%0 Journal Article
%T IL-10 Induction from Implants Delivering Pancreatic Islets and Hyaluronan
%A Paul L. Bollyky
%A Robert B. Vernon
%A Ben A. Falk
%A Anton Preisinger
%A Michel D. Gooden
%A Gerald T. Nepom
%A John A. Gebe
%J Journal of Diabetes Research
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/342479
%X Local induction of pro-tolerogenic cytokines, such as IL-10, is an appealing strategy to help facilitate transplantation of islets and other tissues. Here, we describe a pair of implantable devices that capitalize on our recent finding that hyaluronan (HA) promotes IL-10 production by activated T cells. The first device is an injectable hydrogel made of crosslinked HA and heparan sulfate loaded with anti-CD3/anti-CD28 antibodies and IL-2. T cells embedded within this hydrogel prior to polymerization go on to produce IL-10 in vivo. The second device is a bioengineered implant consisting of a polyvinyl alcohol sponge scaffold, supportive collagen hydrogel, and alginate spheres mediating sustained release of HA in fluid form. Pancreatic islets that expressed ovalbumin (OVA) antigen were implanted within this device for 14 days into immunodeficient mice that received OVA-specific DO.11.10 T cells and a subsequent immunization with OVA peptide. Splenocytes harvested from these mice produced IL-10 upon re-challenge with OVA or anti-CD3 antibodies. Both of these devices represent model systems that will be used, in future studies, to further evaluate IL-10 induction by HA, with the objective of improving the survival and function of transplanted islets in the setting of autoimmune (type 1) diabetes. 1. Introduction Interleukin 10 (IL-10) is a potent immunosuppressive cytokine made by regulatory T cells (Tregs) and other cell types [1¨C3]. IL-10 inhibits antigen-specific immune responses in part via suppression of activated macrophage and monocyte functions, which include cytokine synthesis and expression of class II MHC and costimulatory molecules such as IL-12 and CD80/CD86 [4]. IL-10 has important roles in transplant biology. Endogenous IL-10 production is correlated with transplant acceptance in multiple animal models and human tissues [5¨C8]. IL-10 has been evaluated as a treatment to improve the survival of engrafted islets, which has been accomplished by transfer of IL-10-producing Tregs [6], gene therapy [9, 10] or direct administration of IL-10 alone, or in conjunction with immunomodulatory drugs [11¨C13]. It is noteworthy that systemic IL-10 treatment has failed to support islet engraftment in mice in the setting of established autoimmunity [14] and may induce immune suppression. These results suggest that an alternative approach that provides a sustained, local presence of IL-10 at the graft site might be more effective at preventing islet rejection. We recently reported a role for the extracellular matrix (ECM) macromolecule hyaluronan (HA) in
%U http://www.hindawi.com/journals/jdr/2013/342479/