Protection of Islet Grafts Through Transforming Growth Factor-β–Induced Tolerogenic Dendritic Cells

  1. Maja Wållberg1
  1. 1Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Cambridge, U.K.
  2. 2Diabetes Research Group, Institute of Molecular and Experimental Medicine, Cardiff University School of Medicine, Cardiff, U.K.
  3. 3Department of Pathology, University of Cambridge, Cambridge, U.K.
  4. 4Centre for Immunology and Infection, Hull York Medical School and the Department of Biology, University of York, York, U.K.
  1. Corresponding authors: E. Allison Green, allison.green{at}york.ac.uk, and Maja Wållberg, mw394{at}cam.ac.uk.

Abstract

In type 1 diabetes, the insulin-producing β-cells are destroyed by the immune system. One way of restoring glucose control is to transplant β-cells from a donor. Although 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)-β within islets to achieve long-term graft tolerance. We found that brief expression of TGF-β prevented rejection of syngeneic islets, that there was reduction of dendritic cell (DC) activation in the graft, and that there was reduced reactivation of T cells in the graft-draining lymph nodes. In vitro exposure of bone marrow–derived DCs to TGF-β reduced expression of costimulatory molecules CD80 and CD86, as well as production of proinflammatory cytokines such as interleukin-12 p70 in DCs, but did not alter levels of major histocompatibility complex classes I and II. Furthermore, the capacity of TGF-β–treated bone marrow–derived DCs to activate both CD4+ and CD8+ T cells was reduced. Adding TGF-β–conditioned tolerogenic DCs to the grafted islets led to long-term survival of the graft, demonstrating that TGF-β–induced tolerogenic DCs can provide an effective means to restore immune tolerance in an already established autoimmune disease.

Footnotes

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

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  1. Diabetes vol. 62 no. 9 3132-3142
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