Immunosuppression in islet transplantation

Belle, Tom Van; Herrath, Matthias von

doi:10.1172/jci35639

Cited by 22 publications

(21 citation statements)

References 23 publications

(28 reference statements)

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“…In line with previous data [4], this phenomenon was transient and normalised by day 21 after transplantation. However, the replenishing of the depleted T cell pool coincides with the destruction of the transplanted islet mass in anti-CD3-treated islet recipients, suggesting that anti-CD3 alone is insufficient to restrain the autoreactivity of the homeostatically expanded T cells, a problematic side effect of immunosuppressive therapies [32,33]. Our CT on the other hand resembles anti-CD3 monotherapy in its partial and transient T cell depletion, suggesting that additional phenomena must explain the prolonged diabetes-free period.…”

Section: Discussionmentioning

confidence: 72%

Low doses of anti-CD3, ciclosporin A and the vitamin D analogue, TX527, synergise to delay recurrence of autoimmune diabetes in an islet-transplanted NOD mouse model of diabetes

et al. 2012

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Aims/hypothesis Anti-CD3 monoclonal antibodies remain the most promising immune therapy for reversing recentonset type 1 diabetes. However, current clinical trials have revealed their major drawback, namely the narrow therapeutic window in which low doses are ineffective and higher doses that preserve functional beta cell mass cause side effects. Strategies that sidestep these limitations while preserving or improving anti-CD3's therapeutic efficiency are essential. We hypothesised that combining a potent vitamin D 3 analogue (TX527), ciclosporin A (CsA) and anti-CD3 would act to lower the dose while maintaining or even boosting therapeutic efficacy to counteract autoimmune destruction of transplanted islets. Methods This study involved the use of syngeneic islet transplantation, immunofluorescence microscopy, immune phenotyping by flow cytometry, RT-PCR analysis, and in vitro and in vivo suppression assays. Results Combination therapy with TX527, CsA and anti-CD3 was well tolerated on the basis of weight, bone and calcium variables. Remarkably, combining all three agents at sub-therapeutic doses greatly reduced recurrent autoimmune responses to a grafted islet mass (mean±SEM: 79.5±18.6 days; p<0.01), by far exceeding the therapeutic efficacy of monotherapy (24.8±7.3 days for anti-CD3) and dual therapy (25.5±12.4 days for anti-CD3+CsA). Combination therapy surpassed anti-CD3 monotherapy in reducing islet infiltration by effector/memory phenotype CD8 + T cells, as well as by reducing proinflammatory cytokine responses and increasing the frequency of T regulatory cells that were functional in vitro and in vivo, and acted in a cytotoxic T lymphocyte antigen 4-dependent manner. Conclusions/interpretation Combining the immunomodulatory actions of anti-CD3 mAb with CsA and the vitamin D 3 analogue, TX527, delivers therapeutic efficacy in an islettransplanted NOD mouse model of diabetes.

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Section: Discussionmentioning

confidence: 72%

Low doses of anti-CD3, ciclosporin A and the vitamin D analogue, TX527, synergise to delay recurrence of autoimmune diabetes in an islet-transplanted NOD mouse model of diabetes

et al. 2012

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“…In the original Edmonton protocol, patients infused with pancreatic islets from multiple cadaveric donors simultaneously received immune suppression in the form of a humanized anti-CD25 mAb (daclizumab) and continuous administration of low-dose rapamycin (sirolimus), which inhibits the response to IL-2, and FK-506 (tacrolimus), a calcineurin inhibitor blocking IL-2 production. However, this regimen was shown to cause lymphopenia and an elevation of the levels of homeostatic cytokines that drive the expansion of autoreactive CD8 T cells (294,447). Consequently, the Edmonton protocol has been modified in several ways.…”

Section: Islet Transplantationmentioning

confidence: 99%

Type 1 Diabetes: Etiology, Immunology, and Therapeutic Strategies

Belle

Coppieters

Herrath

2011

Physiological Reviews

854

695

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Type 1 diabetes (T1D) is a chronic autoimmune disease in which destruction or damaging of the beta-cells in the islets of Langerhans results in insulin deficiency and hyperglycemia. We only know for sure that autoimmunity is the predominant effector mechanism of T1D, but may not be its primary cause. T1D precipitates in genetically susceptible individuals, very likely as a result of an environmental trigger. Current genetic data point towards the following genes as susceptibility genes: HLA, insulin, PTPN22, IL2Ra, and CTLA4. Epidemiological and other studies suggest a triggering role for enteroviruses, while other microorganisms might provide protection. Efficacious prevention of T1D will require detection of the earliest events in the process. So far, autoantibodies are most widely used as serum biomarker, but T-cell readouts and metabolome studies might strengthen and bring forward diagnosis. Current preventive clinical trials mostly focus on environmental triggers. Therapeutic trials test the efficacy of antigen-specific and antigen-nonspecific immune interventions, but also include restoration of the affected beta-cell mass by islet transplantation, neogenesis and regeneration, and combinations thereof. In this comprehensive review, we explain the genetic, environmental, and immunological data underlying the prevention and intervention strategies to constrain T1D.

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“…However, this treatment is not suitable for all diabetic patients because of its high risk of hypoglycemia secondary to excessive insulin dosage (1). Additionally, cell therapies, including cadaveric and stem cell–derived islet transplantation, require life-long immunosuppression (2,29). Our approach circumvents a number of the challenges of diabetes therapy.…”

Section: Discussionmentioning

confidence: 99%

Treatment of Diabetes and Long-Term Survival After Insulin and Glucokinase Gene Therapy

et al. 2013

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Diabetes is associated with severe secondary complications, largely caused by poor glycemic control. Treatment with exogenous insulin fails to prevent these complications completely, leading to significant morbidity and mortality. We previously demonstrated that it is possible to generate a “glucose sensor” in skeletal muscle through coexpression of glucokinase and insulin, increasing glucose uptake and correcting hyperglycemia in diabetic mice. Here, we demonstrate long-term efficacy of this approach in a large animal model of diabetes. A one-time intramuscular administration of adeno-associated viral vectors of serotype 1 encoding for glucokinase and insulin in diabetic dogs resulted in normalization of fasting glycemia, accelerated disposal of glucose after oral challenge, and no episodes of hypoglycemia during exercise for >4 years after gene transfer. This was associated with recovery of body weight, reduced glycosylated plasma proteins levels, and long-term survival without secondary complications. Conversely, exogenous insulin or gene transfer for insulin or glucokinase alone failed to achieve complete correction of diabetes, indicating that the synergistic action of insulin and glucokinase is needed for full therapeutic effect. This study provides the first proof-of-concept in a large animal model for a gene transfer approach to treat diabetes.

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Immunosuppression in islet transplantation

Cited by 22 publications

References 23 publications

Low doses of anti-CD3, ciclosporin A and the vitamin D analogue, TX527, synergise to delay recurrence of autoimmune diabetes in an islet-transplanted NOD mouse model of diabetes

Low doses of anti-CD3, ciclosporin A and the vitamin D analogue, TX527, synergise to delay recurrence of autoimmune diabetes in an islet-transplanted NOD mouse model of diabetes

Type 1 Diabetes: Etiology, Immunology, and Therapeutic Strategies

Treatment of Diabetes and Long-Term Survival After Insulin and Glucokinase Gene Therapy

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