which SP-A inhibits the maturation of dendritic cells. Studies will be performed with isolated cells, anti-receptor blocking antibodies, and with cells from receptor and cytokine null mice to test the hypothesis that SP-A interacts with specific receptors to alter production of cytokines or cytokine receptors that inhibit dendritic cell maturation.
Aim 3 will investigate SP-A and SP-D mediated regulation of Type II epithelial cell and lung dendritic cell immune functions in the normal and inflamed lung. Studies will be conducted in vitro with isolated cells and in vivo with collectin null mice using two models of lung inflammation, the LPS model and the ovalbumin model of allergic inflammation. These studies will provide new information about the role of SP-A and SP-D in regulating and coordinating the functions of cells of the innate and adaptive immune system and contribute to our understanding of the role of SP-A and SP-D in inflammatory lung diseases and to development of novel surfactant-containing therapies. ? ? ?
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