Islet Allotransplantation in the Bone Marrow of Patients With Type 1 Diabetes: A Pilot Randomized Trial

Maffi, Paola; Nano, Rita; Monti, Paolo; Melzi, Raffaella; Sordi, Valeria; Mercalli, Alessia; Pellegrini, Silvia; Ponzoni, Maurilio; Peccatori, Jacopo; Messina, Carlo; Nocco, Angela; Cardillo, Massimo; Scavini, Marina; Magistretti, P.; Doglioni, Claudio; Ciceri, Fabio; Bloem, Stef J.; Roep, Bart O.; Secchi, Antonio; Piemonti, Lorenzo

doi:10.1097/tp.0000000000002416

Cited by 31 publications

(18 citation statements)

References 47 publications

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“…Furthermore, the bone marrow microenvironment post-transplantation of islets may contribute to the expansion of autoreactive T cells, such elevated concentrations of IL-7, or the low oxygen tension in the bone marrow despite very high vascular density. Finally, the authors concluded that the success seen in the pre-clinical and NHP models of T1D is difficult to replicate in humans without creating models of autoimmune-mediated rejection of pancreatic beta islets ( 75 ). Bone marrow as a transplantation site may not be ideal for pancreatic islet without first preconditioning the local bone marrow microenvironment for immune-modulation or cytoprotection with localized bone marrow irradiation ( 76 )…”

Section: Transplantation Sitesmentioning

confidence: 99%

Advances in Pancreatic Islet Transplantation Sites for the Treatment of Diabetes

2021

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Diabetes is a complex disease that affects over 400 million people worldwide. The life-long insulin injections and continuous blood glucose monitoring required in type 1 diabetes (T1D) represent a tremendous clinical and economic burdens that urges the need for a medical solution. Pancreatic islet transplantation holds great promise in the treatment of T1D; however, the difficulty in regulating post-transplantation immune reactions to avoid both allogenic and autoimmune graft rejection represent a bottleneck in the field of islet transplantation. Cell replacement strategies have been performed in hepatic, intramuscular, omentum, and subcutaneous sites, and have been performed in both animal models and human patients. However more optimal transplantation sites and methods of improving islet graft survival are needed to successfully translate these studies to a clinical relevant therapy. In this review, we summarize the current progress in the field as well as methods and sites of islet transplantation, including stem cell-derived functional human islets. We also discuss the contribution of immune cells, vessel formation, extracellular matrix, and nutritional supply on islet graft survival. Developing new transplantation sites with emerging technologies to improve islet graft survival and simplify immune regulation will greatly benefit the future success of islet cell therapy in the treatment of diabetes.

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Section: Transplantation Sitesmentioning

confidence: 99%

Advances in Pancreatic Islet Transplantation Sites for the Treatment of Diabetes

2021

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“…Only a few alternative transplantation sites have been tested in clinical trials so far: the bone marrow (15), the muscle of the forearm (16,17), and the omentum (18)(19)(20). Despite positive outcomes for autologous islet transplantation, clinical trials have shown that the bone marrow site is not a suitable alternative site for pancreatic islet allotransplantation in T1D patients, due to recurrence of autoimmunity (21). Survival of alloislets in the intramuscular site has also been shown to be limited so far (17).…”

Section: Why the Need For Stem-cell Based Therapy In Diabetes?mentioning

confidence: 99%

Stem Cell-Based Clinical Trials for Diabetes Mellitus

Klerk

Hebrok

2021

Front. Endocrinol.

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Since its introduction more than twenty years ago, intraportal allogeneic cadaveric islet transplantation has been shown to be a promising therapy for patients with Type I Diabetes (T1D). Despite its positive outcome, the impact of islet transplantation has been limited due to a number of confounding issues, including the limited availability of cadaveric islets, the typically lifelong dependence of immunosuppressive drugs, and the lack of coverage of transplant costs by health insurance companies in some countries. Despite improvements in the immunosuppressive regimen, the number of required islets remains high, with two or more donors per patient often needed. Insulin independence is typically achieved upon islet transplantation, but on average just 25% of patients do not require exogenous insulin injections five years after. For these reasons, implementation of islet transplantation has been restricted almost exclusively to patients with brittle T1D who cannot avoid hypoglycemic events despite optimized insulin therapy. To improve C-peptide levels in patients with both T1 and T2 Diabetes, numerous clinical trials have explored the efficacy of mesenchymal stem cells (MSCs), both as supporting cells to protect existing β cells, and as source for newly generated β cells. Transplantation of MSCs is found to be effective for T2D patients, but its efficacy in T1D is controversial, as the ability of MSCs to differentiate into functional β cells in vitro is poor, and transdifferentiation in vivo does not seem to occur. Instead, to address limitations related to supply, human embryonic stem cell (hESC)-derived β cells are being explored as surrogates for cadaveric islets. Transplantation of allogeneic hESC-derived insulin-producing organoids has recently entered Phase I and Phase II clinical trials. Stem cell replacement therapies overcome the barrier of finite availability, but they still face immune rejection. Immune protective strategies, including coupling hESC-derived insulin-producing organoids with macroencapsulation devices and microencapsulation technologies, are being tested to balance the necessity of immune protection with the need for vascularization. Here, we compare the diverse human stem cell approaches and outcomes of recently completed and ongoing clinical trials, and discuss innovative strategies developed to overcome the most significant challenges remaining for transplanting stem cell-derived β cells.

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“…Thus, one area of ongoing research is the utility of alternate sites for islet allotransplant. Alloislet transplantation into bone marrow was unsuccessful in one small trial, while a biological scaffold created by layering islets with thrombin in an omental pouch has shown some early success, but was not superior to transplanting islets into the liver site [25]. One appeal of creating a biological omental scaffold is that this type of implantation site could allow future transplant-site engineering, including adding trophic factors or local immunoprotection strategies to the scaffold environment [26].…”

Section: Human Islet Transplantationmentioning

confidence: 99%

Transplant strategies for type 1 diabetes: whole pancreas, islet and porcine beta cell therapies

Bellin

Dunn

2020

Diabetologia

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Whole-organ pancreas and islet transplantations are performed in a highly selected group of patients with diabetes mellitus, primarily those with type 1 diabetes mellitus, complicated by recurrent severe hypoglycaemia or renal failure requiring kidney transplantation. Clinical accessibility to pancreases or islets, and patient characteristics and therapeutic goals, may dictate choice of procedure. Pancreas transplantation is most often performed simultaneous with a kidney transplant, but patients with particularly labile type 1 diabetes may be considered for a pancreas transplant alone. While highly successful at restoring insulin independence, pancreas transplants carry the significant risks of major surgery and immunosuppression. Islet transplantation is a relatively minor procedure, usually performed for labile type 1 diabetes with severe hypoglycaemia. It is highly successful at resolving hypoglycaemia, but more than one pancreas donor may be required for insulin independence. Both pancreas and islet transplantation are limited in applicability by a paucity of deceased donors. Pigs provide one promising replenishable source of islets. Porcine islets can successfully reverse diabetes mellitus in non-human primates under the appropriate immunosuppressive conditions, with promise for eventually translating this success to a larger population of patients with diabetes mellitus in the future.

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Islet Allotransplantation in the Bone Marrow of Patients With Type 1 Diabetes: A Pilot Randomized Trial

Abstract: BM is not a suitable alternative site for pancreatic islet allotransplantation in patients with type 1 diabetes.

Cited by 31 publications

References 47 publications

Advances in Pancreatic Islet Transplantation Sites for the Treatment of Diabetes

Advances in Pancreatic Islet Transplantation Sites for the Treatment of Diabetes

Stem Cell-Based Clinical Trials for Diabetes Mellitus

Transplant strategies for type 1 diabetes: whole pancreas, islet and porcine beta cell therapies

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