Need For Lifelong Immunosuppression Research Articles

INNOVATIVE THERAPIES IN REGENERATIVE MEDICINE AND TRANSPLANTATION

Introduction: In the past decade we have observed fast development of a new medical fields including regenerative medicine and reconstructive transplantation of the vascularized composite allografts (VCA). The VCA procedures include the new generation of face transplants, hand transplants and many other organs which opened a new reconstructive option for severely damaged patients. The lecture summarizes the risks and benefits of the VCA transplants specifically in the context of the need for life-long immunosuppression to extend VCA survival. Aim: Novel therapeutic strategies of different cell- based therapies are discussed with special emphasizes on the new generation of the donor-recipient chimeric cells used as a supportive tolerogenic therapy for VCA transplants. Material and Methods: Development of the preclinical studies carried in the experimental animal models for creation of the chimeric cells is outlined. This is followed by the creation of the human hematopoietic chimeric cells of the bone marrow and the Umbilical Cord Blood cells origin, confirming tolerogenic and immunomodulatory properties of these new cell-based therapies for application in theVCA and solod organ transplantation. Further development of chimeric cells in the field of regenerative medicine include creation of the Dystrophin Expressing Chimeric (DEC) cells as a novel therapeutic approach for patients with Duchenne muscular dystrophy (DMD). Results: In preparation to clinical applications DEC cells safety and efficacy was tested in the mdx mouse models of DMD. The safety of DEC biodistribution to the DMD- affected target organs of heart, diaphragm and gastrocnemius muscle was confirmed and correlated with improvement in functional tests assessed by echocardiography, plethysmography and standard tests of muscle strengths. These encouraging results observed in preclinical studies lead to the development of the clinical protocol for DMD patients. Currently the DT-DEC01 therapy was applied to seven DMD patients. Both, safety and efficacy of DT-DEC01 cells was confirmed up to 24 months after systemic intraosseous administration to the DMD patients. Conclusions: This pilot clinical study introduces DEC cells as a novel universal therapeutic approach for treatment of DMD and other muscular dystrophies regardless of gene mutation and ambulatory status of the patients.

Long-term management and outcome of lung transplantation in Japan.

The long-term survival after lung transplantation (LT) is favorable in Japan. However, long-term survivors after LT are subject to late complications, including chronic lung allograft dysfunction (CLAD), malignancy, infection, and chronic kidney disease (CKD) because of the need for lifelong immunosuppression. The rates of single cadaveric LT (CLT) and living-donor lobar LT (LDLLT) are higher than that of bilateral CLT in Japan. Here, we will describe the management of late complications and long-term outcome after LT in Japan. Attention should be paid to not only the phenotype of CLAD but also the difference in CLAD after CLT and after LDLLT as well as the timing of lung re-transplantation for advanced CLAD, especially after single CLT. Since post-transplant lymphoproliferative disorder is the most common malignancy after LT, infection monitoring for infection-related malignancies and appropriate screening are keys to the early diagnosis and treatment of malignancy after LT. The long-term management of infection after LT is also important, especially with regard to community-acquired pathogens, Aspergillus, and cytomegalovirus. When providing long-term care after LT, physicians should be aware of CKD and the timing of renal replacement therapy in cases with severe CKD. The widespread use of computed tomography and dialysis in Japan are beneficial for long-term survivors of LT. The similar survival outcomes of single CLT and LDLLT, compared with bilateral CLT, might contribute to improved long-term survival in Japan. Pulmonologists are encouraged to become further involved in long-term management after LT in Japan.

Genetic Therapy Approaches for Ornithine Transcarbamylase Deficiency.

Ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle disorder with high unmet needs, as current dietary and medical treatments may not be sufficient to prevent hyperammonemic episodes, which can cause death or neurological sequelae. To date, liver transplantation is the only curative choice but is not widely available due to donor shortage, the need for life-long immunosuppression and technical challenges. A field of research that has shown a great deal of promise recently is gene therapy, and OTCD has been an essential candidate for different gene therapy modalities, including AAV gene addition, mRNA therapy and genome editing. This review will first summarise the main steps towards clinical translation, highlighting the benefits and challenges of each gene therapy approach, then focus on current clinical trials and finally outline future directions for the development of gene therapy for OTCD.

Long-term effects of pancreatic islet transplantation on polyneuropathy in patients with brittle diabetes: A single-center experience.

Pancreatic islet transplantation (ITx) is increasingly used in patients with brittle type 1 diabetes (T1D). If successful, ITx results in insulin-free euglycemia, but its application is limited by a need for lifelong immunosuppression. The aim of this study was to assess the long-term effects of ITx on the occurrence and course of polyneuropathy in a cohort of patients with brittle T1D. In this prospective, single-center study, 13 patients (4 males and 9 females) with brittle T1D had a baseline neurological exam with the calculation of Utah Neuropathy Scale (UNS) and a limited nerve conduction study before ITx, and about yearly after in the patients who achieved insulin independence. Patients were followed for a period of 17 to 133 months. There was no significant difference between UNS and nerve conduction study parameters at baseline and at the end of follow-up, except for significant decreases in peroneal (50.34 ± 6.12 vs. 52.42 ± 6.47 ms, P = 0.005) and ulnar (27.5 ± 2.15 vs. 29.45 ± 2.10 ms, P = 0.009) F-wave latencies and an increase in ulnar sensory nerve conduction velocity (49.98 ± 6.27 vs. 47.19 ± 5.36 m/s, P = 0.04). If successful, ITx has a good long-term safety profile for peripheral nerve toxicity, and a favorable effect on diabetic neuropathy.

Gene therapy for urea cycle defects: An update from historical perspectives to future prospects.

Urea cycle defects (UCDs) are severe inherited metabolic diseases with high unmet needs which present a permanent risk of hyperammonaemic decompensation and subsequent acute death or neurological sequelae, when treated with conventional dietetic and medical therapies. Liver transplantation is currently the only curative option, but has the potential to be supplanted by highly effective gene therapy interventions without the attendant need for life-long immunosuppression or limitations imposed by donor liver supply. Over the last three decades, pioneering genetic technologies have been explored to circumvent the consequences of UCDs, improve quality of life and long-term outcomes: adenoviral vectors, adeno-associated viral vectors, gene editing, genome integration and non-viral technology with messenger RNA. In this review, we present a summarised view of this historical path, which includes some seminal milestones of the gene therapy's epic. We provide an update about the state of the art of gene therapy technologies for UCDs and the current advantages and pitfalls driving future directions for research and development.

From islet of Langerhans transplantation to the bioartificial pancreas

Type 1 diabetes is a disease resulting from autoimmune destruction of the insulin-producing beta cells in the pancreas. When type 1 diabetes develops into severe secondary complications, in particular end-stage nephropathy, or life-threatening severe hypoglycemia, the best therapeutic approach is pancreas transplantation, or more recently transplantation of the pancreatic islets of Langerhans. Islet transplantation is a cell therapy procedure, that is minimally invasive and has a low morbidity, but does not display the same rate of functional success as the more invasive pancreas transplantation because of suboptimal engraftment and survival. Another issue is that pancreas or islet transplantation (collectively known as beta cell replacement therapy) is limited by the shortage of organ donors and by the need for lifelong immunosuppression to prevent immune rejection and recurrence of autoimmunity.A bioartificial pancreas is a construct made of functional, insulin-producing tissue, embedded in an anti-inflammatory, immunomodulatory microenvironment and encapsulated in a perm-selective membrane allowing glucose sensing and insulin release, but isolating from attacks by cells of the immune system. A successful bioartificial pancreas would address the issues of engraftment, survival and rejection. Inclusion of unlimited sources of insulin-producing cells, such as xenogeneic porcine islets or stem cell-derived beta cells would further solve the problem of organ shortage.This article reviews the current status of clinical islet transplantation, the strategies aiming at developing a bioartificial pancreas, the clinical trials conducted in the field and the perspectives for further progress.

Stem Cell Transplantation in the Treatment of Type 1 Diabetes Mellitus: From Insulin Replacement to Beta-Cell Replacement.

Type 1 diabetes mellitus (T1DM) is an autoimmune disease that attacks pancreatic β-cells, leading to the destruction of insulitis-related islet β-cells. Islet β-cell transplantation has been proven as a curative measure in T1DM. However, a logarithmic increase in the global population with diabetes, limited donor supply, and the need for lifelong immunosuppression restrict the widespread use of β-cell transplantation. Numerous therapeutic approaches have been taken to search for substitutes of β-cells, among which stem cell transplantation is one of the most promising alternatives. Stem cells have demonstrated the potential efficacy to treat T1DM by reconstitution of immunotolerance and preservation of islet β-cell function in recent research. cGMP-grade stem cell products have been used in human clinical trials, showing that stem cell transplantation has beneficial effects on T1DM, with no obvious adverse reactions. To better achieve remission of T1DM by stem cell transplantation, in this work, we explain the progression of stem cell transplantation such as mesenchymal stem cells (MSCs), human embryonic stem cells (hESCs), and bone marrow hematopoietic stem cells (BM-HSCs) to restore the immunotolerance and preserve the islet β-cell function of T1DM in recent years. This review article provides evidence of the clinical applications of stem cell therapy in the treatment of T1DM.

Pramlintide-Expressing Human-Embryonic Stem Cell Derived Beta Cells as a Strategy to Prevent Islet Amyloid and Cell Death Following Transplantation

Islet transplantation is a promising therapy for people with type 1 diabetes (T1D), yet its impact remains limited with the paucity of organ donors, need for lifelong immunosuppression, and eventual graft dysfunction and failure. Human embryonic stem cell (hESC)-derived insulin-producing cells are currently in clinical trial as a cell source for transplant in T1D, although questions remain regarding long-term survival and function. Aggregation of islet amyloid polypeptide (IAPP), a hormone co-secreted with insulin from β-cells and the major component of cytotoxic islet amyloid in type 2 diabetes, has been implicated in islet transplant failure.

A RARE AND FATAL CASE OF ACUTE FULMINANT LIVER FAILURE INDUCED BY COVID-19 INFECTION

TOPIC: Chest Infections TYPE: Medical Student/Resident Case Reports INTRODUCTION: The SARS-CoV-2 virus, in accordance with the name designated to it by viral taxonomists, primarily causes severe acute respiratory distress syndrome. A challenge of this novel coronavirus has been discovering and preventing its indiscriminate and catastrophic effect on other organs. We present a rare case of the SARS-CoV-2 virus precipitating fulminant hepatic failure in a patient without respiratory symptoms or prior evidence of liver disease. CASE PRESENTATION: A 60 year-old female with history of atrial fibrillation, emphysema, and renal cell carcinoma status post left radical nephrectomy presented with weakness and fatigue. On day 12 of admission, she became hemodynamically unstable due to atrial fibrillation with rapid ventricular response, requiring electrical cardioversion, emergent intubation and transfer to ICU. Repeat SARS-CoV-2 PCR test was positive, although negative on admission. Dexamethasone, vancomycin and piperacillin-tazobactam were initiated, and one dose of Remdesivir was given after an unremarkable liver panel. No further Remdesivir was given, as six hours later, the patient had abrupt worsening of her liver function tests, with eventual peak AST of 2610 IU/L, ALT of 14860 IU/L and INR of 9.12. Fibrinogen was 136 mg/dL, ammonia 290 mcmol/L, lactate 11.51 mmol/L and IL-6 143.9 pg/mL. Viral causes for acute hepatitis were negative and abdominal ultrasound was unremarkable. The patient was treated with N-acetylcysteine, methylprednisolone, lactulose and rifaximin. She was ineligible for transfer to a liver transplant center due to her COVID-19 positive status. Unfortunately, despite conservative management, patient expired after developing severe disseminated intravascular coagulation, renal failure, and refractory septic shock. DISCUSSION: In recent literature, SARS-CoV-2 has primarily been recognized for causing mild liver injury, while fulminant hepatic failure is a rare occurrence (1,2). Remdesivir, which this patient received only one dose of, is known to cause mild transaminitis. It has been shown to cause severe liver injury only when used in combination with amiodarone, due to the latter's role as a moderate inhibitor of CYP3A4 and p-glycoprotein (3). This patient did not have exposure to hepatotoxic agents, prolonged state of shock, evidence of metastatic liver lesions or acute viral hepatitis to explain profound liver failure. Hence, we postulate that the SARS-CoV-2 virus may have directly targeted the hepatobiliary cells. Further studies of the pathophysiology of liver injury from this virus may allow better prevention and treatment. CONCLUSIONS: Understanding SARS-CoV-2's effects on a hepatocellular level may allow for anticipatory monitoring and prevention of liver damage from this virus. For those more severely affected, better treatments would help avoid the difficult course of emergency liver transplantation and resultant need for lifelong immunosuppression. REFERENCE #1: Gupta A, Mahhavan MV, Sehgal K, et al. Extrapulmonary manifestations of COVID19. Nature Medicine 26:1017-1032, July 2020 REFERENCE #2: Melquist S, Estepp K, Aleksandrovich Y, et al. COVID-19 presenting as fulminant hepatic failure. Medicine 99:issue 43, October 23, 2020 doi 10.1097 REFERENCE #3: Remdesivir in LiverTox: Clinical and Research Information on Drug-Induced Liver Injury (Internet). National Institute of Diabetes and Digestive and Kidney Diseases, November 4, 2020; https://www.ncbi.nlm.nih.gov/books/NBK564049/?report=printable DISCLOSURES: No relevant relationships by Chester Choi, source=Web Response No relevant relationships by Madlena Nalbandian, source=Web Response No relevant relationships by Eulia Tlisov, source=Web Response

Evolution of haematopoietic cell transplantation for canine blood disorders and a platform for solid organ transplantation.

Pre‐clinical haematopoietic cell transplantation (HCT) studies in canines have proven to be invaluable for establishing HCT as a highly successful clinical option for the treatment of malignant and non‐malignant haematological diseases in humans. Additionally, studies in canines have shown that immune tolerance, established following HCT, enabled transplantation of solid organs without the need of lifelong immunosuppression. This progress has been possible due to multiple biological similarities between dog and mankind. In this review, the hurdles that were overcome and the methods that were developed in the dog HCT model which made HCT clinically possible are examined. The results of these studies justify the question whether HCT can be used in the veterinary clinical practice for more wide‐spread successful treatment of canine haematologic and non‐haematologic disorders and whether it is prudent to do so.

Update on islet cell transplantation.

Chronic diabetes-related complications continue to exert a rapidly growing and unsustainable pressure on healthcare systems worldwide. In type 1 diabetes, glycemic control is particularly challenging, as intensive management substantially increase the risk of severe hypoglycemic episodes. Alternative approaches to address this issue are required. Islet cell transplantation offers the best approach to reduce hypoglycemic risks and glycemic lability, while providing optimal glycemic control. Although ongoing efforts have improved clinical outcomes, the constraints in tissue sources and the need for chronic immunosuppression limit the application of islet cell transplantation as a curative therapy for diabetes. This review provides an update on islet cell transplantation, focusing on recent clinical experience, ongoing research, and future challenges. Current evidence demonstrates advances in terms of long-term glycemic control, improved insulin independence rates, and novel approaches to eliminate chronic immunosuppression requirements after islet cell transplantation. Advances in stem cell-based therapies provide a promising path towards truly personalized regenerative therapies, solving both tissue supply shortage and the need for lifelong immunosuppression, enabling widespread use of this potentially curative treatment. However, as these therapies enter the clinical realm, regional access variability and ethical questions regarding commercialization are becoming increasingly important and require a collaborative solution. In this state-of-the-art review, we discuss current clinical evidence and discuss key aspects on the present and future of islet cell transplantation.

Harnessing Mechanisms of Immune Tolerance to Improve Outcomes in Solid Organ Transplantation: A Review.

Survival after solid organ transplantation (SOT) is limited by chronic rejection as well as the need for lifelong immunosuppression and its associated toxicities. Several preclinical and clinical studies have tested methods designed to induce transplantation tolerance without lifelong immune suppression. The limited success of these strategies has led to the development of clinical protocols that combine SOT with other approaches, such as allogeneic hematopoietic stem cell transplantation (HSCT). HSCT prior to SOT facilitates engraftment of donor cells that can drive immune tolerance. Recent innovations in graft manipulation strategies and post-HSCT immune therapy provide further advances in promoting tolerance and improving clinical outcomes. In this review, we discuss conventional and unconventional immunological mechanisms underlying the development of immune tolerance in SOT recipients and how they can inform clinical advances. Specifically, we review the most recent mechanistic studies elucidating which immune regulatory cells dampen cytotoxic immune reactivity while fostering a tolerogenic environment. We further discuss how this understanding of regulatory cells can shape graft engineering and other therapeutic strategies to improve long-term outcomes for patients receiving HSCT and SOT.

Exploring the Epidemiology of Cancer after Solid Organ Transplantation (EpCOT): an observational cohort study

IntroductionSolid organ transplant patients are counselled regarding increased risk of cancer (principally due to their need for lifelong immunosuppression) and it ranks as one of their biggest self-reported worries. Post-transplantation...

A Large-Scale Bank of Organ Donor Bone Marrow and Matched Mesenchymal Stem Cells for Promoting Immunomodulation and Transplant Tolerance.

Induction of immune tolerance for solid organ and vascular composite allografts is the Holy Grail for transplantation medicine. This would obviate the need for life-long immunosuppression which is associated with serious adverse outcomes, such as infections, cancers, and renal failure. Currently the most promising means of tolerance induction is through establishing a mixed chimeric state by transplantation of donor hematopoietic stem cells; however, with the exception of living donor renal transplantation, the mixed chimerism approach has not achieved durable immune tolerance on a large scale in preclinical or clinical trials with other solid organs or vascular composite allotransplants (VCA). Ossium Health has established a bank of cryopreserved bone marrow (BM), termed “hematopoietic progenitor cell (HPC), Marrow,” recovered from deceased organ donor vertebral bodies. This new source for hematopoietic cell transplant will be a valuable resource for treating hematological malignancies as well as for inducing transplant tolerance. In addition, we have discovered and developed a large source of mesenchymal stem (stromal) cells (MSC) tightly associated with the vertebral body bone fragment byproduct of the HPC, Marrow recovery process. Thus, these vertebral bone adherent MSC (vBA-MSC) are matched to the banked BM obtained from each donor, as opposed to third-party MSC, which enhances safety and potentially efficacy. Isolation and characterization of vBA-MSC from over 30 donors has demonstrated that the cells are no different than traditional BM-MSC; however, their abundance is >1,000-fold higher than obtainable from living donor BM aspirates. Based on our own unpublished data as well as reports published by others, MSC facilitate chimerism, especially at limiting hematopoietic stem and progenitor cell (HSPC) numbers and increase safety by controlling and/or preventing graft-vs.-host-disease (GvHD). Thus, vBA-MSC have the potential to facilitate mixed chimerism, promote complementary peripheral immunomodulatory functions and increase safety of BM infusions. Both HPC, Marrow and vBA-MSC have potential use in current VCA and solid organ transplant (SOT) tolerance clinical protocols that are amenable to “delayed tolerance.” Current trials with HPC, Marrow are planned with subsequent phases to include vBA-MSC for tolerance of both VCA and SOT.

Prefabricated Expanded Flap Combined With Expanded Scalp Flap for Total Face Resurfacing.

Reconstruction of total facial deformities and defects has been a major challenge of reconstructive surgery. Allotransplantation is limited by the number of donors and the need for life-long immunosuppression. Autotransplantation, where multiple autogenous tissue grafts from various donor sites are used to repair facial defects, inevitably leaves conspicuous patchwork scars. A prefabricated monoblock flap, although the preferred treatment modality, is limited by insufficient blood supply and the large size of the flap. In the Journal of Craniofacial Surgery (2014;25:21-25), Li et al applied the technique of flap prefabrication and stem cell-assisted tissue expansion to reconstruct total facial injuries, but the operations were complicated and the final expanded flap area was also uncertain. This article introduces an approach to reconstruct total facial injuries with a prefabricated expanded thoracic flap combined with an expanded scalp flap (called combined flaps), which not only solves the limitations of blood supply and expanded volume but also reduces patchwork scars. The approach is a simple, feasible, and effective surgical method for total face resurfacing.

Bioengineered Mini Human Livers for Transplantation.

The only curative treatment for end-stage liver disease is liver transplantation. However, a shortage of donor organs, financial burden on the patients, and the need for lifelong immunosuppression are major limitations. One potential solution to these issues would be to bioengineer a functioning liver from a patient's own cells in the lab, and transplant the lab-grown organ into the patient. This technology could theoretically provide unlimited grafts without the need for immunosuppression.

Prophylactic vaccination with a live-attenuated herpes zoster vaccine in lung transplant candidates

Herpes zoster (HZ) is caused by the reactivation of varicella-zoster virus (VZV). Patients with lung transplants are at high risk for HZ owing to their immunocompromised status and the need for lifelong immunosuppression. In this study, patients on the waiting list for lung transplantation were vaccinated by a live-attenuated HZ vaccine (Zostavax, Merck Sharp & Dohme), and the safety and immunogenicity of this vaccine were studied. In total, 105 patients with end-stage pulmonary disease (ESPD) were enrolled (68 participants received 1 dose of Zostavax and 37 participants were enrolled as unvaccinated controls). Among them, 43 patients underwent lung transplantation and were followed up for further analysis. VZV immunoglobulin G antibody titers and VZV-specific cell-mediated immunity (CMI) on multiple time points before and after vaccination and before and after transplantation were measured. Immune response to Zostavax was higher in younger patients, highest within 3 months after vaccination, and not influenced by gender or type of ESPD. Age, cytomegalovirus serostatus, and immunity to VZV at baseline impacted the subsequent immune response to the vaccine. Short-term immunosuppressant treatment had strong effects on VZV CMI levels, which returned to a high level at 6 months after transplantation in vaccinated patients. Zostavax did not impact infection or rejection rate after transplantation. Zostavax was safe and induced a robust humoral and cellular response for patients awaiting lung transplantation regardless of the type of ESPD. Patients younger than the recommended vaccination age of over 50 years showed a strong response and could also benefit from pre-transplant immunization.

Ethical Issues Raised by the Media Portrayal of Adolescent Transplant Refusals.

Cases of adolescents in organ failure who refuse solid organ transplant are not common, but several have been discussed in the media in the United States and the United Kingdom. Using the framework developed by Buchanan and Brock for surrogate decision-making, I examine what role the adolescent should morally play when deciding about therapy for life-threatening conditions. I argue that the greater the efficacy of treatment, the less voice the adolescent (and the parent) should have. I then consider how refusals of highly effective transplant cases are similar to and different from refusals of other lifesaving therapies (eg, chemotherapy for leukemia), which is more commonly discussed in the media and medical literature. I examine whether organ scarcity and the need for lifelong immunosuppression justify differences in whether the state intervenes when an adolescent and his or her parents refuse a transplant. I argue that the state, as parens patriae, has an obligation to provide the social supports needed for a successful transplant and follow-up treatment plan, although family refusals may be permissible when the transplant is experimental or of low efficacy because of comorbidities or other factors. I conclude by discussing the need to limit media coverage of pediatric treatment refusals.

Islet Transplantation in Type 1 Diabetes Mellitus With Hypoglycaemic Unawareness


 The primary indications for ICT in T1DM are glycaemic lability and hypoglycaemia unawareness.
 
 
 
 ICT is an effective, minimally invasive treatment for stabilising glycaemic control, correcting hypoglycaemia unawareness and improving quality of life even when exogenous insulin-independence is not fully achieved. However, the majority of patients require two islet transplants.
 
 
 
 The need for lifelong immunosuppression, in combination with the limited availability of donor pancreases, currently limits the wider application of ICT, particularly in the treatment of children newly diagnosed with T1DM.
 
 
 
 New technologies, including macro- and micro-encapsulation, xenotransplantation and stem cell-derived b cells offer hope for the future of b cell replacement. Yet, until then, a continued focus on optimising donor pancreases, improving the islet isolation procedure, use of novel immunosuppression, and understanding the mechanisms behind graft loss is required.

Culture on a native bone marrow-derived extracellular matrix restores the pancreatic islet basement membrane, preserves islet function, and attenuates islet immunogenicity.

Islet transplantation in man is limited by multiple factors including islet availability, islet cell damage caused by collagenase during isolation, maintenance of islet function between isolation and transplantation, and allograft rejection. In this study, we describe a new approach for preparing islets that enhances islet function in vitro and reduces immunogenicity. The approach involves culture on native decellularized 3D bone marrow-derived extracellular matrix (3D-ECM), which contains many of the matrix components present in pancreas, prior to islet transplantation. Compared to islets cultured on tissue culture plastic (TCP), islets cultured on 3D-ECM exhibited greater attachment, higher survival rate, increased insulin content, and enhanced glucose-stimulated insulin secretion. In addition, culture of islets on 3D-ECM promoted recovery of vascular endothelial cells within the islets and restored basement membrane-related proteins (eg, fibronectin and collagen type VI). More interestingly, culture on 3D-ECM also selectively decontaminated islets of “passenger” cells (co-isolated with the islets) and restored basement membrane-associated type VI collagen, which were associated with an attenuation in islet immunogenicity. These results demonstrate that this novel approach has promise for overcoming two major issues in human islet transplantation: (a) poor yield of islets from donated pancreas tissue and (b) the need for life-long immunosuppression.