Role of Memory T Cells in Pathogenesis and Resolution of Inflammatory Diseases

Chronic hyperplastic sinusitis with nasal polyposis is characterized by mucosal thickening, goblet cell hyperplasia, subepithelial fibrosis and by the infiltration of inflammatory cells including eosinophils, neutrophils, macrophages, plasma cells and lymphocytes. The functional significance of the inflammatory cells and the biologically active factors they produce with respect to the generation and progression of the underlying pathology has not been well- defined or causally linked to the disease. Using a novel xenograft model in which human nasal polyp tissues expand progressively following their implantation into severely immunocompromised NOD/SCID/IL2Rγnull mice, the contributions of lymphocytes and monocytes (and the biologically active factors they produce) to the sustained presence and progression of the histopathology of the nasal polyp xenografts will be determined. This is achieved in Aims 1 and 2 by monitoring and quantifying the effect of the selective blockade of inflammatory mediators or immune-depletion of cytokines and CD4+ and CD8+ T lymphocytes, CD68+ macrophages, and CD138+ plasma cells upon the mucosal thickening, goblet cell hyperplasia, sub-epithelial fibrosis and changes in gene expression patterns within the nasal polyp xenografts. Based upon these initial studies, in Aim 3 protocols will be designed and tested in vitro to change the functional properties of the nasal polyp-associated T cells. Strategies are first designed and tested to reverse the T cell receptor signaling arrest that we have shown to be characteristic of the polyp-associated T cells. Next protocols are designed to reprogram proinflammatory cytokine producing T cells into T cells producing immunosuppressive cytokines. The design of these protocols is based upon the demonstrated plasticity of human T cells in response to specific combinations of cytokines and anti-cytokine antibodies. In the final aim the ability of reactivating and/or reprogramming of T cells in situ to reduce or completely arrest nasal polyp progression, histopathology, and the associated gene expression patterns, is addressed in vivo. This is achieved by monitoring and quantifying changes in the growth, histopathology, and gene expression of established nasal polyp xenografts in response to the cytokine induced alterations in T cell functions. These studies are expected to establish a causal link between lymphocyte-, macrophage- and plasma cell-produced biologically active factors and nasal polyposis, and are expected to provide valuable insights with respect to the design of more rationale and effective therapeutic protocols for this chronic and debilitating disease by selectively targeting and functionally altering polyp-associated immunocompetent cells.