Oral Presentation The 13th International Congress of the Immunology of Diabetes Society 2013

Manipulating beta cells for local modulation of autoimmunity: taking a page from the tumour playbook (#36)

C.Bruce Verchere 1 2
  1. Diabetes Research Program, , Child & Family Research Institute, Vancouver, BC, Canada
  2. University of British Columbia, Departments of Surgery and Pathology & Laboratory Medicine, Vancouver, BC, Canada

Beta cells contribute to their own demise in type 1 diabetes, for example by presenting autoantigens to autoreactive T cells and by releasing chemokines that help incite inflammation. The communication between beta cells and the immune cells that target them for destruction represents a potential therapeutic target, as it may provide a means for beta cells to protect themselves by local modulation of autoimmunity. Tumours do this effectively to foster immune privilege, for example by secreting chemokines to attract regulatory T cells (Tregs); expressing indoleamine 2,3-dioxygenase (IDO) to help create a local tolerogenic milieu; and producing lactate by aerobic glycolysis. We have attempted to exploit some of the strategies used by tumours by manipulating beta cell production of immune-modulatory factors. We recently reported that in vivo beta cell specific expression of the chemokine CCL22, which attracts Tregs via interaction with its receptor CCR4, protects NOD mice from autoimmune diabetes. Adenoviral overexpression of CCL22 in NOD.scid mouse islets led to protection from recurrent autoimmunity following syngeneic transplantation into diabetic NOD recipients. CCL17, another chemokine used by tumours for immune evasion and one that also acts via CCR4, was similarly able to protect beta cells from recurrent autoimmunity. We have recently found that the protective action of CCL22 is not only dependent on the recruitment of Tregs to the islet, but may also involve activation of Tregs, since CCL22 induced expression of CTLA-4, ICOS and CD62L in FACS-sorted Tregs. In addition, CCL22 expression attracted both iNKT cells and plasmacytoid dendritic cells (pDCs) to islets both in vivo and in cell migration assays, suggesting a role for these immune cell subsets in CCL22-mediated protection. In support of this idea, when NOD.scid islets expressing CCL22 were transplanted into diabetic NOD mice lacking CD1d, these grafts were rapidly destroyed, suggesting suggesting a role for iNKT cells. Expression of CCL22 in islet allografts also conferred protection from rejection in MHC-mismatched diabetic recipients. Recipients showed absence of anti-donor antibodies and no lymphocyte response to allogeneic splenocytes, suggesting induction of tolerance. Indeed, when recipients of CCL22-expressing islet allografts were transplanted with a second islet allograft from strain-matched donors, there was no alloimmune response to the second graft, whereas islet allografts from 3rd party donor were rapidly rejected.