Proinflammatory human 6-sulfo LacNAc-positive dendritic cells accumulate in intestinal acute graft-versus-host disease.

نویسندگان

  • Ulrich Sommer
  • Brit Larsson
  • Sebastian Tuve
  • Rebekka Wehner
  • Nick Zimmermann
  • Michael Kramer
  • Anja Kloβ
  • Claudia Günther
  • Jana Babatz
  • Renate Schmelz
  • Stefan Brückner
  • Johannes Schetelig
  • Martin Bornhäuser
  • Knut Schäkel
  • Michael Philipp Bachmann
  • Daniela Aust
  • Gustavo Baretton
  • Marc Schmitz
چکیده

Allogeneic hematopoietic stem cell transplantation (HSCT) represents a potentially curative therapy for various malignant and non-malignant hematologic diseases. However, a frequent and severe complication of this therapeutic approach is acute graft-versus-host disease (aGVHD) characterized by immune-mediated inflammation and tissue destruction. In this context, donor-derived CD4 Thelper (Th) cells and CD8 cytotoxic T lymphocytes (CTLs) play an essential role in the pathogenesis of aGVHD, which is based on their profound capability to produce various proinflammatory cytokines and to lyse target cells of the recipient. Dendritic cells (DCs) are professional antigen-presenting cells (APCs), which display a unique capacity to induce and expand proinflammatory CD8 CTLs and CD4 T cells. Recent murine models revealed that DCs essentially contribute to T-cell-mediated inflammation and tissue destruction in aGVHD. However, in contrast to mouse DCs, little is known about the potential role of native human DCs in the pathogenesis of aGVHD. In this context, it has been demonstrated that patients who develop aGVHD after HSCT show lower numbers of blood circulating DCs. Furthermore, it has been reported that human DCs are able to induce GVHD in a SCID mouse model and that the administration of anti-CD83 antibodies can prevent the development of GVHD. More recently, Bossard et al. demonstrated that native human plasmacytoid DCs, which may play an essential role in the pathogenesis of various autoimmune diseases, accumulate in intestinal tissues of aGVHD patients. The same group also found a significant increase of plasmacytoid DCs in affected skin of aGVHD patients, further substantiating their previous results. To gain novel insights into a potential participation of human myeloid DCs in the inflammatory processes underlying aGVHD, we explored the presence and cytokine expression of 6-sulfo LacNAc (slan) DCs (formerly termed M-DC8 DCs) in affected tissues. SlanDCs represent a particular proinflammatory subset of human myeloid blood DCs. In previous studies, we demonstrated that activated slanDCs produce large amounts of tumor necrosis factor (TNF)-a, interleukin (IL)-1β, IL-6, IL-12 and IL-23, efficiently stimulate CD4 and CD8 T cells, and promote the polarization of naïve CD4 T lymphocytes into Th1 or Th17/Th1 cells. In addition, we found that the high proinflammatory capacity of slanDCs is retained after granulocyte-colony stimulating factor (G-CSF) treatment of peripheral blood stem cell donors. Thus, G-CSF-mobilized slanDCs were able to secrete large amounts of proinflammatory cytokines and to promote the polarization of naïve CD4 T lymphocytes into Th1 cells. We also observed a significantly reduced frequency of slanDCs in the blood of patients with severe aGVHD that could be explained by an increased DC migration into affected tissues. Following these findings, we evaluated the presence of slanDCs in 124 tissue samples derived from 65 patients with aGVHD who underwent HSCT at the University Hospital of Dresden, Germany. Patients, donors and HSCT characteristics are summarized in Table 1. This study was approved by the institutional review board of the University Hospital of Dresden and patients gave their written informed consent. Patients underwent diagnostic

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عنوان ژورنال:
  • Haematologica

دوره 99 6  شماره 

صفحات  -

تاریخ انتشار 2014