Antiaging Glycopeptide Protects Human Islets Against Tacrolimus-Related Injury and Facilitates Engraftment in Mice

Gala-López, Boris; Pepper, Andrew R.; Pawlick, Rena; O’Gorman, Doug; Kin, Tatsuya; Bruni, Antonio; Abualhassan, Nasser; Bral, Mariusz; Bautista, Austin; Fox, Jocelyn E. Manning; Young, Lachlan G; MacDonald, Patrick E.; Shapiro, A.M. James

doi:10.2337/db15-0764

Cited by 24 publications

(20 citation statements)

References 41 publications

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“…Gala-Lopez et al found that an anti-aging glycopeptide (AAGP) protected human islets from tacrolimus toxicity and promoted graft survival and function. 133 Ongoing work in the area of tolerance induction using myeloablative chemotherapy or nonablative cellular therapeutics including facilitating cells or Tregs could transform future opportunities across all aread of transplantation.…”

Section: Post-transplant Limitationsmentioning

confidence: 99%

The journey of islet cell transplantation and future development

Gamble

Pepper

Bruni

2018

Islets

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141

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Intraportal islet transplantation has proven to be efficacious in preventing severe hypoglycemia and restoring insulin independence in selected patients with type 1 diabetes. Multiple islet infusions are often required to achieve and maintain insulin independence. Many challenges remain in clinical islet transplantation, including substantial islet cell loss early and late after islet infusion. Contributions to graft loss include the instant blood-mediated inflammatory reaction, potent host auto- and alloimmune responses, and beta cell toxicity from immunosuppressive agents. Protective strategies are being tested to circumvent several of these events including exploration of alternative transplantation sites, stem cell-derived insulin producing cell therapies, co-transplantation with mesenchymal stem cells or exploration of novel immune protective agents. Herein, we provide a brief introduction and history of islet cell transplantation, limitations associated with this procedure and methods to alleviate islet cell loss as a means to improve engraftment outcomes.

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Section: Post-transplant Limitationsmentioning

confidence: 99%

The journey of islet cell transplantation and future development

Gamble

Pepper

Bruni

2018

Islets

Self Cite

141

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“…It is widely believed that NODAT is caused by exposure to steroids or high dose calcineurin inhibitors, including tacrolimus (TAC; also known as FK506) and cyclosporin (CsA) (1,2). These drugs are shown to damage cell types critical for the maintenance of glucose homeostasis, particularly pancreatic b-cells (3). TAC is a mainstay for prevention of transplant rejection, but effective immunosuppression targeting a concentration range of 4-11 ng/mL still results in NODAT in > 20% of patients (1).…”

Section: Introductionmentioning

confidence: 99%

Differential effects of voclosporin and tacrolimus on insulin secretion from human islets

Kolic

Beet

Overby

et al. 2020

Preprint

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27Context. The incidence of new onset diabetes after transplant (NODAT) has increased over the 28 past decade. It has been suggested that NODAT is caused by exposure to calcineurin inhibitors, 29 particularly tacrolimus (TAC). Voclosporin (VCS), a next generation calcineurin inhibitor is 30 reported to cause fewer incidences of NODAT. 32Objective. Whilst calcineurin plays important roles in pancreatic -cell survival, proliferation, and 33 function, the effects of calcineurin inhibitors on human -cells remain understudied. In particular, 34 we do not understand why some inhibitors have more profound effects on the incidence of 35 NODAT. 37Design. Here, we compared the effects of TAC and VCS on the dynamics of insulin secretory 38 function, the programmed cell death rate, and the transcriptomic profile of human islets. We 39 studied two clinically relevant doses of TAC (10 ng/ml, 30 ng/ml) and VCS (20 ng/ml, 60 ng/ml), 40 meant to approximate the clinical trough and peak concentrations. 42Results. TAC, but not VCS, caused a significant impairment of 15 mM glucose-stimulated insulin 43 secretion and 30 mM KCl-stimulated insulin secretion. This points to molecular defects in the 44 distal stages of exocytosis after voltage-gated Ca2+ entry. No significant effects on islet cell 45 survival or total islet insulin content were identified. RNA sequencing showed that TAC, and to a 46 lesser extent VCS, decreased the expression of genes that regulate insulin exocytosis, trafficking, 47 and processing, including SYT16, SYT5, PITPNM1, and PAM. 49Conclusions. TAC directly inhibits insulin secretion, likely via transcriptional control of exocytosis 50 machinery. VCS was found to be gentler on isolated human islets than TAC. 51 54 steroids or high dose calcineurin inhibitors, particularly tacrolimus, on cell types that are critical 55 for the maintenance of glucose homeostasis (1). Tacrolimus (TAC; also known as FK506) is a 56 mainstay for prevention of transplant rejection, but effective immunosuppression targeting a 57 concentration range of 4-11 ng/mL still results in NODAT in > 20% of patients (2). There is an 58 unmet clinical need for calcineurin inhibitors that do not cause diabetes in this already vulnerable 59 patient population. 60Voclosporin (VCS) is a next-generation calcineurin inhibitor that is structurally related to 61 cyclosporine A (CsA) with the addition of a carbon molecule at amino acid-1 of (CsA). This 62 modification results in enhanced binding of the VCS-cyclophilin complex to calcineurin and shifts 63 metabolism, resulting in increased potency and a consistent pharmacokinetic-pharmacodynamic 64 profile as compared to (CsA). VCS was previously evaluated in a Phase IIb, multi-center, open-65 label, concentration-controlled study in patients undergoing de novo renal transplantation, 66 evaluating the efficacy and safety of three doses of VCS (0.4, 0.6, and 0.8 mg/kg BID) as 67 compared to TAC (3). In that study, the low-dose VCS group had similar efficacy to tacrolimus in 68 controlling acute rejection w...

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“…But tacrolimus is also shown not to cause significant apoptosis in beta-cells [ 6 , 39 ], which correlates well with our findings of no increase in cell death following tacrolimus exposure. Short time exposure of tacrolimus has recently been shown to highly suppress insulin secretion in human islets without changing intracellular insulin content or viability [ 40 ]. This is consistent with our study ( Figure 1(c) ) and others [ 6 , 39 ].…”

Section: Discussionmentioning

confidence: 99%

Treatment with Tacrolimus and Sirolimus Reveals No Additional Adverse Effects on Human IsletsIn VitroCompared to Each Drug Alone but They Are Reduced by Adding Glucocorticoids

Kloster-Jensen

Sahraoui

Vethe

et al. 2016

Journal of Diabetes Research

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Tacrolimus and sirolimus are important immunosuppressive drugs used in human islet transplantation; however, they are linked to detrimental effects on islets and reduction of long-term graft function. Few studies investigate the direct effects of these drugs combined in parallel with single drug exposure. Human islets were treated with or without tacrolimus (30 μg/L), sirolimus (30 μg/L), or a combination thereof for 24 hrs. Islet function as well as apoptosis was assessed by glucose-stimulated insulin secretion (GSIS) and Cell Death ELISA. Proinflammatory cytokines were analysed by qRT-PCR and Bio-Plex. Islets exposed to the combination of sirolimus and tacrolimus were treated with or without methylprednisolone (1000 μg/L) and the expression of the proinflammatory cytokines was investigated. We found the following: (i) No additive reduction in function and viability in islets existed when tacrolimus and sirolimus were combined compared to the single drug. (ii) Increased expression of proinflammatory cytokines mRNA and protein levels in islets took place. (iii) Methylprednisolone significantly decreased the proinflammatory response in islets induced by the drug combination. Although human islets are prone to direct toxic effect of tacrolimus and sirolimus, we found no additive effects of the drug combination. Short-term exposure of glucocorticoids could effectively reduce the proinflammatory response in human islets induced by the combination of tacrolimus and sirolimus.

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Antiaging Glycopeptide Protects Human Islets Against Tacrolimus-Related Injury and Facilitates Engraftment in Mice

Cited by 24 publications

References 41 publications

The journey of islet cell transplantation and future development

The journey of islet cell transplantation and future development

Differential effects of voclosporin and tacrolimus on insulin secretion from human islets

Treatment with Tacrolimus and Sirolimus Reveals No Additional Adverse Effects on Human IsletsIn VitroCompared to Each Drug Alone but They Are Reduced by Adding Glucocorticoids

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