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Permanent link (DOI): https://doi.org/10.7939/R3BR8MW4M

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Advancing Engraftment and Cell Survival in Experimental and Clinical Islet Transplantation Open Access

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Other title
Subject/Keyword
Islet engraftment
Pancreatic islets
Islet survival
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Gala Lopez, Boris L.
Supervisor and department
Dr. Darren Freed. Department of Physiology
Dr. James Shapiro. Department of Surgery
Dr. Colin Anderson. Department of Surgery
Examining committee member and department
Dr. Colin Anderson. Department of Surgery
Dr. Darren Freed. Department of Physiology
Dr. Thomas Churchill. Department of Surgery
Dr. Camillo Ricordi. Department of Surgery, University of Miami. Miami, Florida, USA
Dr. James Shapiro. Department of Surgery
Department
Department of Surgery
Specialization
Experimental Surgery
Date accepted
2016-07-13T09:09:48Z
Graduation date
2016-06:Fall 2016
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Islet transplantation is today a well-established treatment modality for selected patients with type 1 Diabetes mellitus. The procedure has experienced notable refinements over the decades due the continuous efforts of clinicians and scientists to make islet isolation a reality, with a resulting final product to the highest standards, capable of safely treating patients against this autoimmune disease responsible for impaired insulin secretion and hypoglycemia unawareness. After the success of the University of Alberta group with a modified approach to the immune protection of islets, the international experience grew along with the numbers of transplants in highly specialized centers. Yet, long-term analysis of those initial results from the Edmonton group indicated that insulin-independence was not durable and most patients return to modest amounts of insulin around the fifth year, without recurrent hypoglycemia events. This thesis presents the results from multiple projects aimed to improve some of those limiting factors for prolonged islet survival. We provide sufficient background for the reader to learn about the historical perspective, along with the latest efforts to improve islet engraftment, immune protection and ultimately, long-term graft survival. We present our efforts to enhance beta cell viability and potency in vitro through added protection using the Mangano-metalloporphyrin BMX-010 during the isolation and culture process. This molecule has been reported to provide anti-inflammatory and antioxidant effects in pre-clinical transplant models. We here present an assessment of this metalloporphyrin in clinical islet transplantation. Another area of research is the avoidance of immunosuppression toxicity, which is one of the contributing factors for graft loss overtime. We specifically explored the potential cytoprotective effect of Anti-aging Glycopeptide (AAGP), a synthetic analogue of anti-freeze proteins, and demonstrated significant impairment of islets treated with high dose tacrolimus and effective protective effect from culture supplementation with the AAGP. Clinical results of islet transplantation are discussed and new immunosuppressive strategies are presented, along with quality assurance elements for the human islet preparation. In particular, we explore the possibility of microbial contamination of the preparation. Shifting focus to alternative sources for islet transplantation, we present developmental experimental studies towards the implementation of the subcutaneous space for islet and insulin-producing stem cells, which is a promising avenue of research with the potential to provide an unlimited supply for transplantation and a personalized approach to transplant medicine. Various alternatives are tested for prevascularized Cell Transplant under the skin, in experimental and clinical setting to accommodate the future implementation of stem Cell Transplant in humans. Complementary information is provided in appendices with systematic reviews on the advances of immunosuppression in islet transplantation towards the improvement of engraftment and graft durability. Moreover, a special case reports provides an opportunity to debate the practice of islet autotransplantation after total pancreatectomy. In this case, a new indication is presented in a patient with metastatic renal cell carcinoma, prompting for a new view of indication expansion when conditions allow for it. Many phenomena have been identified as limiting factor for the islet engraftment and survival, and today all efforts are aimed to improve the quality of islets and their engrafting process, as well as more optimized immunosuppression to facilitate tolerance and ultimately, better long-term survival. As the field of islet transplantation continues to progress, it is foreseeable that a cure for type 1 diabetes mellitus is obtainable in the near future.
Language
English
DOI
doi:10.7939/R3BR8MW4M
Rights
This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for the purpose of private, scholarly or scientific research. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
Citation for previous publication
Gala-Lopez BL, Kin T, O’Gorman D, Malcolm AJ, Pepper AR, Pawlick RL, Bruni A, Abualhassan N, Bral M, Jones C, Piganelli JD, Crapo JD, Shapiro AMJ. The metalloporphyrin BMX-010 in human islet isolation and clinical transplantation. CellR4 2016 4(3):e2066Gala-Lopez BL, Pepper AR, Pawlick RL, O’Gorman D, Kin T, Bruni A, Abulhassan NM, Bral M, Fox Manning J, Bautista A, Young LG, MacDonald PE, Shapiro AMJ. Anti-Aging Glycopeptide protects human islets against tacrolimus-related injury and facilitates engraftment in mice. Diabetes 2016: 65:451-462Gala-Lopez BL, Kawahara T, Pepper AR, Shapiro AMJ. Islet transplantation for type 1 diabetes. Juntendo Med J 01/2015; 61(2):131-135. DOI:10.14789/jmj.61.131Gala Lopez BL, Kin T, O’Gorman D, Pepper A, Senior P, Humar A, Shapiro AMJ. Microbial contamination of clinical islet transplant preparations is associated with very low risk of infection. Diabetes Technol Therap 2013;15(4): 323-327Pepper AR, Gala-Lopez B, Pawlick RL, Merani S, Kin T, Shapiro AMJ. A pre-vascularized subcutaneous device-less for islet and cellular transplant. Nat Biotech 2015; 33(5):518-23.Gala-Lopez BL, Pepper AR, Pawlick RL, Bruni A, Abualhassan N, Kin T, Keller G, Nostro MC, Shapiro AMJ. A novel pre-vascularized subcutaneous site safely accommodates stem cell derived therapies for treating diabetes. J Stem Trans Bio 2016; 2(1):107.Gala-Lopez BL, Pepper AR, Shapiro AMJ. 2013. Biologic agents in islet transplantation. Curr Diab Rep. 2013 Oct;13(5):713-22Gala-Lopez BL, Semlacher E, Manouchehri N, Kin T, Shapiro AMJ. 2013. Autologous Islet Transplantation after Total Pancreatectomy for Renal Cell Carcinoma Metastases. Am J Transplant. 2013 Sep;13(9):2487-91.

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