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The Th2 cytokines IL-4 and IL-10 are internal controllers of human Th1-biased immunity in vivo
Arthritis Res Ther volume 5, Article number: 88 (2003)
Chronic inflammation in several human autoimmune diseases, such as rheumatoid arthritis, is driven by activated Th1 cells. The delineation of the mechanisms controlling the evolution of Th1-mediated immune responses in autodestructive immune reactions is therefore crucial for the understanding of the pathogenesis of autoimmune diseases. However, analysis of such mechanisms in humans is hampered by the inability to address these questions directly in vivo. We developed a novel in vivo model for human Th1-mediated inflammation and analyzed the regulation of human Th1 inflammation in vivo. Peripheral blood mononuclear cells (PBMC) from healthy human individuals were transferred by intraperitoneal injection into female NOD/SCID mice that lack T cells and B cells and that express reduced natural killer cell activity. At different time points, human PBMC were recovered from the intraperitoneal cavity and analyzed phenotypically and functionally. Human PBMC developed a stongly Th1-biased immune response, as indicated by spontaneous proliferation of CD4 and CD8 T cells, by increased expression of the T-cell activation markers HLA-DR and CD25, and by massive expansion of IFN-γ-producing T cells. In contrast, Th2 cells were absent in the recovered human T cells. Histopathological analysis revealed infiltration of activated human lymphocytes into the portal tracts of the liver and into the perigastrointestinal and perirenal fatty tissues, which was frequently organized in granuloma-like structures resembling Th1-mediated granulomas in sarkoidosis or Wegener's disease. The development of the human Th1-biased immune response in the mice could be blocked by cyclosporine and was dependent on antigen-presenting cells. Further analysis of the regulation of the human Th1 immune response in vivo revealed that the development of the Th1 immune response was tightly controlled by the endogenously produced cytokines IL-4 and IL-10, as neutralization of these cytokines markedly exaggerated the Th1 response. Interestingly, treatment of established inflammation with daily intraperitoneal injections of recombinant IL-4 or IL-10 markedly decreased T-cell activation and IFN-γ production, indicating that the anti-inflammatory cytokines IL-4 and IL-10 are able to interrupt established human Th1-mediated inflammation. These data suggest that potent regulatory mechanisms involving IL-4 and/or IL-10 control the development of Th1-mediated human inflammation in vivo, which might have an important implication for future therapies of chronic autoimmune inflammatory diseases.
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Skapenko, A., Niedobitek, G., Kalden, J. et al. The Th2 cytokines IL-4 and IL-10 are internal controllers of human Th1-biased immunity in vivo. Arthritis Res Ther 5 (Suppl 3), 88 (2003). https://doi.org/10.1186/ar889