Protection of islet grafts through TGF beta induced tolerogenic DC

  1. Maja Wallberg1,3
  1. 1Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Cambridge, UK
  2. 2Diabetes Research Group, Institute of Molecular & Experimental Medicine, Cardiff University School of Medicine, Heath Park, Cardiff, UK
  3. 3Department of Pathology, University of Cambridge, Tennis Court Rd, Cambridge, UK
  4. 4Centre for Immunology and Infection, Hull York Medical School and Department of Biology, University of York, Wentworth Way, York, UK
  1. Corresponding authors: Allison Green, email: allison.green{at}york.ac.uk Maja Wallberg, email: mw394{at}cam.ac.uk

Abstract

In Type 1 Diabetes, the insulin producing beta cells are destroyed by the immune system. One way of restoring glucose control is to transplant beta cells from a donor. While this procedure may restore endogenous insulin production, immunosuppressive treatment is needed to prevent the recipient from rejecting the donor-derived islets. We investigated the possibilities of transient expression of the immunosuppressive cytokine Transforming Growth Factor (TGF) beta within islets to achieve long term graft tolerance. We found that brief expression of TGF beta prevented rejection of syngeneic islets, that there was reduction of dendritic cell activation in the graft and reduced reactivation of T cells in the graft draining lymph nodes. In vitro exposure of bone marrow derived DC to TGF beta reduced expression of costimulatory molecules CD80 and CD86 as well as production of proinflammatory cytokines such as IL-12 p70 in DC, but did not alter levels of MHC class I and II. Furthermore, the capacity of TGF beta-treated bone marrow derived DC to activate both CD4+ and CD8+ T cells was reduced. Adding TGF beta conditioned tolerogenic DC to the grafted islets led to long term survival of the graft, demonstrating that TGF beta-induced tolerogenic DC can provide an effective means to restore immune tolerance in an already established autoimmune disease.

  • Received December 12, 2012.
  • Accepted May 24, 2013.

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