Abstract
Transplantation of alginate-encapsulated islets has the potential to treat patients suffering from type I diabetes, a condition characterized by an autoimmune attack against insulin-secreting beta cells. However, there are multiple immunological challenges associated with this procedure, all of which must be adequately addressed prior to translation from trials in small animal and nonhuman primate models to human clinical trials. Principal threats to graft viability include immune-mediated destruction triggered by immunogenic alginate impurities, unfavorable polymer composition and surface characteristics, and release of membrane-permeable antigens, as well as damage associated molecular patterns (DAMPs) by the encapsulated islets themselves. The lack of standardization of significant parameters of bioencapsulation device design and manufacture (i.e., purification protocols, surface-modification grafting techniques, alginate composition modifications) between labs is yet another obstacle that must be overcome before a clinically effective and applicable protocol for encapsulating islets can be implemented. Nonetheless, substantial progress is being made, as is evident from prolonged graft survival times and improved protection from immune-mediated graft destruction reported by various research groups, but also with regard to discoveries of specific pathways involved in explaining observed outcomes. Progress in the latter is essential for a comprehensive understanding of the mechanisms responsible for the varying levels of immunogenicity of certain alginate devices. Successful translation of encapsulated islet transplantation from in vitro and animal model testing to human clinical trials hinges on application of this knowledge of the pathways and interactions which comprise immune-mediated rejection. Thus, this review not only focuses on the different factors contributing to provocation of the immune reaction by encapsulated islets, but also on the defining characteristics of the response itself.
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References
Brennan DC, Kopetskie HA, Sayre PH, Alejandro R, Cagliero E, Shapiro AM, Goldstein JS, DesMarais MR, Booher S, Bianchine PJ (2015) Long-term follow-up of the Edmonton protocol of islet transplantation in the United States. Am J Transplant. doi:10.1111/ajt.13458
Dang TT, Thai AV, Cohen J, Slosberg JE, Siniakowicz K, Doloff JC, Ma M, Hollister-Lock J, Tang KM, Gu Z, Cheng H, Weir GC, Langer R, Anderson DG (2013) Enhanced function of immuno-isolated islets in diabetes therapy by co-encapsulation with an anti-inflammatory drug. Biomaterials 34(23):5792–5801. doi:10.1016/j.biomaterials.2013.04.016
Paredes Juarez GA, Spasojevic M, Faas MM, de Vos P (2014) Immunological and technical considerations in application of alginate-based microencapsulation systems. Frontiers Bioeng Biotechnol 2:26. doi:10.3389/fbioe.2014.00026
Mallett AG, Korbutt GS (2009) Alginate modification improves long-term survival and function of transplanted encapsulated islets. Tissue Eng Part A 15(6):1301–1309. doi:10.1089/ten.tea.2008.0118
de Vos P, van Hoogmoed CG, de Haan BJ, Busscher HJ (2002) Tissue responses against immunoisolating alginate-PLL capsules in the immediate posttransplant period. J Biomed Mater Res 62(3):430–437. doi:10.1002/jbm.10345
Kumar S, Ingle H, Prasad DV, Kumar H (2013) Recognition of bacterial infection by innate immune sensors. Crit Rev Microbiol 39(3):229–246. doi:10.3109/1040841X.2012.706249
Kawai T, Akira S (2010) The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 11(5):373–384. doi:10.1038/ni.1863
Pearl JI, Ma T, Irani AR, Huang Z, Robinson WH, Smith RL, Goodman SB (2011) Role of the Toll-like receptor pathway in the recognition of orthopedic implant wear-debris particles. Biomaterials 32(24):5535–5542. doi:10.1016/j.biomaterials.2011.04.046
De Vos P, De Haan B, Van Schilfgaarde R (1997) Effect of the alginate composition on the biocompatibility of alginate-polylysine microcapsules. Biomaterials 18(3):273–278
Dusseault J, Tam SK, Menard M, Polizu S, Jourdan G, Yahia L, Halle JP (2006) Evaluation of alginate purification methods: effect on polyphenol, endotoxin, and protein contamination. J Biomed Mater Res A 76(2):243–251. doi:10.1002/jbm.a.30541
Zimmermann U, Thurmer F, Jork A, Weber M, Mimietz S, Hillgartner M, Brunnenmeier F, Zimmermann H, Westphal I, Fuhr G, Noth U, Haase A, Steinert A, Hendrich C (2001) A novel class of amitogenic alginate microcapsules for long-term immunoisolated transplantation. Ann N Y Acad Sci 944:199–215
Tam SK, Dusseault J, Polizu S, Menard M, Halle JP, Yahia L (2006) Impact of residual contamination on the biofunctional properties of purified alginates used for cell encapsulation. Biomaterials 27(8):1296–1305. doi:10.1016/j.biomaterials.2005.08.027
de Haan BJ, Rossi A, Faas MM, Smelt MJ, Sonvico F, Colombo P, de Vos P (2011) Structural surface changes and inflammatory responses against alginate-based microcapsules after exposure to human peritoneal fluid. J Biomed Mater Res A 98(3):394–403. doi:10.1002/jbm.a.33123
de Vos P, van Hoogmoed CG, van Zanten J, Netter S, Strubbe JH, Busscher HJ (2003) Long-term biocompatibility, chemistry, and function of microencapsulated pancreatic islets. Biomaterials 24(2):305–312
Halle JP, Bourassa S, Leblond FA, Chevalier S, Beaudry M, Chapdelaine A, Cousineau S, Saintonge J, Yale JF (1993) Protection of islets of Langerhans from antibodies by microencapsulation with alginate-poly-l-lysine membranes. Transplantation 55(2):350–354
Paredes-Juarez GA, de Haan BJ, Faas MM, de Vos P (2013) The role of pathogen-associated molecular patterns in inflammatory responses against alginate based microcapsules. J Control Release 172(3):983–992. doi:10.1016/j.jconrel.2013.09.009
de Vos P, Spasojevic M, de Haan BJ, Faas MM (2012) The association between in vivo physicochemical changes and inflammatory responses against alginate based microcapsules. Biomaterials 33(22):5552–5559. doi:10.1016/j.biomaterials.2012.04.039
Ponce S, Orive G, Hernandez R, Gascon AR, Pedraz JL, de Haan BJ, Faas MM, Mathieu HJ, de Vos P (2006) Chemistry and the biological response against immunoisolating alginate-polycation capsules of different composition. Biomaterials 27(28):4831–4839. doi:10.1016/j.biomaterials.2006.05.014
Espevik T, Otterlei M, Skjak-Braek G, Ryan L, Wright SD, Sundan A (1993) The involvement of CD14 in stimulation of cytokine production by uronic acid polymers. Eur J Immunol 23(1):255–261. doi:10.1002/eji.1830230140
Otterlei M, Ostgaard K, Skjak-Braek G, Smidsrod O, Soon-Shiong P, Espevik T (1991) Induction of cytokine production from human monocytes stimulated with alginate. J Immunother 10(4):286–291
Tam SK, Bilodeau S, Dusseault J, Langlois G, Halle JP, Yahia LH (2011) Biocompatibility and physicochemical characteristics of alginate-polycation microcapsules. Acta Biomater 7(4):1683–1692. doi:10.1016/j.actbio.2010.12.006
Duvivier-Kali VF, Omer A, Parent RJ, O'Neil JJ, Weir GC (2001) Complete protection of islets against allorejection and autoimmunity by a simple barium-alginate membrane. Diabetes 50(8):1698–1705
Omer A, Duvivier-Kali V, Fernandes J, Tchipashvili V, Colton CK, Weir GC (2005) Long-term normoglycemia in rats receiving transplants with encapsulated islets. Transplantation 79(1):52–58
Orive G, Hernandez RM, Rodriguez Gascon A, Calafiore R, Chang TM, de Vos P, Hortelano G, Hunkeler D, Lacik I, Pedraz JL (2004) History, challenges and perspectives of cell microencapsulation. Trends Biotechnol 22(2):87–92
Tam SK, Dusseault J, Bilodeau S, Langlois G, Halle JP, Yahia L (2011) Factors influencing alginate gel biocompatibility. J Biomed Mater Res A 98(1):40–52. doi:10.1002/jbm.a.33047
Park H, Park K (1996) Biocompatibility issues of implantable drug delivery systems. Pharm Res 13(12):1770–1776
Juste S, Lessard M, Henley N, Menard M, Halle JP (2005) Effect of poly-l-lysine coating on macrophage activation by alginate-based microcapsules: assessment using a new in vitro method. J Biomed Mater Res A 72(4):389–398. doi:10.1002/jbm.a.30254
Vandenbossche GM, Bracke ME, Cuvelier CA, Bortier HE, Mareel MM, Remon JP (1993) Host reaction against empty alginate-polylysine microcapsules. Influence of preparation procedure. J Pharm Pharmacol 45(2):115–120
Thu B, Bruheim P, Espevik T, Smidsrod O, Soon-Shiong P, Skjak-Braek G (1996) Alginate polycation microcapsules. I. Interaction between alginate and polycation. Biomaterials 17(10):1031–1040
Darrabie MD, Kendall WF Jr, Opara EC (2005) Characteristics of poly-l-ornithine-coated alginate microcapsules. Biomaterials 26(34):6846–6852. doi:10.1016/j.biomaterials.2005.05.009
Gon S, Fang B, Santore MM (2011) Interaction of cationic proteins and polypeptides with biocompatible cationically-anchored PEG brushes. Macromolecules 44(20)
Veronese FM, Mero A (2008) The impact of PEGylation on biological therapies. BioDrugs 22(5):315–329
van Schilfgaarde R, de Vos P (1999) Factors influencing the properties and performance of microcapsules for immunoprotection of pancreatic islets. J Mol Med 77(1):199–205
Safley SA, Cui H, Cauffiel S, Tucker-Burden C, Weber CJ (2008) Biocompatibility and immune acceptance of adult porcine islets transplanted intraperitoneally in diabetic NOD mice in calcium alginate poly-l-lysine microcapsules versus barium alginate microcapsules without poly-l-lysine. J Diabetes Sci Technol 2(5):760–767
Qi M, Morch Y, Lacik I, Formo K, Marchese E, Wang Y, Danielson KK, Kinzer K, Wang S, Barbaro B, Kollarikova G, Chorvat D Jr, Hunkeler D, Skjak-Braek G, Oberholzer J, Strand BL (2012) Survival of human islets in microbeads containing high guluronic acid alginate crosslinked with Ca2+ and Ba2+. Xenotransplantation 19(6):355–364. doi:10.1111/xen.12009
Morch YA, Qi M, Gundersen PO, Formo K, Lacik I, Skjak-Braek G, Oberholzer J, Strand BL (2012) Binding and leakage of barium in alginate microbeads. J Biomed Mater Res A 100(11):2939–2947. doi:10.1002/jbm.a.34237
Morch YA, Donati I, Strand BL, Skjak-Braek G (2006) Effect of Ca2+, Ba2+, and Sr2+ on alginate microbeads. Biomacromolecules 7(5):1471–1480. doi:10.1021/bm060010d
Li HB, Jiang H, Wang CY, Duan CM, Ye Y, Su XP, Kong QX, Wu JF, Guo XM (2006) Comparison of two types of alginate microcapsules on stability and biocompatibility in vitro and in vivo. Biomed Mater 1(1):42–47. doi:10.1088/1748-6041/1/1/007
Elbert DL, Herbert CB, Hubbell JA (1999) Thin polymer layers formed by polyelectrolyte multilayer techniques on biological surfaces. Langmuir 15(16)
Elliott RB, Escobar L, Tan PL, Garkavenko O, Calafiore R, Basta P, Vasconcellos AV, Emerich DF, Thanos C, Bambra C (2005) Intraperitoneal alginate-encapsulated neonatal porcine islets in a placebo-controlled study with 16 diabetic cynomolgus primates. Transplant Proc 37(8):3505–3508. doi:10.1016/j.transproceed.2005.09.038
Tuch BE, Keogh GW, Williams LJ, Wu W, Foster JL, Vaithilingam V, Philips R (2009) Safety and viability of microencapsulated human islets transplanted into diabetic humans. Diabetes Care 32(10):1887–1889. doi:10.2337/dc09-0744
Vaithilingam V, Fung C, Ratnapala S, Foster J, Vaghjiani V, Manuelpillai U, Tuch BE (2013) Characterisation of the xenogeneic immune response to microencapsulated fetal pig islet-like cell clusters transplanted into immunocompetent C57BL/6 mice. PLoS One 8(3):e59120. doi:10.1371/journal.pone.0059120
Bennet W, Bjorkland A, Sundberg B, Davies H, Liu J, Holgersson J, Korsgren O (2000) A comparison of fetal and adult porcine islets with regard to Gal alpha (1,3)Gal expression and the role of human immunoglobulins and complement in islet cell cytotoxicity. Transplantation 69(8):1711–1717
Marigliano M, Bertera S, Grupillo M, Trucco M, Bottino R (2011) Pig-to-nonhuman primates pancreatic islet xenotransplantation: an overview. Curr Diab Rep 11(5):402–412. doi:10.1007/s11892-011-0213-z
Rayat GR, Rajotte RV, Hering BJ, Binette TM, Korbutt GS (2003) In vitro and in vivo expression of Galalpha-(1,3)Gal on porcine islet cells is age dependent. J Endocrinol 177(1):127–135
Bai L, Tuch BE, Hering B, Simpson AM (2002) Fetal pig beta cells are resistant to the toxic effects of human cytokines. Transplantation 73(5):714–722
Nagaraju S, Bottino R, Wijkstrom M, Trucco M, Cooper DK (2015) Islet xenotransplantation: what is the optimal age of the islet-source pig? Xenotransplantation 22(1):7–19. doi:10.1111/xen.12130
de Vos P, Wolters GH, van Schilfgaarde R (1994) Possible relationship between fibrotic overgrowth of alginate-polylysine-alginate microencapsulated pancreatic islets and the microcapsule integrity. Transplant Proc 26(2):782–783
Omori T, Nishida T, Komoda H, Fumimoto Y, Ito T, Sawa Y, Gao C, Nakatsu S, Shirakura R, Miyagawa S (2006) A study of the xenoantigenicity of neonatal porcine islet-like cell clusters (NPCC) and the efficiency of adenovirus-mediated DAF (CD55) expression. Xenotransplantation 13(5):455–464. doi:10.1111/j.1399-3089.2006.00335.x
Rayat GR, Johnson ZA, Beilke JN, Korbutt GS, Rajotte RV, Gill RG (2003) The degree of phylogenetic disparity of islet grafts dictates the reliance on indirect CD4 T-cell antigen recognition for rejection. Diabetes 52(6):1433–1440
Chitilian HV, Laufer TM, Stenger K, Shea S, Auchincloss H Jr (1998) The strength of cell-mediated xenograft rejection in the mouse is due to the CD4+ indirect response. Xenotransplantation 5(1):93–98
Dufrane D, Goebbels RM, Saliez A, Guiot Y, Gianello P (2006) Six-month survival of microencapsulated pig islets and alginate biocompatibility in primates: proof of concept. Transplantation 81(9):1345–1353. doi:10.1097/01.tp.0000208610.75997.20
Kobayashi T, Harb G, Rajotte RV, Korbutt GS, Mallett AG, Arefanian H, Mok D, Rayat GR (2006) Immune mechanisms associated with the rejection of encapsulated neonatal porcine islet xenografts. Xenotransplantation 13(6):547–559. doi:10.1111/j.1399-3089.2006.00349.x
Kobayashi T, Harb G, Rayat GR (2005) Prolonged survival of microencapsulated neonatal porcine islets in mice treated with a combination of anti-CD154 and anti-LFA-1 monoclonal antibodies. Transplantation 80(6):821–827
Rayat GR, Gill RG (2005) Indefinite survival of neonatal porcine islet xenografts by simultaneous targeting of LFA-1 and CD154 or CD45RB. Diabetes 54(2):443–451
Rayat GR, Rajotte RV, Ao Z, Korbutt GS (2000) Microencapsulation of neonatal porcine islets: protection from human antibody/complement-mediated cytolysis in vitro and long-term reversal of diabetes in nude mice. Transplantation 69(6):1084–1090
Siebers U, Horcher A, Brandhorst H, Brandhorst D, Hering B, Federlin K, Bretzel RG, Zekorn T (1999) Analysis of the cellular reaction towards microencapsulated xenogeneic islets after intraperitoneal transplantation. J Mol Med 77(1):215–218
Yi S, Hawthorne WJ, Lehnert AM, Ha H, Wong JK, van Rooijen N, Davey K, Patel AT, Walters SN, Chandra A, O'Connell PJ (2003) T cell-activated macrophages are capable of both recognition and rejection of pancreatic islet xenografts. J Immunol 170(5):2750–2758
Omer A, Keegan M, Czismadia E, De Vos P, Van Rooijen N, Bonner-Weir S, Weir GC (2003) Macrophage depletion improves survival of porcine neonatal pancreatic cell clusters contained in alginate macrocapsules transplanted into rats. Xenotransplantation 10(3):240–251
Andersen HU, Jorgensen KH, Egeberg J, Mandrup-Poulsen T, Nerup J (1994) Nicotinamide prevents interleukin-1 effects on accumulated insulin release and nitric oxide production in rat islets of Langerhans. Diabetes 43(6):770–777
Tu J, Khoury P, Williams L, Tuch BE (2004) Comparison of fetal porcine aggregates of purified beta-cells versus islet-like cell clusters as a treatment of diabetes. Cell Transplant 13(5):525–534
Solomon MF, Kuziel WA, Mann DA, Simeonovic CJ (2003) The role of chemokines and their receptors in the rejection of pig islet tissue xenografts. Xenotransplantation 10(2):164–177
Koulmanda M, Laufer TM, Auchincloss H Jr, Smith RN (2004) Prolonged survival of fetal pig islet xenografts in mice lacking the capacity for an indirect response. Xenotransplantation 11(6):525–530. doi:10.1111/j.1399-3089.2004.00174.x
Krook H, Hagberg A, Song Z, Landegren U, Wennberg L, Korsgren O (2002) A distinct Th1 immune response precedes the described Th2 response in islet xenograft rejection. Diabetes 51(1):79–86
Foster JL, Williams G, Williams LJ, Tuch BE (2007) Differentiation of transplanted microencapsulated fetal pancreatic cells. Transplantation 83(11):1440–1448. doi:10.1097/01.tp.0000264555.46417.7d
Vaithilingam V, Kollarikova G, Qi M, Lacik I, Oberholzer J, Guillemin GJ, Tuch BE (2011) Effect of prolonged gelling time on the intrinsic properties of barium alginate microcapsules and its biocompatibility. J Microencapsul 28(6):499–507. doi:10.3109/02652048.2011.586067
Vaithilingam V, Oberholzer J, Guillemin GJ, Tuch BE (2010) The humanized NOD/SCID mouse as a preclinical model to study the fate of encapsulated human islets. The review of diabetic studies. Rev Diabet Stud 7(1):62–73. doi:10.1900/RDS.2010.7.62
Candinas D, Belliveau S, Koyamada N, Miyatake T, Hechenleitner P, Mark W, Bach FH, Hancock WW (1996) T cell independence of macrophage and natural killer cell infiltration, cytokine production, and endothelial activation during delayed xenograft rejection. Transplantation 62(12):1920–1927
Lin Y, Vandeputte M, Waer M (1997) Natural killer cell- and macrophage-mediated rejection of concordant xenografts in the absence of T and B cell responses. J Immunol 158(12):5658–5667
Basu S, Binder RJ, Suto R, Anderson KM, Srivastava PK (2000) Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-kappa B pathway. Int Immunol 12(11):1539–1546
Byrd CA, Bornmann W, Erdjument-Bromage H, Tempst P, Pavletich N, Rosen N, Nathan CF, Ding A (1999) Heat shock protein 90 mediates macrophage activation by Taxol and bacterial lipopolysaccharide. Proc Natl Acad Sci U S A 96(10):5645–5650
Vilcek J, Palombella VJ, Henriksen-DeStefano D, Swenson C, Feinman R, Hirai M, Tsujimoto M (1986) Fibroblast growth enhancing activity of tumor necrosis factor and its relationship to other polypeptide growth factors. J Exp Med 163(3):632–643
Komoda H, Miyagawa S, Kubo T, Kitano E, Kitamura H, Omori T, Ito T, Matsuda H, Shirakura R (2004) A study of the xenoantigenicity of adult pig islets cells. Xenotransplantation 11(3):237–246. doi:10.1111/j.1399-3089.2004.00121.x
Bennet W, Sundberg B, Lundgren T, Tibell A, Groth CG, Richards A, White DJ, Elgue G, Larsson R, Nilsson B, Korsgren O (2000) Damage to porcine islets of Langerhans after exposure to human blood in vitro, or after intraportal transplantation to cynomolgus monkeys: protective effects of sCR1 and heparin. Transplantation 69(5):711–719
Mandel TE, Dillon H, Koulmanda M (1995) The effect of a depleting anti-CD4 monoclonal antibody on T cells and fetal pig islet xenograft survival in various strains of mice. Transpl Immunol 3(3):265–272
Simeonovic CJ, Ceredig R, Wilson JD (1990) Effect of GK1.5 monoclonal antibody dosage on survival of pig proislet xenografts in CD4+ T cell-depleted mice. Transplantation 49(5):849–856
Wilson JD, Simeonovic CJ, Ting JH, Ceredig R (1989) Role of CD4+ T-lymphocytes in rejection by mice of fetal pig proislet xenografts. Diabetes 38(Suppl 1):217–219
Benda B, Karlsson-Parra A, Ridderstad A, Korsgren O (1996) Xenograft rejection of porcine islet-like cell clusters in immunoglobulin- or Fc-receptor gamma-deficient mice. Transplantation 62(9):1207–1211
Simeonovic CJ, McKenzie KU, Wilson JD, Zarb JC, Hodgkin PD (1998) Role of anti-donor antibody in the rejection of pig proislet xenografts in mice. Xenotransplantation 5(1):18–28
Cui H, Tucker-Burden C, Cauffiel SM, Barry AK, Iwakoshi NN, Weber CJ, Safley SA (2009) Long-term metabolic control of autoimmune diabetes in spontaneously diabetic nonobese diabetic mice by nonvascularized microencapsulated adult porcine islets. Transplantation 88(2):160–169. doi:10.1097/TP.0b013e3181abbfc1
Safley SA, Kapp LM, Tucker-Burden C, Hering B, Kapp JA, Weber CJ (2005) Inhibition of cellular immune responses to encapsulated porcine islet xenografts by simultaneous blockade of two different costimulatory pathways. Transplantation 79(4):409–418
Hering BJ, Wijkstrom M, Graham ML, Hardstedt M, Aasheim TC, Jie T, Ansite JD, Nakano M, Cheng J, Li W, Moran K, Christians U, Finnegan C, Mills CD, Sutherland DE, Bansal-Pakala P, Murtaugh MP, Kirchhof N, Schuurman HJ (2006) Prolonged diabetes reversal after intraportal xenotransplantation of wild-type porcine islets in immunosuppressed nonhuman primates. Nat Med 12(3):301–303. doi:10.1038/nm1369
Kirchhof N, Shibata S, Wijkstrom M, Kulick DM, Salerno CT, Clemmings SM, Heremans Y, Galili U, Sutherland DE, Dalmasso AP, Hering BJ (2004) Reversal of diabetes in non-immunosuppressed rhesus macaques by intraportal porcine islet xenografts precedes acute cellular rejection. Xenotransplantation 11(5):396–407. doi:10.1111/j.1399-3089.2004.00157.x
Thompson P, Cardona K, Russell M, Badell IR, Shaffer V, Korbutt G, Rayat GR, Cano J, Song M, Jiang W, Strobert E, Rajotte R, Pearson T, Kirk AD, Larsen CP (2011) CD40-specific costimulation blockade enhances neonatal porcine islet survival in nonhuman primates. Am J Transplant 11(5):947–957. doi:10.1111/j.1600-6143.2011.03509.x
Cardona K, Korbutt GS, Milas Z, Lyon J, Cano J, Jiang W, Bello-Laborn H, Hacquoil B, Strobert E, Gangappa S, Weber CJ, Pearson TC, Rajotte RV, Larsen CP (2006) Long-term survival of neonatal porcine islets in nonhuman primates by targeting costimulation pathways. Nat Med 12(3):304–306. doi:10.1038/nm1375
Casu A, Bottino R, Balamurugan AN, Hara H, van der Windt DJ, Campanile N, Smetanka C, Cooper DK, Trucco M (2008) Metabolic aspects of pig-to-monkey (Macaca fascicularis) islet transplantation: implications for translation into clinical practice. Diabetologia 51(1):120–129. doi:10.1007/s00125-007-0844-4
van der Windt DJ, Bottino R, Casu A, Campanile N, Smetanka C, He J, Murase N, Hara H, Ball S, Loveland BE, Ayares D, Lakkis FG, Cooper DK, Trucco M (2009) Long-term controlled normoglycemia in diabetic non-human primates after transplantation with hCD46 transgenic porcine islets. Am J Transplant 9(12):2716–2726. doi:10.1111/j.1600-6143.2009.02850.x
Graham ML, Mutch LA, Rieke EF, Kittredge JA, Faig AW, DuFour TA, Munson JW, Zolondek EK, Hering BJ, Schuurman HJ (2011) Refining the high-dose streptozotocin-induced diabetic non-human primate model: an evaluation of risk factors and outcomes. Exp Biol Med 236(10):1218–1230. doi:10.1258/ebm.2011.011064
Sun Y, Ma X, Zhou D, Vacek I, Sun AM (1996) Normalization of diabetes in spontaneously diabetic cynomolgus monkeys by xenografts of microencapsulated porcine islets without immunosuppression. J Clin Invest 98(6):1417–1422. doi:10.1172/JCI118929
Dufrane D, Goebbels RM, Gianello P (2010) Alginate macroencapsulation of pig islets allows correction of streptozotocin-induced diabetes in primates up to 6 months without immunosuppression. Transplantation 90(10):1054–1062. doi:10.1097/TP.0b013e3181f6e267
Nauta AJ, Fibbe WE (2007) Immunomodulatory properties of mesenchymal stromal cells. Blood 110(10):3499–3506. doi:10.1182/blood-2007-02-069716
English K (2013) Mechanisms of mesenchymal stromal cell immunomodulation. Immunol Cell Biol 91(1):19–26. doi:10.1038/icb.2012.56
English K, Barry FP, Field-Corbett CP, Mahon BP (2007) IFN-gamma and TNF-alpha differentially regulate immunomodulation by murine mesenchymal stem cells. Immunol Lett 110(2):91–100. doi:10.1016/j.imlet.2007.04.001
Ge W, Jiang J, Arp J, Liu W, Garcia B, Wang H (2010) Regulatory T-cell generation and kidney allograft tolerance induced by mesenchymal stem cells associated with indoleamine 2,3-dioxygenase expression. Transplantation 90(12):1312–1320. doi:10.1097/TP.0b013e3181fed001
Francois M, Romieu-Mourez R, Li M, Galipeau J (2012) Human MSC suppression correlates with cytokine induction of indoleamine 2,3-dioxygenase and bystander M2 macrophage differentiation. Mol Ther 20(1):187–195. doi:10.1038/mt.2011.189
Nemeth K, Leelahavanichkul A, Yuen PS, Mayer B, Parmelee A, Doi K, Robey PG, Leelahavanichkul K, Koller BH, Brown JM, Hu X, Jelinek I, Star RA, Mezey E (2009) Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med 15(1):42–49. doi:10.1038/nm.1905
English K, Barry FP, Mahon BP (2008) Murine mesenchymal stem cells suppress dendritic cell migration, maturation and antigen presentation. Immunol Lett 115(1):50–58. doi:10.1016/j.imlet.2007.10.002
Ren G, Zhang L, Zhao X, Xu G, Zhang Y, Roberts AI, Zhao RC, Shi Y (2008) Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell 2(2):141–150. doi:10.1016/j.stem.2007.11.014
Klyushnenkova E, Mosca JD, Zernetkina V, Majumdar MK, Beggs KJ, Simonetti DW, Deans RJ, McIntosh KR (2005) T cell responses to allogeneic human mesenchymal stem cells: immunogenicity, tolerance, and suppression. J Biomed Sci 12(1):47–57. doi:10.1007/s11373-004-8183-7
Le Blanc K, Ringden O (2007) Immunomodulation by mesenchymal stem cells and clinical experience. J Intern Med 262(5):509–525. doi:10.1111/j.1365-2796.2007.01844.x
Augello A, Tasso R, Negrini SM, Amateis A, Indiveri F, Cancedda R, Pennesi G (2005) Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway. Eur J Immunol 35(5):1482–1490. doi:10.1002/eji.200425405
Li YP, Paczesny S, Lauret E, Poirault S, Bordigoni P, Mekhloufi F, Hequet O, Bertrand Y, Ou-Yang JP, Stoltz JF, Miossec P, Eljaafari A (2008) Human mesenchymal stem cells license adult CD34+ hemopoietic progenitor cells to differentiate into regulatory dendritic cells through activation of the Notch pathway. J Immunol 180(3):1598–1608
Perez-Basterrechea M, Obaya AJ, Meana A, Otero J, Esteban MM (2013) Cooperation by fibroblasts and bone marrow-mesenchymal stem cells to improve pancreatic rat-to-mouse islet xenotransplantation. PLoS One 8(8): e73526. doi:10.1371/journal.pone.0073526
Wu H, Wen D, Mahato RI (2013) Third-party mesenchymal stem cells improved human islet transplantation in a humanized diabetic mouse model. Mol Ther 21(9):1778–1786. doi:10.1038/mt.2013.147
Berman DM, Willman MA, Han D, Kleiner G, Kenyon NM, Cabrera O, Karl JA, Wiseman RW, O'Connor DH, Bartholomew AM, Kenyon NS (2010) Mesenchymal stem cells enhance allogeneic islet engraftment in nonhuman primates. Diabetes 59(10):2558–2568. doi:10.2337/db10-0136
Ding Y, Xu D, Feng G, Bushell A, Muschel RJ, Wood KJ (2009) Mesenchymal stem cells prevent the rejection of fully allogenic islet grafts by the immunosuppressive activity of matrix metalloproteinase-2 and -9. Diabetes 58(8):1797–1806. doi:10.2337/db09-0317
Longoni B, Szilagyi E, Quaranta P, Paoli GT, Tripodi S, Urbani S, Mazzanti B, Rossi B, Fanci R, Demontis GC, Marzola P, Saccardi R, Cintorino M, Mosca F (2010) Mesenchymal stem cells prevent acute rejection and prolong graft function in pancreatic islet transplantation. Diabetes Technol Ther 12(6):435–446. doi:10.1089/dia.2009.0154
Mundra V, Wu H, Mahato RI (2013) Genetically modified human bone marrow derived mesenchymal stem cells for improving the outcome of human islet transplantation. PLoS One 8(10):e77591. doi:10.1371/journal.pone.0077591
Park HS, Kim JW, Lee SH, Yang HK, Ham DS, Sun CL, Hong TH, Khang G, Park CG, Yoon KH (2015) Antifibrotic effect of rapamycin containing polyethylene glycol-coated alginate microcapsule in islet xenotransplantation. J Tissue Eng Regen Med. doi:10.1002/term.2029
Vaithilingam V, Kollarikova G, Qi M, Larsson R, Lacik I, Formo K, Marchese E, Oberholzer J, Guillemin GJ, Tuch BE (2014) Beneficial effects of coating alginate microcapsules with macromolecular heparin conjugates-in vitro and in vivo study. Tissue Eng Part A 20(1–2):324–334. doi:10.1089/ten.TEA.2013.0254
Ma M, Chiu A, Sahay G, Doloff JC, Dholakia N, Thakrar R, Cohen J, Vegas A, Chen D, Bratlie KM, Dang T, York RL, Hollister-Lock J, Weir GC, Anderson DG (2013) Core-shell hydrogel microcapsules for improved islets encapsulation. Adv Healthcare Mater 2(5):667–672. doi:10.1002/adhm.201200341
Tomei AA, Manzoli V, Fraker CA, Giraldo J, Velluto D, Najjar M, Pileggi A, Molano RD, Ricordi C, Stabler CL, Hubbell JA (2014) Device design and materials optimization of conformal coating for islets of Langerhans. Proc Natl Acad Sci U S A 111(29):10514–10519. doi:10.1073/pnas.1402216111
Chen T, Yuan J, Duncanson S, Hibert ML, Kodish BC, Mylavaganam G, Maker M, Li H, Sremac M, Santosuosso M, Forbes B, Kashiwagi S, Cao J, Lei J, Thomas M, Hartono C, Sachs D, Markmann J, Sambanis A, Poznansky MC (2015) Alginate encapsulant incorporating CXCL12 supports long-term allo- and xenoislet transplantation without systemic immune suppression. Am J Transplant 15(3):618–627. doi:10.1111/ajt.13049
Park JB, Jeong JH, Lee M, Lee DY, Byun Y (2013) Xenotransplantation of exendin-4 gene transduced pancreatic islets using multi-component (alginate, poly-l-lysine, and polyethylene glycol) microcapsules for the treatment of type 1 diabetes mellitus. J Biomater Sci Polym Ed 24(18):2045–2057. doi:10.1080/09205063.2013.823071
Acknowledgements
The authors gratefully acknowledge Esther Yu-Tin Chen from the Department of Biomedical Engineering, University of California, Irvine for providing illustrations for this chapter.
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Krishnan, R. et al. (2017). Immunological Challenges Facing Translation of Alginate Encapsulated Porcine Islet Xenotransplantation to Human Clinical Trials. In: Opara, E. (eds) Cell Microencapsulation. Methods in Molecular Biology, vol 1479. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-6364-5_24
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DOI: https://doi.org/10.1007/978-1-4939-6364-5_24
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