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Engman C.,Institute of Cellular Therapeutics | Wen Y.,University of Chicago | Bottino R.,Institute of Cellular Therapeutics | Trucco M.,Institute of Cellular Therapeutics | Giannoukakis N.,Institute of Cellular Therapeutics
Clinical Immunology | Year: 2015

We have developed novel antisense oligonucleotide-formulated microspheres that can reverse hyperglycemia in newly-onset diabetic mice. Dendritic cells taking up the microspheres adopt a restrained co-stimulation ability and migrate to the pancreatic lymph nodes when injected into an abdominal region that is drained by those lymph nodes. Furthermore, we demonstrate that the absolute numbers of antigen-specific Foxp3. + T regulatory cells are increased only in the lymph nodes draining the site of administration and that these T-cells proliferate independently of antigen supply in the microspheres. Taken together, our data add to the emerging model where antigen supply may not be a requirement in "vaccines" for autoimmune disease, but the site of administration - subserved by lymph nodes draining the target organ - is in fact critical to foster the generation of antigen-specific regulatory cells. The implications of these observations on "vaccine" design for autoimmunity are discussed and summarized. © 2015 Elsevier Inc.

PubMed | University of British Columbia, Oxford Genetics, Institute of Cellular Therapeutics and University of Victoria
Type: Journal Article | Journal: Cell metabolism | Year: 2016

Pancreatic cells are mostly post-mitotic, but it is unclear what locks them in this state. Perturbations including uncontrolled hyperglycemia can drive cells into more pliable states with reduced cellular insulin levels, increased cell proliferation, and hormone mis-expression, but it is unknown whether reduced insulin production itself plays a role. Here, we define the effects of 50% reduced insulin production in Ins1(-/-):Ins2(f/f):Pdx1Cre(ERT):mTmG mice prior to robust hyperglycemia. Transcriptome, proteome, and network analysis revealed alleviation of chronic endoplasmic reticulum (ER) stress, indicatedby reduced Ddit3, Trib3, and Atf4 expression; reduced Xbp1 splicing; and reduced phospho-eIF2. This state was associated with hyper-phosphorylation of Akt, which is negatively regulated byTrib3, and with cyclinD1 upregulation. Remarkably, cell proliferation was increased 2-fold after reduced insulin production independently of hyperglycemia. Eventually, recombined cells mis-expressed glucagon in the hyperglycemic state. We conclude that the normally high rate of insulin production suppresses cell proliferation in a cell-autonomous manner.

PubMed | Howard Hughes Medical Institute, Stanford University, Institute of Cellular Therapeutics, University of Oregon and 2 more.
Type: Journal Article | Journal: Cell metabolism | Year: 2016

Intensive efforts are focused on identifying regulators of human pancreatic islet cell growth and maturation to accelerate development of therapies for diabetes. After birth, islet cell growth and function are dynamically regulated; however, establishing these age-dependent changes in humans has been challenging. Here, we describe a multimodal strategy for isolating pancreatic endocrine and exocrine cells from children and adults to identify age-dependent gene expression and chromatin changes on a genomic scale. These profiles revealed distinct proliferative and functional states of islet cells or cells and histone modifications underlying age-dependent gene expression changes. Expression of SIX2 and SIX3, transcription factors without prior known functions in the pancreas and linked to fasting hyperglycemia risk, increased with age specifically in human islet cells. SIX2 and SIX3 were sufficient toenhance insulin content or secretion in immature cells. Our work provides a unique resource to study human-specific regulators of islet cell maturation and function.

Park C.-G.,Institute of Endemic Diseases | Park C.-G.,Seoul National University | Bottino R.,Institute of Cellular Therapeutics | Hawthorne W.J.,Westmead Research Institute | Hawthorne W.J.,University of Sydney
International Journal of Surgery | Year: 2015

Cell therapy for Type 1 diabetes (T1D) utilizing islet cell transplantation can successfully restore endogenous insulin production in affected patients. Islet cell engraftment and survival are conditional on the use of efficacious anti-rejection therapies and on the availability of healthy donor cells. The scarcity of healthy human donor pancreata is a limiting factor in providing sufficient tissue to meet the demand for islet transplantation worldwide. A potential alternative to the use of cadaveric human donor pancreases is the use of animal sourced islets.Pancreatic islets obtained from pigs have emerged as an alternative to human tissues due to their great availability, physiological similarities to human islets, including the time-tested use of porcine insulin in diabetic patients and the ability to genetically modify the donor source.The evolution of refined, efficacious immunosuppressive therapies with reduced toxicity, improvements in donor management and genetic manipulation of the donor have all contributed to facilitate long-term function in pre-clinical models of pig islet grafts in non-human primates.As clinical consideration for this option is growing, and trials involving the use of porcine islets have begun, more compelling experimental data suggest that the use of pig islets may soon become a viable, safe, effective and readily available treatment for insulin deficiency in T1D patients. © 2015 IJS Publishing Group Limited.

News Article | October 28, 2016
Site: www.prweb.com

The National Pancreas Foundation (NPF), a nonprofit organization that provides hope for those suffering from pancreatitis and pancreatic cancer, has designated Allegheny Health Network (AHN) as a National Pancreas Foundation Center for the treatment and care of patients with pancreatic cancer, one of just 28 such centers nationwide. NPF Centers are based at premier healthcare facilities that focus on multidisciplinary treatment of pancreatic cancer, treating the “whole patient” with a focus on the best possible outcomes and an improved quality of life. AHN joins other nationally recognized healthcare organizations, including the Cleveland Clinic, Massachusetts General Hospital and the Mayo Clinic in earning this designation. “We are honored by our designation as a National Pancreas Foundation Center for pancreatic cancer treatment,” said David Parda, MD, Chair, Allegheny Health Network Cancer Institute. “We share the Foundation’s philosophy of providing compassionate, innovative, multidisciplinary care that encompasses the total well-being of each individual patient.” According to the NPF, people coping with pancreatic cancer or other pancreatic disorders may find inconsistencies in the level of care they receive. The NPF Centers designation helps facilitate the development of high-quality, multidisciplinary care approaches for the field. Designated centers are also at the forefront of advancing research and leading the way for heightened awareness and understanding of pancreatic cancer among community physicians, allied health professionals, patients, families and the general public. “Being an approved NPF Center is an important recognition,” said NPF Center Task Force member Eileen O’Reilly, MD. “Having the NPF Center designation will help distinguish institutions whose focus is on a multidisciplinary, patient centered approach to their care.” Approved NPF Centers go through an extensive auditing process and meet criteria developed by a task force made up of invited subject matter experts and patient advocates. The criteria includes having the required expert physician specialties such as oncologists, gastroenterologists, pancreatic surgeons, interventional radiologists, palliative care services and clinical trials, along with more patient focused programs such as a pain management service, psychosocial support and more. “At Allegheny Health Network, we offer some of the most innovative clinical trials and treatments available for pancreatic cancer, giving patients a variety of options in surgery, chemotherapy, targeted therapies and radiation therapy,” said Suzanne Schiffman, MD, surgical oncologist specializing in hepatobiliary surgery at AHN. In addition, AHN’s Institute of Cellular Therapeutics, led by Massimo Trucco, MD, is known for pioneering research and treatment of patients who suffer from chronic pancreatic diseases, including pancreatitis and type 1 diabetes. The Institute’s Islet Cell Isolation Laboratory is one of just a few in the nation that supports an innovative therapy in which islet cells, such as those that produce insulin, are extracted from a donor pancreas or the patient’s own removed organ and transplanted back into the body. For more information about the National Pancreas Foundation, our NPF Centers for pancreatitis or pancreatic cancer, please visit http://www.pancreasfoundation.org. For more information on cancer care at AHN, call 412-DOCTORS (362-8677) or visit http://www.ahn.org/cancer-institute About Allegheny Health Network Allegheny Health Network is a western Pennsylvania-based integrated healthcare system that serves patients from across a five state region that includes Pennsylvania, Ohio, West Virginia, Maryland and New York. The Network’s Cancer Institute offers a complete spectrum of oncology care, including access to state-of-the-art technologies and new therapies being explored in clinical cancer trials. Allegheny Health Network has one of the largest networks of radiation oncology clinics in the country credentialed by the American College of Radiology. This accreditation signifies exceptional cancer care quality, safety and patient outcomes. AHN is also ranked in the top 10 percent nationally for cancer care quality, according to Comparion® Medical Analytics, 2016 National Quality Rating. AHN also has a formal affiliation with the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, one of the nation’s 41 comprehensive cancer centers designated by the National Cancer Institute, for research, medical education and clinical services. To schedule an appointment with an AHN oncologist, please call 412.DOCTORS or visit http://www.ahn.org/find-a-doctor.

Bottino R.,University of Pittsburgh | Bottino R.,Institute of Cellular Therapeutics | Wijkstrom M.,University of Pittsburgh | Van Der Windt D.J.,University of Pittsburgh | And 9 more authors.
American Journal of Transplantation | Year: 2014

The generation of pigs with genetic modifications has significantly advanced the field of xenotransplantation. New genetically engineered pigs were produced on an α1,3-galactosyltransferase gene-knockout background with ubiquitous expression of human CD46, with islet beta cell-specific expression of human tissue factor pathway inhibitor and/or human CD39 and/or porcine CTLA4-lg. Isolated islets from pigs with 3, 4 or 5 genetic modifications were transplanted intraportally into streptozotocin-diabetic, immunosuppressed cynomolgus monkeys (n=5). Immunosuppression was based on anti-CD154 mAb costimulation blockade. Monitoring included features of early islet destruction, glycemia, exogenous insulin requirement and histopathology of the islets at necropsy. Using these modified pig islets, there was evidence of reduced islet destruction in the first hours after transplantation, compared with two series of historical controls that received identical therapy but were transplanted with islets from pigs with either no or only one genetic modification. Despite encouraging effects on early islet loss, these multi-transgenic islet grafts did not demonstrate consistency in regard to long-term success, with only two of five demonstrating function beyond 5 months. © 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.

Johnston P.C.,Cleveland Clinic | Johnston P.C.,Royal Victoria Hospital | Lin Y.K.,Cleveland Clinic | Walsh R.M.,Cleveland Clinic | And 8 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2015

Context: Total pancreatectomy (TP) with islet cell autotransplantation (IAT) can reduce or prevent diabetes by preserving beta cell function and is normally performed with on-site isolation laboratory facilities. Objective: We examined factors associated with islet yield and metabolic outcomes in patients with chronic pancreatitis undergoing TP-IAT. We report our experience of TP-IAT with an off-site islet isolation laboratory. Patients and Methods: Data (August 2008 to February 2014) were obtained from a TP-IAT database which included information from medical records, clinic visits, questionnaires, and follow-up telephone calls. Each patient was assessed with pre- and postoperative 5-hour mixedmeal tolerance tests for metabolic measurements and with serial glycosylated hemoglobin (HbA1c) determinations. Results: Thirty-six patients with a mean age of 38 years (range, 16-72 y) underwent TP-IAT for different etiologies. At a median follow-up time of 28 months (range, 3-66 mo), 12 patients were insulin independent and 24 patients were on at least one insulin injection a day. Postoperatively, C-peptide levels ≥0.3 ng/mL were present in 23/33 (70%) of the patients, with a median fasting C-peptide value of 0.8 ng/mL (range, <0.2-1.5 ng/mL). Those who were insulin independent were more likely to be female (P = .012), have normal morphology on pre-operative pancreatic imaging (P = .011), and have significantly higher median islet yield (6845 islet equivalent numbers [IEQ]/kg, n = 12 vs 3333 IEQ/kg, n = 24; P < .001). Conclusions: IAT after TP performed in our facility with an off-site islet isolation laboratory shows islet yield and rates of insulin independence that are comparable to other large centers with on-site laboratories. Copyright © 2015 by the Endocrine Society.

Giannoukakis N.,Institute of Cellular Therapeutics | Trucco M.,Institute of Cellular Therapeutics
Pediatric Diabetes | Year: 2015

Stem cell technology has recently gained a substantial amount of interest as one method to create a potentially limitless supply of transplantable insulin-producing cells to treat, and possibly cure diabetes mellitus. In this review, we summarize the state-of-the art of stem cell technology and list the potential sources of stem cells that have been shown to be useful as insulin-expressing surrogates. We also discuss the milestones that have been reached and those that remain to be addressed to generate bona fide beta cell-similar, insulin-producing surrogates. The caveats, limitations, and realistic expectations are also considered for current and future technology. In spite of the tremendous technical advances realized in the past decade, especially in the field of reprogramming adult somatic cells to become stem cells, the state-of-the art still relies on lengthy and cumbersome in vitro culture methods that yield cell populations that are not particularly glucose-responsive when transplanted into diabetic hosts. Despite the current impediments toward clinical translation, including the potential for immune rejection, the availability of technology to generate patient-specific reprogrammable stem cells has, and will be critical for, important insights into the genetics, epigenetics, biology, and physiology of insulin-producing cells in normal and pathologic states. This knowledge could accelerate the time to reach the desired breakthrough for safe and efficacious beta cell surrogates. © 2015 John Wiley & Sons A/S.

Bottino R.,Institute of Cellular Therapeutics | Trucco M.,Institute of Cellular Therapeutics
Pediatric Diabetes | Year: 2015

Beta-cell replacement is the only physiologically relevant alternative to insulin injections in patients with type 1 diabetes (T1D). Pancreas and islet transplantation from deceased organ donors can provide a new beta-cell pool to produce insulin, help blood glucose management, and delay secondary diabetes complications. For children and adolescents with T1D, whole pancreas transplantation is not a viable option because of surgical complications, whereas islet transplantation, even if it is procedurally simpler, must still overcome the burden of immunosuppression to become a routine therapy for children in the future. © 2015 John Wiley & Sons A/S.

Garciafigueroa Y.,Institute of Cellular Therapeutics | Trucco M.,Institute of Cellular Therapeutics | Giannoukakis N.,Institute of Cellular Therapeutics
Clinical Immunology | Year: 2015

The pace at which nanotherapeutic technology for human disease is evolving has accelerated exponentially over the past five years. Most of the technology is centered on drug delivery which, in some instances, offers tunable control of drug release. Emerging technologies have resulted in improvements in tissue and cell targeting while others are at the initial stages of pairing drug release and drug release kinetics with microenvironmental stimuli or changes in homeostasis. Nanotherapeutics has only recently been adopted for consideration as a prophylaxis/treatment approach in autoimmunity. Herein, we summarize the current state-of-the art of nanotherapeutics specifically for type 1 diabetes mellitus and offer our view over the horizon of where we envisage this modality evolving towards. © 2015 Elsevier Inc.

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