Altered Dendritic Cell Function in Sarcoidosis Anergy

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DESCRIPTION (provided by applicant): Sarcoidosis is a disease of unknown etiology characterized by persistent granulomas with damage to surrounding tissues. Despite the presence of focal inflammation, sarcoidosis patients frequently have partial or complete anergy to common skin reactants, along with other evidence of suppressed systemic cellular immunity. Evidence suggests that dendritic cells (DCs), key regulators of cellular immunity, could contribute to anergy in sarcoidosis. The type of T cell response induced by DCs after uptake and presentation of antigen depends on the DC subset and maturation stage. Mature DCs primarily induce Thl-type responses critical for effector T cell responses, macrophage activation and delayed-type hypersensitivity. However, immature DCs of either subset can induce T cell anergy, resulting in impaired T cell responses and decreased resistance to intracellular pathogens. Since DC maturation is critical in determining the resulting immune response to antigenic stimuli, abnormal DC maturation could lead to dysfunctional immunity and disease. Examples of attenuated DC maturation have been reported in neoplastic and infectious disease processes. This proposal hypothesizes that the anergy in sarcoidosis is due to altered DC maturation. This hypothesis is supported by evidence in sarcoidosis for high plasma levels of IL-10 and vitamin D3, both )otential suppressors of DC maturation. This proposal outlines an approach to characterizing circulating blood DC subsets in normal volunteers and individuals with sarcoidosis, using flow cytometry phenotyping of whole blood DCs and magnetic column isolation and purification of these DCs to determine their effect on allogeneic T cell responses. Dendritic cell function will be correlated with in vivo cellular immune function as determined by PPD/anergy skin test panel. Associating altered DC maturation with T cell dysfunction in sarcoidosis would provide the basis for novel approaches in sarcoidosis therapies, including applying new DC-activating agents currently under development for the oncology and infectious disease fields.