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Clinical Islet Cell Transplantation – Recent Advances


Affiliations
1 Baylor Research Institute, Dallas, Texas, United States
2 Clinical Islet Cell Laboratory, Centre for Cellular Transplantation, Cardiovascular Innovation Institute, Department of Surgery, University of Louisville, Louisville, KY, United States
 

Type-1 diabetes mellitus (T1DM) caused by autoimmune destruction of insulin-producing beta-cells essentially requires treatment with exogenous insulin therapy. Despite the education, technology and improvements in insulin formulations, patients face the ongoing life-threatening hypoglycaemia with poor quality of life as well as progressive disease leading to micro-and macro-vascular complications of diabetes. Islet transplantation offers an alternative therapeutic option for these patients. In this review, we discuss the recent advancements in this field tracking from the history of pancreatic islet transplantation to the present-day challenges of clinical islet cell transplantation. We summarize the cutting-edge clinical research with special reference to the results of current trials, including Clinical Islet Transplant Consortium, improvements in immuno-suppressive protocols, the need for beta-cell replacement therapies, including the application of induced pluripotent stem cells and mesenchymal stem cells.

Keywords

Diabetes, Insulin, Islet Cell Transplantation, Immunosuppression, Stem Cells.
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  • Banting, F. G., Best, C. H., Collip, J. B., Campbell, W. R. and Fletcher, A. A., Pancreatic extracts in the treatment of diabetes mellitus. Can. Med. Assoc. J., 1922, 12(3), 141–146.

  • Polonsky, K. S., The past 200 years in diabetes. N. Engl. J. Med., 2012, 367(14), 1332–1340.

  • Lacy, P. E. and Kostianovsky, M., Method for the isolation of intact islets of Langerhans from the rat pancreas. Diabetes, 1967, 16(1), 35–39.

  • Lakey, J. R., Burridge, P. W. and Shapiro, A. M., Technical aspects of islet preparation and transplantation. Transplant. Int., 2003, 16(9), 613–632.

  • Najarian, J. S., Sutherland, D. E., Matas, A. J., Steffes, M. W., Simmons, R. L. and Goetz, F. C., Human islet transplantation: a preliminary report. Transplant. Proc., 1977, 9(1), 233–236.

  • Ricordi, C., Lacy, P. E., Finke, E. H., Olack, B. J. and Scharp, D. W., Automated method for isolation of human pancreatic islets. Diabetes, 1988, 37(4), 413–420.

  • Carroll, P. B. et al., Intrahepatic human islet transplantation at the University of Pittsburgh: results in 25 consecutive cases. Transplant. Proc., 1992, 24(6), 3038–3039.

  • Shapiro, A. M. et al., Islet transplantation in seven patients with type-1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N. Engl. J. Med., 2000, 343(4), 230–238.

  • Shapiro, A. M. et al., International trial of the Edmonton Protocol for islet transplantation. N. Engl. J. Med., 2006, 355(13), 1318–1330.

  • Shapiro, A. M., Lakey, J. R., Paty, B. W., Senior, P. A., Bigam, D. L. and Ryan, E. A., Strategic opportunities in clinical islet transplantation. Transplantation, 2005, 79(10), 1304–1307.

  • Gaglia, J. L., Shapiro, A. M. and Weir, G. C., Islet transplantation: progress and challenge. Arch. Med. Res., 2005, 36(3), 273–280.

  • The NIH CIT Consortium, Purified human pancreatic islets (PHPI) master production batch record – a standard operating procedure of the NIH Clinical Islet Transplantation Consortium. CellR4, 2014, 1(1); http://www.cellr4.org/article/891.

  • The NIH CIT Consortium, Standard Methods and operating procedures, CellR4, 2014, 1(1); http://www.cellr4.org/article/891

  • Balamurugan, A. N. et al., Islet product characteristics and factors related to successful human islet transplantation from the Collaborative Islet Transplant Registry (CITR) 1999–2010. Am. J. Transplant., 2014, 14(11), 2595–2606.

  • Bruni, A., Gala-Lopez, B., Pepper, A. R., Abualhassan, N. S. and Shapiro, A. J., Islet cell transplantation for the treatment of type1 diabetes: recent advances and future challenges. Diabetes Metab. Syndr. Obes., 2014, 7, 211–223.

  • Barton, F. B. et al., Improvement in outcomes of clinical islet transplantation: 1999–2010. Diabetes Care, 2012, 35(7), 1436–1345.

  • Hering, B. J. et al., Phase 3 trial of transplantation of human islets in type-1 diabetes complicated by severe hypoglycemia. Diabetes Care, 2016, 39(7), 1230–1240.

  • Kanak, M. A. et al., Alleviation of instant blood mediated inflammatory reaction in autologous conditions through treatment of human islets with NF-B inhibitors. Transplantation, 2014, 98(5), 578–584.

  • Bennet, W. et al., Incompatibility between human blood and isolated islets of Langerhans: a finding with implications for clinical intraportal islet transplantation? Diabetes, 1999, 48(10), 1907–1914.

  • Moberg, L. et al., Production of tissue factor by pancreatic islet cells as a trigger of detrimental thrombotic reactions in clinical islet transplantation. Lancet, 2002, 360(9350), 2039–2045.

  • Nilsson, B., Ekdahl, K. N. and Korsgren, O., Control of instant blood-mediated inflammatory reaction to improve islets of Langerhans engraftment. Curr. Opin. Organ. Transplant., 2011, 16(6), 620–626.

  • Naziruddin, B., Iwahashi, S., Kanak, M. A., Takita, M., Itoh, T. and Levy, M. F., Evidence for instant blood-mediated inflammatory reaction in clinical autologous islet transplantation. Am. J. Transplant., 2014, 14(2), 428–437.

  • Tjernberg, J., Ekdahl, K. N., Lambris, J. D., Korsgren, O. and Nilsson, B., Acute antibody-mediated complement activation mediates lysis of pancreatic islets cells and may cause tissue loss in clinical islet transplantation. Transplantation, 2008, 85(8), 1193–1199.

  • Fujita, E., Farkas, I., Campbell, W., Baranyi, L., Okada, H. and Okada, N., Inactivation of C5a anaphylatoxin by a peptide that is complementary to a region of C5a. J. Immunol., 2004, 172(10), 6382–6387.

  • Ritis, K. et al., A novel C5a receptor-tissue factor cross-talk in neutrophils links innate immunity to coagulation pathways. J. Immunol., 2006, 177(7), 4794–4802.

  • Goto, M. et al., Dissecting the instant blood-mediated inflammatory reaction in islet xenotransplantation. Xenotransplantation, 2008, 15(4), 225–234.

  • Rajab, A., Islet transplantation: alternative sites. Curr. Diab. Rep., 2010, 10(5), 332–337.

  • Kin, T., Korbutt, G. S. and Rajotte, R. V., Survival and metabolic function of syngeneic rat islet grafts transplanted in the omental pouch. Am. J. Transplant., 2003, 3(3), 281–285.

  • Al-Abdullah, I. H., Anil Kumar, M. S., Kelly-Sullivan, D. and Abouna, G. M., Site for unpurified islet transplantation is an important parameter for determination of the outcome of graft survival and function. Cell Transplant., 1995, 4(3), 297–305.

  • Berman, D. M. et al., Bioengineering the endocrine pancreas: intraomental islet transplantation within a biologic resorbable scaffold. Diabetes, 2016, 65(5), 1350–1361.

  • Berman, D. M. et al., Long-term survival of nonhuman primate islets implanted in an omental pouch on a biodegradable scaffold. Am. J. Transplant., 2009, 9(1), 91–104.

  • Calne, R. Y. et al., Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases, and 2 livers. Lancet, 1979, 2(8151), 1033–1036.

  • Ozbay, L. A., Smidt, K., Mortensen, D. M., Carstens, J., Jorgensen, K. A. and Rungby, J., Cyclosporin and tacrolimus impair insulin secretion and transcriptional regulation in INS-1E betacells. Br. J. Pharmacol., 2011, 162(1), 136–146.

  • Andersson, A., Borg, H., Hallberg, A., Hellerstrom, C., Sandler, S. and Schnell, A., Long-term effects of cyclosporin A on cultured mouse pancreatic islets. Diabetologia, 1984, 27(Suppl.), 66–69.

  • Robertson, R. P., Cyclosporin-induced inhibition of insulin secretion in isolated rat islets and HIT cells. Diabetes, 1986, 35(9), 1016–1019.

  • Nielsen, J. H., Mandruppoulsen, T. and Nerup, J., Direct effects of cyclosporine-a on human pancreatic beta-cells. Diabetes, 1986, 35(9), 1049–1052.

  • Yoshimura, N., Matsui, S., Hamashima, T. and Oka, T., Effect of a new immunosuppressive agent, FK506, on human lymphocyte responses in vitro. II. Inhibition of the production of IL-2 and gamma-IFN, but not B cell-stimulating factor 2. Transplantation, 1989, 47(2), 356–359.

  • Yakimets, W. J. et al., Prolongation of canine pancreatic islet allograft survival with combined rapamycin and cyclosporine therapy at low doses. Rapamycin efficacy is blood level related. Transplantation, 1993, 56(6), 1293–1298.

  • Shibata, S. et al., Temporary treatment with sirolimus and lowtrough cyclosporine prevents acute islet allograft rejection, and combination with starch-conjugated deferoxamine promotes islet engraftment in the preclinical pig model. Transplant. Proc., 2001, 33(1–2), 509.

  • Korsgren, O., Islet encapsulation: physiological possibilities and limitations. Diabetes, 2017, 66(7), 1748–1754.

  • Farney, A. C. et al., Inhibition of pancreatic islet beta cell function by tumor necrosis factor is blocked by a soluble tumor necrosis factor receptor. Transplant. Proc., 1993, 25(1 Pt 2), 865–866.

  • Maffi, P. et al., Kidney function after islet transplant alone in type-1 diabetes: impact of immunosuppressive therapy on progression of diabetic nephropathy. Diabetes Care, 2007, 30(5), 1150–1155.

  • Pepper, A. R., Gala-Lopez, B., Ziff, O. and Shapiro, A. J., Current status of clinical islet transplantation. World J. Transplant., 2013, 3(4), 48–53.

  • Posselt, A. M. et al., Islet transplantation in type-1 diabetics using an immunosuppressive protocol based on the anti-LFA-1 antibody efalizumab. Am. J. Transplant., 2010, 10(8), 1870–1780.

  • Turgeon, N. A. et al., Experience with a novel efalizumab-based immunosuppressive regimen to facilitate single donor islet cell transplantation. Am. J. Transplant., 2010, 10(9), 2082–2091.

  • Chang, C. A., Haque, W. Z., Yoshimatsu, G., Balajii, P. S., Lawrence, M. C. and Naziruddin, B., Monitoring of beta cell replacement outcomes. Panminerva Med., 2016, 58(1), 59–71.

  • Bonifacio, E., Predicting type-1 diabetes using biomarkers. Diabetes Care, 2015, 38(6), 989–996.

  • Itoh, T. et al., Correlation of released HMGB1 levels with the degree of islet damage in mice and humans and with the outcomes of islet transplantation in mice. Cell Transplant., 2012; 21(7), 1371–1381.

  • Ling, Z. et al., Plasma GAD65, a marker for early beta-cell loss after intraportal islet cell transplantation in diabetic patients. J. Clin. Endocrinol. Metab., 2015, 100(6), 2314–2321.

  • Jiang, L. et al., Potential of protein phosphatase inhibitor 1 as biomarker of pancreatic beta-cell injury in vitro and in vivo. Diabetes. 2013, 62(8), 2683–2688.

  • Poy, M. N. et al., A pancreatic islet-specific microRNA regulates insulin secretion. Nature, 2004, 432(7014), 226–230.

  • Poy, M. N. et al., miR-375 maintains normal pancreatic alphaand beta-cell mass. Proc. Natl. Acad. Sci. USA, 2009, 106(14), 5813–5818.

  • Kanak, M. A. et al., Evaluation of MicroRNA375 as a novel biomarker for graft damage in clinical islet transplantation. Transplantation, 2015, 99(8), 1568–1573.

  • Gadi, V. K. et al., Soluble donor DNA and islet injury after transplantation. Transplantation, 2011, 92(5), 607–611.

  • Akirav, E. M. et al., Detection of beta cell death in diabetes using differentially methylated circulating DNA. Proc. Natl. Acad. Sci. USA, 2011, 108(47), 19018–19023.

  • Usmani-Brown, S., Lebastchi, J., Steck, A. K., Beam, C., Herold, K. C. and Ledizet, M., Analysis of beta-cell death in type-1 diabetes by droplet digital PCR. Endocrinology, 2014, 155(9), 3694–3698.

  • Husseiny, M. I., Kaye, A., Zebadua, E., Kandeel, F. and Ferreri, K., Tissue-specific methylation of human insulin gene and PCR assay for monitoring beta cell death. PLoS ONE, 2014, 9(4), e94591.

  • Herold, K. C. et al., beta cell death and dysfunction during type-1 diabetes development in at-risk individuals. J. Clin. Invest., 2015, 125(3), 1163–1173.

  • Lo, Y. M., Zhang, J., Leung, T. N., Lau, T. K., Chang, A. M. and Hjelm, N. M., Rapid clearance of fetal DNA from maternal plasma. Am. J. Hum. Genet., 1999, 64(1), 218–224.

  • Shi, Y., Generation of functional insulin-producing cells from human embryonic stem cells in vitro. Meth. Mol. Biol., 2010, 636, 79–85.

  • Assady, S., Maor, G., Amit, M., Itskovitz-Eldor, J., Skorecki, K. L. and Tzukerman, M., Insulin production by human embryonic stem cells. Diabetes, 2001, 50(8), 1691–1697.

  • Hua, X. F. et al., Pancreatic insulin-producing cells differentiated from human embryonic stem cells correct hyperglycemia in SCID/NOD mice, an animal model of diabetes. PLoS ONE, 2014, 9(7), e102198.

  • Alipio, Z. et al., Reversal of hyperglycemia in diabetic mouse models using induced-pluripotent stem (iPS)-derived pancreatic beta-like cells. Proc. Natl. Acad. Sci. USA, 2010, 107(30), 13426–13431.

  • Phadnis, S. M., Ghaskadbi, S. M., Hardikar, A. A. and Bhonde, R. R., Mesenchymal stem cells derived from bone marrow of diabetic patients portrait unique markers influenced by the diabetic microenvironment. Rev. Diabetic Stud., 2009, 6(4), 260–270.

  • Trivedi, H. L. et al., Human adipose tissue-derived mesenchymal stem cells combined with hematopoietic stem cell transplantation synthesize insulin. Transplant. Proc., 2008, 40(4), 1135–1139.

  • Jiang, R. et al., Transplantation of placenta-derived mesenchymal stem cells in type-2 diabetes: a pilot study. Front Med., 2011, 5(1), 94–100.

  • Yang, Y., Akinci, E., Dutton, J. R., Banga, A. and Slack, J. M., Stage specific reprogramming of mouse embryo liver cells to a beta cell-like phenotype. Mech. Dev., 2013, 130(11–12), 602–612.

  • Sapir, T. et al., Cell-replacement therapy for diabetes: generating functional insulin-producing tissue from adult human liver cells. Proc. Natl. Acad. Sci. USA, 2005, 102(22), 7964–7969.

  • Minami, K. et al., Lineage tracing and characterization of insulinsecreting cells generated from adult pancreatic acinar cells. Proc. Natl. Acad. Sci. USA, 2005, 102(42), 15116–15121.

  • Zhou, Q., Brown, J., Kanarek, A., Rajagopal, J. and Melton, D. A., In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature, 2008, 455(7213), 627–632.

  • Thorel, F. et al., Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. Nature, 2010, 464(7292), 1149–1154.

  • Bouwens, L. and Pipeleers, D. G., Extra-insular beta cells associated with ductules are frequent in adult human pancreas. Diabetologia, 1998, 41(6), 629–633.

  • Bonner-Weir, S. et al., The pancreatic ductal epithelium serves as a potential pool of progenitor cells. Pediatr. Diabetes (Suppl. 2), 2004, 5, 16–22.

  • Pan, F. C. and Wright, C., Pancreas organogenesis: from bud to plexus to gland. Dev. Dyn., 2011, 240(3), 530–565.

  • Bonner-Weir, S., Baxter, L. A., Schuppin, G. T. and Smith, F. E., A second pathway for regeneration of adult exocrine and endocrine pancreas. A possible recapitulation of embryonic development. Diabetes, 1993, 42(12), 1715–1720.

  • Rovira, M., Scott, S. G., Liss, A. S., Jensen, J., Thayer, S. P. and Leach, S. D., Isolation and characterization of centroacinar/ terminal ductal progenitor cells in adult mouse pancreas. Proc. Natl. Acad. Sci. USA, 2010, 107(1), 75–80.

  • Swales, N. et al., Plasticity of adult human pancreatic duct cells by neurogenin3-mediated reprogramming. PLoS ONE, 2012, 7(5), e37055.

  • Rescan, C. et al., EGF-induced proliferation of adult human pancreatic duct cells is mediated by the MEK/ERK cascade. Lab. Invest., 2005, 85(1), 65–74.

  • Onaca, N., Naziruddin, B., Matsumoto, S., Noguchi, H., Klintmalm, G. B. and Levy, M. F., Pancreatic islet cell transplantation: update and new developments. Nutr. Clin. Pract., 2007, 22(5), 485–493.

  • Bellin, M. D. et al., Total pancreatectomy and islet autotransplantation in chronic pancreatitis: recommendations from PancreasFest. Pancreatology, 2014, 14(1), 27–35.

  • Clayton, H. A., Davies, J. E., Pollard, C. A., White, S. A., Musto, P. P. and Dennison, A. R., Pancreatectomy with islet autotransplantation for the treatment of severe chronic pancreatitis: the first 40 patients at the leicester general hospital. Transplantation, 2003, 76(1), 92–98.

  • Rabkin, J. M. et al., Distant processing of pancreas islets for autotransplantation following total pancreatectomy. Am. J. Surg., 1999, 177(5), 423–427.

  • Matsumoto, S. et al., Usefulness of the Secretary Unit of Islet Transplant Objects (SUITO) index for evaluation of clinical autologous islet transplantation. Transplant Proc., 2011, 43(9), 3246–3249.

  • Sutherland, D. E. et al., Islet autotransplant outcomes after total pancreatectomy: a contrast to islet allograft outcomes. Transplantation, 2008, 86(12), 1799–1802.

  • Hering, B. J. et al., Single-donor, marginal-dose islet transplantation in patients with type-1 diabetes. JAMA, 2005, 293(7), 830–835.

  • Froud, T. et al., Islet transplantation in type-1 diabetes mellitus using cultured islets and steroid-free immunosuppression: Miami experience. Am. J. Transplant., 2005, 5(8), 2037–2046.

  • Kempf, M. C. et al., Logistics and transplant coordination activity in the GRAGIL Swiss–French multicentre network of islet transplantation. Transplantation, 2005, 79(9), 1200–1205.

  • Ryan, E. A. et al., Five-year follow-up after clinical islet transplantation. Diabetes, 2005, 54(7), 2060–2069.

  • Warnock, G. L. et al., Improved human pancreatic islet isolation for a prospective cohort study of islet transplantation vs best medical therapy in type-1 diabetes mellitus. Arch. Surg., 2005, 140(8), 735–744.

  • Toso, C. et al., Sequential kidney/islet transplantation: efficacy and safety assessment of a steroid-free immunosuppression protocol. Am. J. Transplant., 2006, 6(5 Pt 1), 1049–1058.

  • O’Connell, P. J. et al., Clinical islet transplantation in type-1 diabetes mellitus: results of Australia’s first trial. Med. J. Aust., 2006, 184(5), 221–225.

  • Ghofaili, K. A. et al., Effect of exenatide on beta cell function after islet transplantation in type-1 diabetes. Transplantation, 2007, 83(1), 24–28.

  • Badet, L. et al., Expectations and strategies regarding islet transplantation: metabolic data from the GRAGIL 2 trial. Transplantation, 2007, 84(1), 89–96.

  • Gerber, P. A. et al., Simultaneous islet-kidney vs pancreas– kidney transplantation in type-1 diabetes mellitus: a 5 year single centre follow-up. Diabetologia, 2008, 51(1), 110–119.

  • Cure, P. et al., Improved metabolic control and quality of life in seven patients with type-1 diabetes following islet after kidney transplantation. Transplantation, 2008, 85(6), 801–812.

  • Bellin, M. D. et al., Prolonged insulin independence after islet allotransplants in recipients with type-1 diabetes. Am. J. Transplant., 2008, 8(11), 2463–2470.

  • Froud, T. et al., Islet transplantation with alemtuzumab induction and calcineurin-free maintenance immunosuppression results in improved short- and long-term outcomes. Transplantation, 2008, 86(12), 1695–1701.

  • Gangemi, A. et al., Islet transplantation for brittle type-1 diabetes: the UIC protocol. Am. J. Transplant., 2008, 8(6), 1250–1261.

  • Froud, T. et al., Islet transplantation with alemtuzumab induction and calcineurin-free maintenance immunosuppression results in improved short- and long-term outcomes. Transplantation, 2008, 86(12), 1695–1701.

  • Mineo, D. et al., Combined islet and hematopoietic stem cell allotransplantation: a clinical pilot trial to induce chimerism and graft tolerance. Am. J. Transplant., 2008, 8(6), 1262–1274.

  • Vantyghem, M. C. et al., Primary graft function, metabolic control, and graft survival after islet transplantation. Diabetes Care, 2009, 32(8), 1473–1478.

  • Borot, S. et al., Impact of the number of infusions on 2-year results of islet-after-kidney transplantation in the GRAGIL network. Transplantation, 2011, 92(9), 1031–1038.

  • Posselt, A. M. et al., Islet transplantation in type-1 diabetic patients using calcineurin inhibitor-free immunosuppressive protocols based on T-cell adhesion or costimulation blockade. Transplantation, 2010, 90(12), 1595–1601.

  • Matsumoto, S. et al., Improving efficacy of clinical islet transplantation with iodixanol based islet purification, thymoglobulin induction and blockage of IL-1-beta and TNF-alpha. Cell Transplant, 2011, 20(10), 1641–1647.

  • Bellin, M. D. et al., Potent induction immunotherapy promotes long-term insulin independence after islet transplantation in type1 diabetes. Am. J. Transplant., 2012, 12(6), 1576–1583.

  • Maffi, P. et al., Calcineurin inhibitor-free immunosuppressive regimen in type-1 diabetes patients receiving islet transplantation: single-group phase 1/2 trial. Transplantation, 2014, 98(12), 1301–1309.

  • Gillard, P. et al., Early alteration of kidney function in nonuremic type-1 diabetic islet transplant recipients under tacrolimusmycophenolate therapy. Transplantation, 2014, 98(4), 451–457.

  • Lehmann, R. et al., Glycemic control in simultaneous isletkidney versus pancreas-kidney transplantation in type-1 diabetes: a prospective 13-year follow-up. Diabetes Care, 2015, 38(5), 752–759.


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  • Clinical Islet Cell Transplantation – Recent Advances

Abstract Views: 290  |  PDF Views: 95

Authors

Prathab Balaji Saravanan
Baylor Research Institute, Dallas, Texas, United States
Gopalakrishnan Loganathan
Clinical Islet Cell Laboratory, Centre for Cellular Transplantation, Cardiovascular Innovation Institute, Department of Surgery, University of Louisville, Louisville, KY, United States
Bashoo Naziruddin
Baylor Research Institute, Dallas, Texas, United States
Appakalai N. Balamurugan
Clinical Islet Cell Laboratory, Centre for Cellular Transplantation, Cardiovascular Innovation Institute, Department of Surgery, University of Louisville, Louisville, KY, United States

Abstract


Type-1 diabetes mellitus (T1DM) caused by autoimmune destruction of insulin-producing beta-cells essentially requires treatment with exogenous insulin therapy. Despite the education, technology and improvements in insulin formulations, patients face the ongoing life-threatening hypoglycaemia with poor quality of life as well as progressive disease leading to micro-and macro-vascular complications of diabetes. Islet transplantation offers an alternative therapeutic option for these patients. In this review, we discuss the recent advancements in this field tracking from the history of pancreatic islet transplantation to the present-day challenges of clinical islet cell transplantation. We summarize the cutting-edge clinical research with special reference to the results of current trials, including Clinical Islet Transplant Consortium, improvements in immuno-suppressive protocols, the need for beta-cell replacement therapies, including the application of induced pluripotent stem cells and mesenchymal stem cells.

Keywords


Diabetes, Insulin, Islet Cell Transplantation, Immunosuppression, Stem Cells.

References





DOI: https://doi.org/10.18520/cs%2Fv113%2Fi07%2F1267-1276