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Islet Transplantation for Type 1 Diabetes: So Close and Yet So Far Away

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Islet Transplantation for Type 1 Diabetes: So Close and Yet So Far Away M Khosravi-Maharlooei, Islet transplantation for type 1 173:5 R165–R183 Review E Hajizadeh-Saffar and others diabetes THERAPY OF ENDOCRINE DISEASE Islet transplantation for type 1 diabetes: so close and yet so far away Mohsen Khosravi-Maharlooei1,*,†, Ensiyeh Hajizadeh-Saffar1,*, Yaser Tahamtani1, Mohsen Basiri1, Leila Montazeri1, Keynoosh Khalooghi1, Mohammad Kazemi Ashtiani1, Ali Farrokhi1,†, Nasser Aghdami2, Anavasadat Sadr Hashemi Nejad1, Mohammad-Bagher Larijani3, Nico De Leu4, Harry Heimberg4, Xunrong Luo5 and Hossein Baharvand1,6 1Department of Stem Cells and Developmental Biology at Cell Science Research Center and 2Department of Regenerative Medicine at Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran, 3Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, Tehran, Iran, 4Diabetes Research Center, Vrije Universiteit Brussel, Laarbeeklaan 103, Brussels, Belgium, 5Division of Nephrology and Hypertension, Department of Medicine, Northwestern University Feinberg School of Medicine, Correspondence Chicago, Illinois, USA and 6Department of Developmental Biology, University of Science and Culture, ACECR, should be addressed Tehran 148-16635, Iran to H Baharvand *(M Khosravi-Maharlooei and E Hajizadeh-Saffar contributed equally to this work) Email †M Khosravi-Maharlooei and A Farrokhi are now at Department of Surgery, University of British Columbia, Baharvand@ Vancouver, British Columbia, Canada royaninstitute.org Abstract Over the past decades, tremendous efforts have been made to establish pancreatic islet transplantation as a standard therapy for type 1 diabetes. Recent advances in islet transplantation have resulted in steady improvements in the 5-year insulin independence rates for diabetic patients. Here we review the key challenges encountered in the islet transplantation field which include islet source limitation, sub-optimal engraftment of islets, lack of oxygen and blood supply for transplanted European Journal of Endocrinology islets, and immune rejection of islets. Additionally, we discuss possible solutions for these challenges. European Journal of Endocrinology (2015) 173, R165–R183 Introduction Type 1 diabetes (T1D) is an autoimmune disease where Pancreatic islet transplantation has been introduced as the immune system destroys insulin-producing pancreatic an alternative approach to transplantation of the pancreas. b cells, leading to increased serum blood glucose levels. This procedure does not require major surgery and few Despite tremendous efforts to tightly regulate blood complications arise. However, lifelong immunosuppres- glucose levels in diabetic patients by different methods sion is still needed to preserve the transplanted islets. of insulin therapy, pathologic processes that result in Although during the past two decades significant progress long-term complications exist (1). Another approach, in islet transplantation conditions and outcomes has been transplantation of the pancreas as a pancreas-after-kidney achieved, challenges remain that hinder the use of this or simultaneous pancreas–kidney transplant is used for the therapy as a widely available treatment for T1D. After majority of T1D patients with end stage renal failure. reviewing the history of islet transplantation, we classify Surgical complications and lifelong immunosuppression the major challenges of islet transplantation into four are among the major pitfalls of this treatment (2). distinct categories relative to the transplantation time www.eje-online.org Ñ 2015 European Society of Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/EJE-15-0094 Printed in Great Britain Downloaded from Bioscientifica.com at 10/02/2021 03:14:43PM via free access Review M Khosravi-Maharlooei, Islet transplantation for type 1 173:5 R166 E Hajizadeh-Saffar and others diabetes point: islet source limitation, sub-optimal engraftment of This research led to the first partially successful clinical islets, lack of oxygen and blood supply, and immune islet transplantation at Washington University in 1989. rejection (Fig. 1). We also discuss possible solutions to By 1999, w270 patients received transplanted islets with these challenges. an estimated 1 year insulin independence rate of 10%. In 2000, a successful trial was published by Shapiro et al. (5). In their study, all seven patients who underwent islet History of islet transplantation and clinical transplantation at the University of Alberta achieved results insulin independence. Of these, five maintained insulin The first clinical allogenic islet transplantation performed independence 1 year after transplantation. This strategy, by Najarian et al. (3) at the University of Minnesota in known as the Edmonton protocol, had three major 1977 resulted in an unsatisfactory outcome. In 1988, while differences compared to the previous transplant Dr Camilio Ricordi was a postdoctoral researcher in procedures. These differences included a shorter time Dr Lacy’s laboratory, they introduced an automated between preparation of islets and transplantation, use of method for isolation of human pancreatic islets (4). islets from two or three donors (w11 000 islet equivalents Tx Before Tx Peri Tx Early post Tx Late post Tx Intraportal Islet Islet-immune system Islet islet transplantation vascularization interaction isolation Donor pancreas Procedure β cell source limitation Poor islet engraftment European Journal of Endocrinology Lack of oxygen and blood supply Challenges Auto and allo-immunity • Central tolerance induction • Allo/xeno-genic islets • Prevention of apoptosis, • Enhancement of islet vasculature: • Human embryonic stem inflammatory cytokines • Suppressor cells: β effect and oxidative - Pro-angiogenic factors cell-derived cells damage - Tolerogenic dendritic cells • Patient-specific cell sources: - Co-transplantation with - Regulatory T cells • Prevention of anoikis helper cells - Differentiation of TSSCs - Modification of ECM • Signal modification: • Attenuating the instant - Differentiation of iPSCs - Providing pre-vascularized - Co-stimulatory and blood-mediated co-inhibitory signals - Transdifferentiation of inflammatory reaction sites somatic cells - Migration and recruitment • Oxygen delivery to the islets - β cell regeneration signals • Encapsulation strategies Possible solutionsPossible Timing Figure 1 Major challenges and possible solutions for islet trans- mentioned below each category. Tx, transplantation; iPSCs, plantation. In a time-dependent manner, major challenges induced pluripotent stem cells; TSSCs, tissue specific stem cells; of islet transplantation are divided into four categories. ECM, extracellular matrix. A full colour version of this figure is The possible solutions to overcome each challenge are available at http://dx.doi.org/10.1530/EJE-15-0094. www.eje-online.org Downloaded from Bioscientifica.com at 10/02/2021 03:14:43PM via free access Review M Khosravi-Maharlooei, Islet transplantation for type 1 173:5 R167 E Hajizadeh-Saffar and others diabetes per kilogram of recipient body weight), and a steroid-free transplantation due to the long-term results, the harvested immune suppressant regimen (5). In their next year’s pancreata are frequently not used for islet isolation. report, it was shown that the risk-to-benefit ratio favored However, the long-term insulin independence rate after islet transplantation for patients with labile T1D (6).Ina islet transplantation is approaching the outcome of whole 5-year follow-up of 47 patients by the Edmonton group, pancreas transplantation (15). The rules for allocating w10% remained insulin-free and about 80% still had harvested pancreas organs may change in the future and positive C-peptide levels. Other advantages of islet provide an increased source of pancreata for islet transplantation included well-controlled HbA1c levels, transplantation. reduced episodes of hypoglycemia, and diminished Non-heart-beating donors (NHBDs) may emerge as fluctuations in blood glucose levels (7). potential sources for islet isolation. Due to the potential Two studies by Hering et al. at the University of ischemic damage to exocrine cells which may induce Minnesota reported promising outcomes in achieving pancreatitis, NHBDs’ pancreata are not preferred for whole insulin independence from a single donor. In 2004, they pancreas transplantation. A study by Markmann et al. (16) reported achievement of insulin independence in four out has reported that the quality of ten NHBDs’ pancreatic of six islet transplant recipients (8). In their next report, all islets was proven to be similar to islets obtained from eight patients who underwent islet transplantation ten BDDs. achieved insulin independence after a single transplant; Xenogenic islets are another promising source of pre- five remained insulin-free 1 year later (9). Dr Warnock’s existing islets for transplantation. Pig islets are the only group at the University of British Columbia showed better source of xenogeneic islets that have been used for metabolic indices and slower progression of diabetes transplantation into humans, not only because of avail- complications after islet transplantation compared to the ability but also due to similarities in islet structure and best medical therapy program (10, 11, 12, 13). physiology to human islets (17). Nonetheless the same The last decade has shown consistent improvement in challenges for allotransplantation, yet more severe, the clinical outcomes of islet transplantation. A
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