The long term objective of the proposed research is to analyze the immune functions of accessory cells in the lung and to relate them to immune responses triggered by foreign antigens. Dendritic cells (DC), one of the most potent accessory cells, have been isolated from airway epithelium and interstitium of peripheral lung. Those in airway epithelium resemble epidermal Langerhans cells; they process antigen, but do not readily stimulate resting T-cells. Those in lung interstitium, by contrast, do not directly process particulate antigens, but are potent accessory cells in a mixed leukocyte reaction. In this proposal, experiments are designed to examine, in the Lewis rat, the ability of DC in airway epithelium to endocytose and process soluble and particulate antigens in situ and to identify factors that stimulate their migration to local lymph nodes. Many DC isolated from the pulmonary vascular compartment are phenotypically less mature than those in the general circulation. Experiments are devised to characterize the phenotype and function of DC isolated from the pulmonary vascular compartment and compare them to DC isolated from the general circulation. The augmented traffic of DC to the lung vasculature following intra-tracheal instillation and/or systemic administration of selected cytokines will be utilized to determine the role of: a. cytokine mediated chemoattraction of DC to lungs and b. ICAM-l/LFA-l mediated adhesion of DC to lung endothelium. The important co-stimulatory antigen. B7 is present on a subset of lung DC. Studies are designed to determine in DC, cultured from mouse bone marrow and/or blood, the stage of differentiation at which B7 is expressed on DC and to identify, in vitro and in situ using mouse lung, those cytokines that regulate its expression. With the ability to culture DC from Ia DC precursors in mouse blood and from bone marrow, it is now feasible to examine, utilizing immunogold labeling on ultra-thin cryosections, the intracellular compartments in which MHC class II antigens, invariant chain and antigen interact. While highly purified interstitial DC from the peripheral lung do not phagocytose bacteria, addition of small numbers of interstitial macrophages results in a 200% increase in antigen presentation by DC. Potential mechanisms involved are explored. To develop rational strategies to control pulmonary immunity at early stages of sensitization it is important to understand in detail the mechanisms by which pulmonary accessory cells interact with other elements of the immune system and to define the factors regulating their function.
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