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Gliadin-primed CD4+CD45RBlowCD25- effector/memory T cells drive gluten-dependent small intestinal damage after adoptive transfer into lymphopenic mice
  1. Tobias Freitag (tobias.freitag{at}helsinki.fi)
  1. Haartman Institute, Finland
    1. Svend Rietdijk
    1. Beth Israel Deaconess Medical Center, United States
      1. Yvonne Junker
      1. Beth Israel Deaconess Medical Center, United States
        1. Yury Popov
        1. Beth Israel Deaconess Medical Center, United States
          1. Atul K Bhan
          1. Massachusetts General Hospital, United States
            1. Ciaran P Kelly
            1. Beth Israel Deaconess Medical Center, United States
              1. Cox Terhorst
              1. Beth Israel Deaconess Medical Center, United States
                1. Detlef Schuppan (dschuppa{at}bidmc.harvard.edu)
                1. Beth Israel Deaconess Medical Center, United States

                  Abstract

                  Background and aims: Celiac disease (cd) is a common small intestinal inflammatory disorder that results from a breach of intestinal tolerance to dietary gluten proteins, driven by gluten-reactive effector T cells. We aimed to assess the pathogenic role of gluten-reactive effector T cells and to generate a model of gluten-induced enteropathy.

                  Methods: CD4+CD25- T cell fractions were adoptively transferred into lymphopenic mice, leading to "baseline" small intestinal inflammation.

                  Results: Rag1-/- recipients of gliadin-presensitized CD4+CD45RBlowCD25- effector/memory T cells, but not CD4+CD45RBhigh naive T cells, gained less weight and suffered from more severe duodenitis when challenged with oral gluten than recipients on gluten-free diet, or recipients of control (ovalbumin)-presensitized T cells. This was accompanied by deterioration of mucosal histological features characteristic of cd, and increased Th1/Th17 cell polarization in the duodenum and the periphery. Interestingly, reintroduction of a gluten-free diet led to weight gain, improvement of histological duodenitis, and a decrease in duodenal IFNγ and IL-17 transcripts. Moreover, B cell-competent nude recipients of gliadin-presensitized effector/memory T cells produced high levels of serum anti-gliadin IgA and IgG1/IgG2c only when challenged with oral gluten.

                  Conclusions: CD4+ effector T cell immunity to gluten leads to a breach of oral gluten tolerance and small intestinal pathology in lymphopenic mice, similar to human cd. This model will be useful for the study of cd pathogenesis, but also for testing novel non-dietary therapies for cd.

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