Autologous Islet Transplantation After Total Pancreatectomy in a Patient Recovered from SARS-CoV-2: A Case Report.

BACKGROUND SARS-CoV-2 infection or COVID-19 disease has been linked to the onset of diabetes and metabolic dysregulation because it has been suggested that viral entry proteins, specifically ACE2 and TMPRSS2, are expressed in the exocrine cells and ductal epithelium of the pancreas. Because of the unknown effect this can have on islet function, there can be doubt that patients with previous SARS-CoV-2 infections are good candidates for autologous islet transplantation after total pancreatectomy (TPAIT). CASE REPORT A patient with a history of chronic pancreatitis and previous non-surgical interventions was presented as a viable candidate for TPAIT at our institution. Approximately 1 month later, the patient contracted a SARS-CoV-2 infection, resulting in a mild case of COVID-19. The infection resolved without the need for hospitalization. At the time of this occurrence, COVID-19 was primarily considered a respiratory ailment, and little was known of the potential association between metabolic dysfunction and SARS-CoV-2. Islet isolation and surgery proceeded in a textbook manner with no surgical complications. The patient was weaned off exogenous insulin within 3 months after transplantation. CONCLUSIONS Favorable outcomes after surgery included pain reduction, islet function, and improved quality of life for the patient in the first 6 months after the procedure. These successful results demonstrate that SARS-CoV-2 infection did not prevent the patient from achieving good glucose regulation after auto-islet transplantation. This outcome suggests that, at least in this instance of mild infection, there were no long-lasting negative COVID-19-associated effects on the transplanted islets that might impact islet function.

Human Hemangioblast-Derived Mesenchymal Stem Cells Promote Islet Engraftment in a Minimal Islet Mass Transplantation Model in Mice.

Islet transplantation can restore glycemic control in patients with type 1 diabetes. Using this procedure, the early stages of engraftment are often crucial to long-term islet function, and outcomes are not always successful. Numerous studies have shown that mesenchymal stem cells (MSCs) facilitate islet graft function. However, experimental data can be inconsistent due to variables associated with MSC generation (including donor characteristics and tissue source), thus, demonstrating the need for a well-characterized and uniform cell product before translation to the clinic. Unlike bone marrow- or adipose tissue-derived MSCs, human embryonic stem cell-derived-MSCs (hESC-MSCs) offer an unlimited source of stable and highly-characterized cells that are easily scalable. Here, we studied the effects of human hemangioblast-derived mesenchymal cells (HMCs), (i.e., MSCs differentiated from hESCs using a hemangioblast intermediate), on islet cell transplantation using a minimal islet mass model. The co-transplantation of the HMCs allowed a mass of islets that was insufficient to correct diabetes on its own to restore glycemic control in all recipients. Our in vitro studies help to elucidate the mechanisms including reduction of cytokine stress by which the HMCs support islet graft protection in vivo. Derivation, stability, and scalability of the HMC source may offer unique advantages for clinical applications, including fewer islets needed for successful islet transplantation.

How the COVID-19 pandemic may impact public support for clinical xenotransplantation in the United States?

Many patients who would undergo organ transplantation cannot proceed due to the inability of human organ donation to satisfy medical needs. Xenotransplantation has the potential to offer unlimited availability of pig organs for transplantation, and pig-to-non-human primate models have demonstrated outcomes that may soon justify clinical trials. However, one of the unique ethical challenges faced by xenotransplantation is that the risk of introducing potential zoonotic disease into the community must be weighed along with the benefit to the patient. While most experts believe that zoonosis is manageable, apprehension over disease transmission from animal donors to human recipients remains a frequent concern of many who are undecided or opposed to clinical xenotransplantation. The COVID-19 pandemic represents a scenario (rapid worldwide spread of a highly contagious novel zoonotic disease with no natural defense in humans) that would seem to justify apprehension, especially in the United States, which has largely avoided previous pandemic outbreaks. However, there are many differences between zoonosis found in the wild or after xenotransplantation that favor the safety of the latter. Still, these differences, as well as the benefits of xenotransplantation, are not widely understood outside of the field. We must therefore ask what impact the COVID-19 pandemic will have on attitudes toward xenotransplantation.

Pig-to-Macaque Islet Xenotransplantation.

The advancement toward a clinical application for porcine islets to cure diabetes in humans must include reproducible long-term successes in non-human primate (NHP) models. Many dedicated researchers around the world are continuing to work toward this goal. In this chapter, we describe procedures for islet isolation of pancreatic islets from adult and neonatal/fetal pigs. We further include procedures for the induction of diabetes in non-human primates and subsequent insulin therapy, islet transplantation, immunosuppression, and also the daily maintenance of xenotransplanted NHPs. The procedures that we outline in this chapter are ones that we have successfully utilized in pig-to-NHP islet transplantation models. However, where appropriate, alternative methods will also be identified.

Immunological aspects of allogeneic pancreatic islet transplantation: a comparison between mouse and human.

Pancreatic islet allotransplantation is a treatment for patients with severe forms of type 1 diabetes. As long-term graft function and survival are not yet optimal, additional studies are warranted in order to continue improving transplant outcomes. The mechanisms of islet graft loss and tolerance induction are often studied in murine diabetes models. Despite numerous islet transplantation studies successfully performed over recent years, translation from experimental mouse models to human clinical application remains elusive. This review aims at critically discussing the strengths and limitations of current mouse models of diabetes and experimental islet transplantation. In particular, we will analyze the causes leading to diabetes and compare the immunological mechanisms responsible for rejection between mouse and human. A better understanding of the experimental mouse models should facilitate translation to human clinical application.

The Future of Islet Transplantation Is Now.

Milestones in the history of diabetes therapy include the discovery of insulin and successful methods of beta cell replacement including whole pancreas and islet cell transplantation options. While pancreas transplantation remains the gold standard for patients who have difficulty controlling their symptoms with exogenous insulin, islet allotransplantation is now able to provide similar results with some advantages that make it an attractive potential alternative. The Edmonton Protocol, which incorporated a large dose of islets from multiple donors with steroid-free immunosuppression helped to establish the modern era of islet transplantation almost 20 years ago. While islet allotransplantation is recognized around the world as a powerful clinical therapy for type 1 diabetes it is not yet recognized by the Federal Drug Administration of the United States. Large-scale clinical trials administered by the Clinical Islet Transplantation Consortium have recently demonstrated that the well-regulated manufacture of a human islet product transplanted into patients with difficult to control type 1 diabetes and with a history of severe hyperglycemic episodes can safely and efficaciously maintain glycemic balance and eliminate the most severe complications associated with diabetes. The results of these clinical trials have established a strong basis for licensure of clinical islet allotransplantation in the US. Recognition by the Federal Drug Administration would likely lead to third party reimbursement for islet allotransplantation as a therapeutic option in the United States and would make the treatment available to many more patients. The high costs of rampant diabetes justify the expense of the treatment, which is in-line with the costs of clinical pancreas transplantation. While much enthusiasm and hope is raised toward the development and optimization of stem cell therapy, the islet transplantation community should push toward licensure, if that means broader access of this procedure to patients who may benefit from it. Even as we prepare to take the first steps in that direction, we must acknowledge the new challenges that a shift from the experimental to clinical will bring. Clinical islet allotransplantation in the United States would be a game-changing event in the treatment of type 1 diabetes and also generate enthusiasm for continued research.

Safe use of anti-CD154 monoclonal antibody in pig islet xenotransplantation in monkeys.

Anti-CD154mAb is a powerful co-stimulation blockade agent that is efficacious in preventing rejection, even in xenogeneic settings. It has been used in the majority of successful long-term pig-to-non-human primate islet transplantation models. However, its clinical use was halted as a result of thromboembolic complications that were also observed in preclinical and clinical organ transplantation models. An anti-CD154mAb was administered to 14 streptozotocin-induced diabetic cynomolgus monkey recipients of porcine islets, some of which received the agent for many months. Monkeys were monitored for complications, and blood monitoring was carried out frequently. After euthanasia, multiple biopsies of all organs were examined for histological features of thromboembolism. Anti-CD154mAb prevented rejection of genetically engineered pig islets in all monkeys. No significant complications were attributable specifically to anti-CD154mAb. There was no evidence of thromboembolism in multiple histological sections from all major organs, including the brain. Our data suggest that in diabetic monkeys with pig islet grafts, anti-CD154mAb would appear to be an effective and safe therapy, and is not associated with thromboembolic complications.