Mouse Pancreatic Islets Are Resistant to Indoleamine 2,3 Dioxygenase-Induced General Control Nonderepressible-2 Kinase Stress Pathway and Maintain Normal Viability and Function

Abstract

Islet transplantation is a promising treatment for diabetes. However, it faces several challenges including requirement of systemic immunosuppression. Indoleamine 2,3-dioxygenase (IDO), a tryptophan degrading enzyme, is a potent immunomodulatory factor. Local expression of IDO in bystander fibroblasts suppresses islet allogeneic immune response in vitro. The aim of the present study was to investigate the impact of IDO on viability and function of mouse islets embedded within IDO-expressing fibroblastpopulated collagen scaffold. Mouse islets were embedded within collagen matrix populated with IDO adenovector-transduced or control fibroblasts. Proliferation, insulin content, glucose responsiveness, and activation of general control nonderepressible-2 kinase stress-responsive pathway were then measured in IDOexposed islets. In vivo viabilities of composite islet grafts were also tested in a syngeneic diabetic animal model. No reduction in islet cells proliferation was detected in both IDO-expressing and control composites compared to the baseline rates. Islet functional studies showed normal insulin content and secretion in both preparations. In contrast to lymphocytes, general control nonderepressible-2 kinase pathway was not activated in islets cocultured with IDO-expressing fibroblasts. When transplanted to diabetic mice, syngeneic IDO-expressing composite islet grafts were functional up to 100 days tested. These findings collectively confirm normal viability and functionality of islets cocultured with IDO-expressing cells and indicate the feasibility of development of a functional nonrejectable islet graft.

Indoleamine 2,3-dioxygenase, Tregs and Cancer

“…Compared to other cell types, T cells appear particularly sensitive to the effects of GCN2 [106]. However, like many signaling pathways, GCN2 elicits different downstream cellular responses in different subsets of T cells [104].…”

Immuno-Regulatory Function of Indoleamine 2,3 Dioxygenase through Modulation of Innate Immune Responses

“…Forouzandeh et al studies [23] also revealed that selective activation of GCN2 kinase pathway in response to IDO induced tryptophan deficiency is responsible for T cell apoptosis. Further studies by our group [8], [24], [25] demonstrated that IDO expression by bystander fibroblasts can prevent cellular and humoral allo-immune responses against islet allotransplant without having any adverse effect on viability and functionality of the graft. Although these data support the feasibility of using local IDO expression as an alternative for systemic immunosuppressive treatments following allotransplantation, there are limited reports [26], [27] that have examined the use of IDO expression for graft protection following xenotransplantation.…”

Immunoprotection and Functional Improvement of Allogeneic Islets in Diabetic Mice, Using a Stable Indoleamine 2,3-Dioxygenase Producing Scaffold

“…13 Indoleamine 2,3-dioxygenase generates a microenvironment, low in tryptophan and rich in kynurenine metabolites, that is selectively toxic to T-cells, whereas allogeneic islets remain intact. 13,14 Using the FPCM, we demonstrated that transient adenoviral transduction of IDO in fibroblasts prolongs the survival of allogeneic islets embedded within this scaffold up to 6 weeks. 15 The purpose of this study was, therefore, to overcome 2 main difficulties that we encountered in our previous research: (i) the gradual biodegradation and contractibility of FPCM that could compromise long-term transplant outcome 8 ; and (ii) the transient IDO expression in fibroblasts, limiting the period of graft survival.…”