Prevention of what

Clinical islet transplantation has transitioned from curiosity to realistic therapy over the past decade. An estimated 750 patients have undergone intraportal islet-alone transplantation over this period, and a smaller subset received combined islet-kidney transplants. The primary benefit of successful islet transplantation has been to eliminate severe, recurrent hypoglycemia, a problem that has been hard to eliminate by other means in 15% of those with type 1 diabetes. The secondary benefit of independence from insulin has attracted patients, but has had limited sustainability previously, especially with a single-donor graft, but recent results from four independent centers suggest marked improvement in long-term outcome, with 5-year results now approximating solitary pancreas transplantation. Emerging data confirm that islet transplantation can stabilize and reverse several secondary diabetic complications similar to whole pancreas transplantation, but larger, head-to-head trials are needed to compare islet transplantation with best medical therapies. Current goals are to extend durability, and to make islet transplantation more widely available for patients in need. Governmental and health insurance providers in several countries now reimburse islet transplantation as part of clinical care. As the safety of the procedure and of adjunctive immunosuppressive therapies improve, and benefit accrues over potential risk, islet transplantation will be offered earlier in the course of the disease, including newly diagnosed children. The role of islet transplantation in type 2 diabetes has yet to be defined. We review the current status of islet transplantation, and discuss current and future immunosuppressive protocols that will pave the way to more broad application of cellular replacement in diabetes.

State of the Art of Clinical Islet Transplantation and Novel Protocols of Immunosuppression

Caspases are an evolutionary conserved family of cysteine-dependent proteases that are involved in many vital cellular processes including apoptosis, proliferation, differentiation and inflammatory response. Dysregulation of caspase-mediated apoptosis and inflammation has been linked to the pathogenesis of various diseases such as inflammatory diseases, neurological disorders, metabolic diseases, and cancer. Multiple caspase inhibitors have been designed and synthesized as a potential therapeutic tool for the treatment of cell death-related pathologies. However, only a few have progressed to clinical trials because of the consistent challenges faced amongst the different types of caspase inhibitors used for the treatment of the various pathologies, namely an inadequate efficacy, poor target specificity, or adverse side effects. Importantly, a large proportion of this failure lies in the lack of understanding various caspase functions. To overcome the current challenges, further studies on understanding caspase function in a disease model is a fundamental requirement to effectively develop their inhibitors as a treatment for the different pathologies. Therefore, the present review focuses on the descriptive properties and characteristics of caspase inhibitors known to date, and their therapeutic application in animal and clinical studies. In addition, a brief discussion on the achievements, and current challenges faced, are presented in support to providing more perspectives for further development of successful therapeutic caspase inhibitors for various diseases.

/pdf/a-long-way-to-go-caspase-inhibitors-in-clinical-use-4e40mjnfk3.pdf

A long way to go: caspase inhibitors in clinical use.

Aims/hypothesis
Transplantation of pancreatic islets constitutes a promising alternative treatment for type 1 diabetes. However, it is limited by the shortage of organ donors. Previous results from our laboratory have demonstrated beneficial effects of recombinant human prolactin (rhPRL) treatment on beta cell cultures. We therefore investigated the role of rhPRL action in human beta cell survival, focusing on the molecular mechanisms involved in this process.

/pdf/recombinant-human-prolactin-promotes-human-beta-cell-1ojgrkinwe.pdf

Recombinant human prolactin promotes human beta cell survival via inhibition of extrinsic and intrinsic apoptosis pathways

Background We recently found that γ-aminobutyric acid (GABA) protects mouse islet β cells. It prevented autoimmune type 1 diabetes in mice, induced islet β-cell regeneration, and exerted immunoinhibitory effects. However, it is not known whether GABA would be equally active on human islet and immune cells. Methods In vitro culture of human islets and immune cells with or without GABA and immunosuppressive drugs. In vitro analysis of apoptosis, proliferation, nuclear factor (NF)-κB activation, calcium signaling, and insulin secretion. Results GABA reduced human islet cell apoptosis in culture, such that the yield of live cells was approximately tripled after 1 week, and it stimulated insulin secretion. It protected against the deleterious effects of rapamycin, tacrolimus, and mycophenolate mofetil. In human immune cells, GABA had inhibitory effects similar to mouse cells, such as suppressed anti-CD3-stimulated T-cell proliferation, in a GABA type A receptor-dependent fashion. The immunosuppressive mechanisms have been unclear, but we found that GABA blocked calcium influx, which is a key activation signal. GABA also suppressed NF-κB activation in both human islet cells and immune cells. We found that it could be combined with rapamycin to increase its suppressive effects. Conclusions GABA improved human islet cell survival and had suppressive effects on human immune cells. It inhibited canonical NF-κB activation in both islet and immune cells. This is important because activation of this pathway is detrimental to islet cells and likely promotes damaging autoimmunity and alloreactivity against transplanted islets. These findings suggest that GABA might find applications in clinical islet transplantation.

GABA protects human islet cells against the deleterious effects of immunosuppressive drugs and exerts immunoinhibitory effects alone.

Background: Costimulation blockade has emerged as a selective, nontoxic maintenance therapy in transplantation However, these drugs must be combined with other immunomodulatory agents to ensure long term graft survival Recent work has demonstrated that caspase inhibitor therapy (EP1013) prevents engraftment phase islet loss and markedly reduces the islet mass required to reverse diabetes The ‘danger’ hypothesis suggests that reduction in graft apoptosis should reduce the threshold for immunosuppression and increase the possibility for tolerance induction Thus, the impact of combination of EP1013 treatment with costimulation blockade (CTLA4-Ig) was investigated in this study Results: Islet allografts were completed in fully MHC-mismatched mice (Balb/C to B6) When animals received vehicle or EP1013, there was no difference in graft survival CTLA4-Ig resulted in prolonged graft survival in 40% of the animals, while EP1013+CLTA4-Ig resulted in a significant increase in graft survival (91% >180 days; P=002) Ex vivo analysis revealed that animals receiving EP1013 or EP1013+CTLA4-Ig had a reduced frequency of alloreactive IFNγ-secreting T-cells and an increased frequency of intragraft Foxp3+ Treg cells Alloantibody assays indicated that treatment with EP1013 or CTLA4-Ig prevented allosensitization Conclusion: This study suggests that addition of caspase inhibitor therapy to costimulation blockade will improve clinical transplantation by minimizing immune stimulation and thus reduce the requirement for long term immunosuppressive therapy The approach also prevents allosensitization, which may be an important component of chronic graft loss in clinical transplantation

/pdf/caspase-inhibitor-therapy-synergizes-with-costimulation-20gz5z0h56.pdf

Caspase inhibitor therapy synergizes with costimulation blockade to promote indefinite islet allograft survival.

OBJECTIVE— Clinical islet transplantation can provide insulin independence in patients with type 1 diabetes, but chronic graft failure has been observed. This has been attributed in part to loss of ≥60% of the transplanted islets in the peritransplant period, resulting in a marginal implant mass. Strategies designed to maximize survival of the initial islet mass are likely to have major impact in enhancing long-term clinical outcomes. EP1013 ( N -benzyloxycabonyl-Val Asp-fluoromethyl ketone [zVD-FMK]), is a broad-spectrum caspase selective inhibitor with no observed toxicity in rodents. RESEARCH DESIGN AND METHODS— The therapeutic benefit of EP1013 was examined in a syngeneic rodent islet transplant model using deceased donor human islets to determine whether the amount of tissue required to restore euglycemia in diabetic animals could be reduced. RESULTS— EP1013 (combined pretransplant islet culture for 2 h and in vivo treatment for days 0–5 posttransplant) significantly improved marginal islet mass function following syngeneic islet transplantation in mice, even at lower doses, compared with previous studies using the pan-caspase inhibitor N -benzyloxycabonyl-Val Ala-Asp-fluoromethyl ketone (zVAD-FMK). EP1013 supplementation in vitro improved human islet yields following prolonged culture and reversed diabetes following implantation of a marginal human islet mass (80–90% reduction) into mice. CONCLUSIONS— Our data suggest that EP1013 therapy will markedly reduce the islet mass required in clinical islet transplantation, improving insulin independence rates following single-donor infusion.

https://diabetes.diabetesjournals.org/content/diabetes/57/6/1556.full.pdf

The caspase selective inhibitor EP1013 augments human islet graft function and longevity in marginal mass islet transplantation in mice

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Caspase inhibitor therapy synergizes with costimulation blockade to promote indefinite islet allograft survival.

The caspase selective inhibitor EP1013 augments human islet graft function and longevity in marginal mass islet transplantation in mice