Islet transplantation modulates macrophage to induce immune tolerance and angiogenesis of islet tissue in type I diabetes mice model

Islet transplantation holds renewed promise as a cure for type I diabetes mellitus. Results of recent clinical trials have shown remarkable success, and have reignited universal optimism for this procedure. In spite of this success, the need for life–long immunosuppression of the recipient still limits islet transplantation to patients with poorly controlled diabetes or to those requiring kidney transplantation. It is obvious that the achievement of immunological tolerance would broaden the indication for islet transplantation to a much larger cohort of patients with type I diabetes mellitus, most likely preventing long–term complications and contributing to a much improved quality of life. Increased understanding of the basic mechanisms of tolerance induction has resulted in the implementation of numerous experimental approaches to achieve long–term survival of islet grafts in the absence of chronic immunosuppression. In this brief review we will attempt to summarize the current status of research and knowledge.

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Pancreas and islet transplantation in the treatment of type I diabetes

Transplantation and Changing Management of Organ Failure ◽

10.1007/978-94-011-4118-5_13 ◽

2000 ◽

pp. 139-143

Author(s):

X. Martin ◽

P. Petruzzo ◽

N. Lefrancois ◽

L. Badet ◽

J. M. Dubernard

Keyword(s):

Islet Transplantation ◽

Type I Diabetes ◽

Type I

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VP40 Comprehensive Evaluation Of Islet Transplantation For Type I Diabetes

International Journal of Technology Assessment in Health Care ◽

10.1017/s0266462317003269 ◽

2017 ◽

Vol 33 (S1) ◽

pp. 166-167

Author(s):

Danni Chen ◽

Kun Xiong ◽

Di Xue

Keyword(s):

Cost Effectiveness ◽

Islet Transplantation ◽

Type I Diabetes ◽

Insulin Dose ◽

Cochrane Library ◽

Type I ◽

Islet Graft ◽

Pancreatic Islet Transplantation ◽

Insulin Independence

INTRODUCTION:Despite several therapeutic options existing for the patients with type I diabetes, the patients are still at high risk for severe acute and chronic complications (1). Pancreatic islet transplantation is a promising therapy to achieve good glycemic control with no or little additional insulin (2). This study was to evaluate the effectiveness, safety, economics and social ethics of islet transplantation (IT) for the patients with type I diabetes.METHODS:We searched PubMed, Cochrane Library, CNKI and CBM to retrieve eligible literatures. The values of H1bAc before and after transplantation, the rates of insulin independence and functional islet graft at the last follow-up, and the insulin dose per patient-day were analyzed. Descriptive statistics, t tests and random effects meta-analyses were used in the study.RESULTS:Totally 21 original papers with 488 cases from 9 different countries were reviewed and analyzed. The studies showed that the H1bAc was decreased from 7.7 percent (95 percent Confidence Interval, CI: 7.4, 8.1) before IT to 6.2 percent (95 percent CI: 5.9, 6.4) after IT. At the last follow-up, the rate of insulin independence was 48.96 percent (95 percent CI: 31.32, 66.73) and the rate of functional islet graft was 65.79 percent (95 percent CI: 47.06, 82.21). The daily insulin requirement dropped from 0.52U/kg/d to 0.21 U/kg/d. The main adverse events of islet transplantation were bleeding (7.01 percent) and the complications related to immunosuppression therapy (6.37 percent), but they were less than those of whole pancreas transplantation.Another study with a 20-year follow-up also showed that the cost-effectiveness of islet transplantation (USD47,800 per QALY) was better than that of insulin therapy (USD71,000 per QALY). In spite of the better evidences of islet transplantation, the insufficient organ donation and issues of cell purification and immunological rejection limited islet transplantation's widespread utilization (1).CONCLUSIONS:The islet transplantation therapy for the patients with type I diabetes has a potential to achieve insulin independence and better cost-effectiveness, and is relatively safe. But there are some obstacles for its wide utilization.

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Improving islet transplantation: a road map for a widespread application for the cure of persons with type I diabetes

Current Opinion in Organ Transplantation ◽

10.1097/mot.0b013e328332c44c ◽

2009 ◽

Vol 14 (6) ◽

pp. 683-687 ◽

Cited By ~ 23

Author(s):

Olle Korsgren ◽

Bo Nilsson

Keyword(s):

Islet Transplantation ◽

Type I Diabetes ◽

Type I ◽

Widespread Application ◽

Road Map

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Activation of Macrophage-Associated Molecules after Brain Death in Islets

Cell Transplantation ◽

10.3727/000000003783985205 ◽

2003 ◽

Vol 12 (1) ◽

pp. 27-32 ◽

Cited By ~ 33

Author(s):

Hirochika Toyama ◽

Moriatsu Takada ◽

Yasuyuki Suzuki ◽

Yoshikazu Kuroda

Keyword(s):

Brain Death ◽

Islet Transplantation ◽

Type I Diabetes ◽

Statistical Significance ◽

Graft Loss ◽

Flow Cytometric Analysis ◽

Type I ◽

Significant Augmentation ◽

Liver And Kidney ◽

Early Graft

Islet transplantation is now established as an optional treatment for type I diabetes. However, rates of insulin independence in islet transplant recipients are still low. Although the major source of allograft is derived from brain-dead patient, the nonphysiologic state of brain death (BD) deteriorates organs such as liver and kidney. To determine the effects of BD on islets, a rodent model of BD has been used. Histologically, islets of BD rats showed decreased permeability and impaired integrity of the cell membranes. Flow cytometric analysis showed that CD11b/c-positive cells within islets were slightly increased in BD. This result suggests that BD induces macrophage infiltration into the islets. Moreover, RT-PCR revealed significant augmentation of macrophages-associated inflammatory molecules (IL-1β, IL-6, TNF-α, and MCP-1) in islets from a BD donor. Inducible nitric oxide synthase (iNOS) was weakly expressed, although not reaching statistical significance compared with control. Our results indicate that islets from a BD donor are immunologically activated and have a potential risk factor for early graft loss and a poor long-term function of grafts in clinical setting of islet transplantation. Immunomodulation, to eliminate intraislet immunocytes and/or activated macrophage-associated molecules, might be necessary for the better outcome after islet graft from BD donors.

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Therapy of experimental type 1 diabetes by isolated Sertoli cell xenografts alone

Journal of Experimental Medicine ◽

10.1084/jem.20090134 ◽

2009 ◽

Vol 206 (11) ◽

pp. 2511-2526 ◽

Cited By ~ 60

Author(s):

Francesca Fallarino ◽

Giovanni Luca ◽

Mario Calvitti ◽

Francesca Mancuso ◽

Claudio Nastruzzi ◽

...

Keyword(s):

Immune Tolerance ◽

Cell Function ◽

Type I Diabetes ◽

Nod Mice ◽

Surrounding Tissue ◽

Main Task ◽

Type I ◽

Β Cell ◽

Β Cell Function ◽

Experimental Type

Type I diabetes mellitus is caused by autoimmune destruction of pancreatic β cells, and effective treatment of the disease might require rescuing β cell function in a context of reinstalled immune tolerance. Sertoli cells (SCs) are found in the testes, where their main task is to provide local immunological protection and nourishment to developing germ cells. SCs engraft, self-protect, and coprotect allogeneic and xenogeneic grafts from immune destruction in different experimental settings. SCs have also been successfully implanted into the central nervous system to create a regulatory environment to the surrounding tissue which is trophic and counter-inflammatory. We report that isolated neonatal porcine SC, administered alone in highly biocompatible microcapsules, led to diabetes prevention and reversion in the respective 88 and 81% of overtly diabetic (nonobese diabetic [NOD]) mice, with no need for additional β cell or insulin therapy. The effect was associated with restoration of systemic immune tolerance and detection of functional pancreatic islets that consisted of glucose-responsive and insulin-secreting cells. Curative effects by SC were strictly dependent on efficient tryptophan metabolism in the xenografts, leading to TGF-β–dependent emergence of autoantigen-specific regulatory T cells and recovery of β cell function in the diabetic recipients.

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