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 [1–3]. 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 [5–8]. 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 [11–13]. 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
References
[1]
C. Asseman, S. Mauze, M. W. Leach, R. L. Coffman, and F. Powrie, “An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation,” Journal of Experimental Medicine, vol. 190, no. 7, pp. 995–1004, 1999.
[2]
E.-O. Glocker, D. Kotlarz, K. Boztug et al., “Inflammatory bowel disease and mutations affecting the interleukin-10 receptor,” The New England Journal of Medicine, vol. 361, no. 21, pp. 2033–2045, 2009.
[3]
M. G. Roncarolo, S. Gregori, M. Battaglia, R. Bacchetta, K. Fleischhauer, and M. K. Levings, “Interleukin-10-secreting type 1 regulatory T cells in rodents and humans,” Immunological Reviews, vol. 212, pp. 28–50, 2006.
[4]
K. W. Moore, M. R. de Waal, R. L. Coffman, and A. O'Garra, “Interleukin-10 and the interleukin-10 receptor,” Annual Review of Immunology, vol. 19, pp. 683–765, 2001.
[5]
A. M. VanBuskirk, W. J. Burlingham, E. Jankowska-Gan et al., “Human allograft acceptance is associated with immune regulation,” Journal of Clinical Investigation, vol. 106, no. 1, pp. 145–155, 2000.
[6]
S. Yi, M. Ji, J. Wu et al., “Adoptive transfer with in vitro expanded human regulatory T cells protects against porcine islet xenograft rejection via interleukin-10 in humanized mice,” Diabetes, vol. 61, no. 5, pp. 1180–1191, 2012.
[7]
K. S. Baker, M.-G. Roncarolo, C. Peters, M. Bigler, T. DeFor, and B. R. Blazar, “High spontaneous IL-10 production in unrelated bone marrow transplant recipients is associated with fewer transplant-related complications and early deaths,” Bone Marrow Transplantation, vol. 23, no. 11, pp. 1123–1129, 1999.
[8]
V. Daniel, C. Naujokat, M. Sadeghi, M. Wiesel, O. Hergesell, and G. Opelz, “Association of circulating interleukin (IL)-12- and IL-10-producing dendritic cells with time posttransplant, dose of immunosuppression, and plasma cytokines in renal-transplant recipients,” Transplantation, vol. 79, no. 11, pp. 1498–1506, 2005.
[9]
Y. C. Zhang, A. Pileggi, A. Agarwal et al., “Adeno-associated virus-mediated IL-10 gene therapy inhibits diabetes recurrence in syngeneic islet cell transplantation of NOD mice,” Diabetes, vol. 52, no. 3, pp. 708–716, 2003.
[10]
Y.-H. Kim, D.-G. Lim, Y.-M. Wee et al., “Viral IL-10 gene transfer prolongs rat islet allograft survival,” Cell Transplantation, vol. 17, no. 6, pp. 609–618, 2008.
[11]
A. Rabinovitch, W. L. Suarez-Pinzon, O. Sorensen, R. V. Rajotte, and R. F. Power, “Combination therapy with cyclosporine and interleukin-4 or interleukin- 10 prolongs survival of syngeneic pancreatic islet grafts in nonobese diabetic mice: islet graft survival does not correlate with mRNA levels of type 1 or type 2 cytokines, or transforming growth factor-β in the islet grafts,” Transplantation, vol. 64, no. 11, pp. 1525–1531, 1997.
[12]
M. Battaglia, A. Stabilini, E. Draghici et al., “Rapamycin and interleukin-10 treatment induces T regulatory type 1 cells that mediate antigen-specific transplantation tolerance,” Diabetes, vol. 55, no. 1, pp. 40–49, 2006.
[13]
N. Gagliani, S. Gregori, T. Jofra et al., “Rapamycin combined with anti-CD45RB mAB and IL-10 or with G-CSF induces tolerance in a stringent mouse model of islet transplantation,” PloS One, vol. 6, no. 12, article e28434, 2011.
[14]
Y. C. Zhang, A. Pileggi, R. D. Molano et al., “Systemic overexpression of interleukin-10 fails to protect allogeneic islet transplants in nonobese diabetic mice,” Transplantation, vol. 80, no. 4, pp. 530–533, 2005.
[15]
T. C. Laurent and J. R. E. Fraser, “Hyaluronan,” The FASEB Journal, vol. 6, no. 7, pp. 2397–2404, 1992.
[16]
D. Jiang, J. Liang, J. Fan et al., “Regulation of lung injury and repair by Toll-like receptors and hyaluronan,” Nature Medicine, vol. 11, no. 11, pp. 1173–1179, 2005.
[17]
C. Termeer, F. Benedix, J. Sleeman et al., “Oligosaccharides of hyaluronan activate dendritic cells via Toll-like receptor 4,” Journal of Experimental Medicine, vol. 195, no. 1, pp. 99–111, 2002.
[18]
J. D. Powell and M. R. Horton, “Threat matrix: low-molecular-weight hyaluronan (HA) as a danger signal,” Immunologic Research, vol. 31, no. 3, pp. 207–218, 2005.
[19]
P. L. Bollyky, B. A. Falk, S. A. Long et al., “CD44 costimulation promotes FoxP3+ regulatory T cell persistence and function via production of IL-2, IL-10, and TGF-β,” Journal of Immunology, vol. 183, no. 4, pp. 2232–2241, 2009.
[20]
P. L. Bollyky, R. P. Wu, B. A. Falk et al., “ECM components guide IL-10 producing regulatory T-cell (TR1) induction from effector memory T-cell precursors,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 19, pp. 7938–7943, 2011.
[21]
T.-L. Huang, H.-C. Hsu, K.-C. Yang, and F.-H. Lin, “Hyaluronan up-regulates IL-10 expression in fibroblast-like synoviocytes from patients with tibia plateau fracture,” Journal of Orthopaedic Research, vol. 29, no. 4, pp. 495–500, 2011.
[22]
A. Asari, T. Kanemitsu, and H. Kurihara, “Oral administration of high molecular weight hyaluronan (900？kDa) controls immune system via toll-like receptor 4 in the intestinal epithelium,” Journal of Biological Chemistry, vol. 285, no. 32, pp. 24751–24758, 2010.
[23]
A. Gigante and L. Callegari, “The role of intra-articular hyaluronan (Sinovial) in the treatment of osteoarthritis,” Rheumatology International, vol. 31, no. 4, pp. 427–444, 2011.
[24]
Y. Kim, Y.-S. Lee, J.-H. Hahn et al., “Hyaluronic acid targets CD44 and inhibits FcεRI signaling involving PKCδ, Rac1, ROS, and MAPK to exert anti-allergic effect,” Molecular Immunology, vol. 45, no. 9, pp. 2537–2547, 2008.
[25]
Q. Zeng, Z. Yu, J. You, and Q. Zhang, “Efficacy and safety of seprafilm for preventing postoperative abdominal adhesion: systematic review and meta-analysis,” World Journal of Surgery, vol. 31, no. 11, pp. 2125–2131, 2007.
[26]
G. Kogan, L. ？oltés, R. Stern, and P. Gemeiner, “Hyaluronic acid: a natural biopolymer with a broad range of biomedical and industrial applications,” Biotechnology Letters, vol. 29, no. 1, pp. 17–25, 2007.
[27]
R. D. Price, V. Das-Gupta, I. M. Leigh, and H. A. Navsaria, “A comparison of tissue-engineered hyaluronic acid dermal matrices in a human wound model,” Tissue Engineering, vol. 12, no. 10, pp. 2985–2995, 2006.
[28]
G. Gravante, R. Sorge, A. Merone et al., “Hyalomatrix PA in burn care practice: results from a national retrospective survey, 2005 to 2006,” Annals of Plastic Surgery, vol. 64, no. 1, pp. 69–79, 2010.
[29]
G. D. Prestwich, X. Z. Shu, Y. Liu et al., “Injectable synthetic extracellular matrices for tissue engineering and repair,” Advances in Experimental Medicine and Biology, vol. 585, pp. 125–133, 2006.
[30]
R. B. Vernon, A. Preisinger, M. D. Gooden et al., “Reversal of diabetes in mice with a bioengineered islet implant incorporating a type I collagen hydrogel and sustained release of vascular endothelial growth factor,” Cell Transplantation, vol. 21, no. 10, pp. 2099–2110, 2012.
[31]
M. A. Serban, A. Scott, and G. D. Prestwich, “Use of hyaluronan-derived hydrogels for three-dimensional cell culture and tumor xenografts,” Current Protocols in Cell Biology, chapter 10, unit 10.14, 2008.
[32]
K. R. Kirker, Y. Luo, J. H. Nielson, J. Shelby, and G. D. Prestwich, “Glycosaminoglycan hydrogel films as bio-interactive dressings for wound healing,” Biomaterials, vol. 23, no. 17, pp. 3661–3671, 2002.
[33]
E. Laughlin, G. Burke, A. Pugliese, B. Falk, and G. Nepom, “Recurrence of autoreactive antigen-specific CD4+ T cells in autoimmune diabetes after pancreas transplantation,” Clinical Immunology, vol. 128, pp. 23–30, 2008.
[34]
F. Vendrame, A. Pileggi, E. Laughlin et al., “Recurrence of type 1 diabetes after simultaneous pancreas-kidney transplantation, despite immunosuppression, is associated with autoantibodies and pathogenic autoreactive CD4 T-cells,” Diabetes, vol. 59, pp. 947–957, 2010.
[35]
M. S. Rugg, A. C. Willis, D. Mukhopadhyay et al., “Characterization of complexes formed between TSG-6 and inter-α-inhibitor that act as intermediates in the covalent transfer of heavy chains onto hyaluronan,” Journal of Biological Chemistry, vol. 280, no. 27, pp. 25674–25686, 2005.
[36]
L. Zhuo and K. Kimata, “Structure and function of inter-α-trypsin inhibitor heavy chains,” Connective Tissue Research, vol. 49, no. 5, pp. 311–320, 2008.
[37]
D. Mukhopadhyay, A. Asari, M. S. Rugg, A. J. Day, and C. Fül？p, “Specificity of the tumor necrosis factor-induced protein 6-mediated heavy chain transfer from inter-α-trypsin inhibitor to hyaluronan: implications for the assembly of the cumulus extracellular matrix,” Journal of Biological Chemistry, vol. 279, no. 12, pp. 11119–11128, 2004.
