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

Hosseini‐Tabatabaei, Azadeh; Jalili, Reza B.; Khosravi‐Maharlooei, Mohsen; Hartwell, Ryan; Kilani, Ruhangiz T.; Zhang, Yun; Ghahary, Aziz

doi:10.1097/tp.0000000000000661

Cited by 15 publications

(15 citation statements)

References 23 publications

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“…This was attributed to several different immune factors, including reduced T-cell infiltration into the graft, a shift from a pro-inflammatory Th1 to an anti-inflammatory Th2 response and impaired T-cell priming, although the IDO1-expressing islets did eventually succumb to host immune attack [295,296]. In an effort to further prolong allogenic islet acceptance, Hosseini-Tabatabaei et al [297] recently developed a stable biomimetic scaffold (to re-establish the extracellular matrix that is lost during islet isolation) housing IDO1-expressing fibroblasts to support islet implantation and survival in mice. This method lengthened the survival of islet allografts 4-fold by enhancing Treg infiltration into the graft itself and the draining lymph nodes [297].…”

Section: Transplantation the Ultimate Goal In Organ Transplantationmentioning

confidence: 97%

“…In an effort to further prolong allogenic islet acceptance, Hosseini-Tabatabaei et al [297] recently developed a stable biomimetic scaffold (to re-establish the extracellular matrix that is lost during islet isolation) housing IDO1-expressing fibroblasts to support islet implantation and survival in mice. This method lengthened the survival of islet allografts 4-fold by enhancing Treg infiltration into the graft itself and the draining lymph nodes [297]. Importantly, insulin staining determined that these islets maintained their functionality.…”

Section: Transplantation the Ultimate Goal In Organ Transplantationmentioning

confidence: 99%

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Role of indoleamine 2,3-dioxygenase in health and disease

et al. 2015

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IDO1 (indoleamine 2,3-dioxygenase 1) is a member of a unique class of mammalian haem dioxygenases that catalyse the oxidative catabolism of the least-abundant essential amino acid, L-Trp (L-tryptophan), along the kynurenine pathway. Significant increases in knowledge have been recently gained with respect to understanding the fundamental biochemistry of IDO1 including its catalytic reaction mechanism, the scope of enzyme reactions it catalyses, the biochemical mechanisms controlling IDO1 expression and enzyme activity, and the discovery of enzyme inhibitors. Major advances in understanding the roles of IDO1 in physiology and disease have also been realised. IDO1 is recognised as a prominent immune regulatory enzyme capable of modulating immune cell activation status and phenotype via several molecular mechanisms including enzyme-dependent deprivation of L-Trp and its conversion into the aryl hydrocarbon receptor ligand kynurenine and other bioactive kynurenine pathway metabolites, or non-enzymatic cell signalling actions involving tyrosine phosphorylation of IDO1. Through these different modes of biochemical signalling, IDO1 regulates certain physiological functions (e.g. pregnancy) and modulates the pathogenesis and severity of diverse conditions including chronic inflammation, infectious disease, allergic and autoimmune disorders, transplantation, neuropathology and cancer. In the present review, we detail the current understanding of IDO1's catalytic actions and the biochemical mechanisms regulating IDO1 expression and activity. We also discuss the biological functions of IDO1 with a focus on the enzyme's immune-modulatory function, its medical implications in diverse pathological settings and its utility as a therapeutic target.

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Section: Transplantation the Ultimate Goal In Organ Transplantationmentioning

confidence: 97%

Section: Transplantation the Ultimate Goal In Organ Transplantationmentioning

confidence: 99%

Role of indoleamine 2,3-dioxygenase in health and disease

et al. 2015

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“…We found that they functionally recovered the remaining islet beta cells and successfully reversed hyperglycemia in a prominently high percentage of NOD mouse recipients due to regulating several possible immunological contributing factors of T1D. Although the previous studies from our group have identified the suppressive effects of IDO on alloimmunity in islet transplantation (Jalili et al, ; Poormasjedi‐Meibod et al, ; Hosseini‐Tabatabaei et al, ), this is the first study to show the role of optimized IDO‐expressing fibroblasts in the regulation of autoimmune diabetes and the underlying mechanisms.…”

Section: Discussionmentioning

confidence: 57%

IDO‐Expressing Fibroblasts Protect Islet Beta Cells From Immunological Attack and Reverse Hyperglycemia in Non‐Obese Diabetic Mice

Zhang

Jalili

Kilani

et al. 2016

Journal Cellular Physiology

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Indoleamine 2,3-dioxygenase (IDO) induces immunological tolerance in physiological and pathological conditions. Therefore, we used dermal fibroblasts with stable IDO expression as a cell therapy to: (i) Investigate the factors determining the efficacy of this cell therapy for autoimmune diabetes in non-obese diabetic (NOD) mice; (ii) Scrutinize the potential immunological mechanisms. Newly diabetic NOD mice were randomly injected with either 10 × 10(6) (10M) or 15 × 10(6) (15M) IDO-expressing dermal fibroblasts. Blood glucose levels (BGLs), body weight, plasma kynurenine levels, insulitis severity, islet beta cell function, autoreactive CD8(+) T cells, Th17 cells and regulatory T cells (Tregs) were then investigated in these mice. IL-1β and cleaved caspase-3 levels were assessed in islets co-cultured with IDO-expressing fibroblasts. BGLs in 83% mice treated with 15M IDO-expressing fibroblasts recovered to normal up to 120 days. However, only 17% mice treated with 10M IDO-expressing cells were reversed to normoglycemia. A 15M IDO-expressing fibroblasts significantly reduced infiltrated immune cells in islets and recovered the functionality of remaining islet beta cells in NOD mice. Additionally, they successfully inhibited autoreactive CD8(+) T cells and Th17 cells as well as increased Tregs in different organs of NOD mice. Islet beta cells co-cultured with IDO-expressing fibroblasts had reduced IL-1β levels and cell apoptosis. Both cell number and IDO enzymatic activity contributes to the efficiency of IDO cell therapy. Optimized IDO-expressing fibroblasts successfully reverse the progression of diabetes in NOD mice through induction of Tregs as well as inhibition of beta cell specific autoreactive CD8(+) T cells and Th17 cells. J. Cell. Physiol. 231: 1964-1973, 2016. © 2016 Wiley Periodicals, Inc.

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“…Mesenchymal stem cells expressing IDO have been linked to increased renal graft survival. Mice experiments showed that islets equipped with IDO‐expressing fibroblasts extend graft survival . This example nicely illustrates the interplay between these different immunoprotective factors.…”

Section: Ctla‐4 Pd‐l1 and Idomentioning

confidence: 64%

Targeting CTLA‐4, PD‐L1 and IDO to modulate immune responses in vitiligo

Speeckaert

Geel

2016

Experimental Dermatology

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For decades, an extensive debate is continued on the pathophysiology of vitiligo. Numerous hypotheses have been put forward, and many supported by well-documented arguments. Regardless of the initiating steps, most experts agree that an immune-based melanocyte destruction is responsible for the final steps leading to epidermal depigmentation. It is remarkable that currently the only therapeutic approach to counter this phenomenon consists of non-specific local and systemic immunosuppressants. Immunotherapy for melanoma reveals that targeting factors involved in peripheral tolerance are sufficient to break the natural defense mechanisms to develop skin depigmentations. Therapeutically enhancing these immune checkpoints seems therefore a promising long-term therapy for vitiligo. In this viewpoint, we propose this strategy as a promising therapeutic option for vitiligo. Several approaches are proposed with a focus on cytotoxic T-lymphocyte-associated protein 4, programmed death ligand-1 and indoleamine 2,3-dioxygenase.

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

Abstract: This study shows that incorporation of islets within our novel matrix that is equipped with stable IDO-expressing fibroblasts prolongs allograft survival.

Cited by 15 publications

References 23 publications

Role of indoleamine 2,3-dioxygenase in health and disease

Role of indoleamine 2,3-dioxygenase in health and disease

IDO‐Expressing Fibroblasts Protect Islet Beta Cells From Immunological Attack and Reverse Hyperglycemia in Non‐Obese Diabetic Mice

Targeting CTLA‐4, PD‐L1 and IDO to modulate immune responses in vitiligo

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