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      Pig-to-Primate Islet Xenotransplantation: Past, Present, and Future

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          Abstract

          <p class="first" id="d2826318e188">Islet allotransplantation results in increasing success in treating type 1 diabetes, but the shortage of deceased human donor pancreata limits progress. Islet xenotransplantation, using pigs as a source of islets, is a promising approach to overcome this limitation. The greatest obstacle is the primate immune/inflammatory response to the porcine (pig) islets, which may take the form of rapid early graft rejection (the instant blood-mediated inflammatory reaction) or T-cell-mediated rejection. These problems are being resolved by the genetic engineering of the source pigs combined with improved immunosuppressive therapy. The results of pig-to-diabetic nonhuman primate islet xenotransplantation are steadily improving, with insulin independence being achieved for periods &gt;1 year. An alternative approach is to isolate islets within a micro- or macroencapsulation device aimed at protecting them from the human recipient's immune response. Clinical trials using this approach are currently underway. This review focuses on the major aspects of pig-to-primate islet xenotransplantation and its potential for treatment of type 1 diabetes. </p>

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          Generation of functional human pancreatic β cells in vitro.

          Felicia W Pagliuca, Jeffrey Millman, Mads Gürtler … (2014)
          The generation of insulin-producing pancreatic β cells from stem cells in vitro would provide an unprecedented cell source for drug discovery and cell transplantation therapy in diabetes. However, insulin-producing cells previously generated from human pluripotent stem cells (hPSC) lack many functional characteristics of bona fide β cells. Here, we report a scalable differentiation protocol that can generate hundreds of millions of glucose-responsive β cells from hPSC in vitro. These stem-cell-derived β cells (SC-β) express markers found in mature β cells, flux Ca(2+) in response to glucose, package insulin into secretory granules, and secrete quantities of insulin comparable to adult β cells in response to multiple sequential glucose challenges in vitro. Furthermore, these cells secrete human insulin into the serum of mice shortly after transplantation in a glucose-regulated manner, and transplantation of these cells ameliorates hyperglycemia in diabetic mice. Copyright © 2014 Elsevier Inc. All rights reserved.
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            In vivo reprogramming of adult pancreatic exocrine cells to beta-cells.

            Qiao Zhou, Juliana R Brown, Andrew Kanarek … (2008)
            One goal of regenerative medicine is to instructively convert adult cells into other cell types for tissue repair and regeneration. Although isolated examples of adult cell reprogramming are known, there is no general understanding of how to turn one cell type into another in a controlled manner. Here, using a strategy of re-expressing key developmental regulators in vivo, we identify a specific combination of three transcription factors (Ngn3 (also known as Neurog3) Pdx1 and Mafa) that reprograms differentiated pancreatic exocrine cells in adult mice into cells that closely resemble beta-cells. The induced beta-cells are indistinguishable from endogenous islet beta-cells in size, shape and ultrastructure. They express genes essential for beta-cell function and can ameliorate hyperglycaemia by remodelling local vasculature and secreting insulin. This study provides an example of cellular reprogramming using defined factors in an adult organ and suggests a general paradigm for directing cell reprogramming without reversion to a pluripotent stem cell state.
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              Phase 3 Trial of Transplantation of Human Islets in Type 1 Diabetes Complicated by Severe Hypoglycemia

              Bernhard J. Hering, William Clarke, Nancy D Bridges … (2016)
              OBJECTIVE Impaired awareness of hypoglycemia (IAH) and severe hypoglycemic events (SHEs) cause substantial morbidity and mortality in patients with type 1 diabetes (T1D). Current therapies are effective in preventing SHEs in 50–80% of patients with IAH and SHEs, leaving a substantial number of patients at risk. We evaluated the effectiveness and safety of a standardized human pancreatic islet product in subjects in whom IAH and SHEs persisted despite medical treatment. RESEARCH DESIGN AND METHODS This multicenter, single-arm, phase 3 study of the investigational product purified human pancreatic islets (PHPI) was conducted at eight centers in North America. Forty-eight adults with T1D for >5 years, absent stimulated C-peptide, and documented IAH and SHEs despite expert care were enrolled. Each received immunosuppression and one or more transplants of PHPI, manufactured on-site under good manufacturing practice conditions using a common batch record and standardized lot release criteria and test methods. The primary end point was the achievement of HbA1c 0.0001). No study-related deaths or disabilities occurred. Five of the enrollees (10.4%) experienced bleeds requiring transfusions (corresponding to 5 of 75 procedures), and two enrollees (4.1%) had infections attributed to immunosuppression. Glomerular filtration rate decreased significantly on immunosuppression, and donor-specific antibodies developed in two patients. CONCLUSIONS Transplanted PHPI provided glycemic control, restoration of hypoglycemia awareness, and protection from SHEs in subjects with intractable IAH and SHEs. Safety events occurred related to the infusion procedure and immunosuppression, including bleeding and decreased renal function. Islet transplantation should be considered for patients with T1D and IAH in whom other, less invasive current treatments have been ineffective in preventing SHEs.
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                Author and article information

                Journal
                Title: Cell Transplantation
                Abbreviated Title: Cell Transplant
                Publisher: Cognizant, LLC
                ISSN (Print): 0963-6897
                ISSN (Electronic): 1555-3892
                Publication date Created: June 09 2017
                Publication date Created: June 2017
                Publication date (Electronic): June 09 2017
                Publication date (Print): June 2017
                Volume: 26
                Issue: 6
                Pages: 925-947
                Affiliations
                [1 ]Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong, P.R. China
                [2 ]Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, Jiangsu, P.R. China
                [3 ]Xenotransplantation Program/Department of Surgery, The University of Alabama at Birmingham, Birmingham, AL, USA
                [4 ]Institute for Cellular Therapeutics, Allegheny-Singer Research Institute, Pittsburgh, PA, USA
                Article
                DOI: 10.3727/096368917X694859
                PMC ID: 5657750
                PubMed ID: 28155815
                SO-VID: d02efe44-e4e6-4d81-86cd-8d6db9e1aaf6
                Copyright © © 2017
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