Local Expression of Indoleamine 2,3 Dioxygenase in Syngeneic Fibroblasts Significantly Prolongs Survival of an Engineered Three-Dimensional Islet Allograft

Jalili, Reza B.; Forouzandeh, Farshad; Rezakhanlou, Alireza M.; Hartwell, Ryan; Medina, Abelardo; Warnock, Garth L.; Larijani, Bagher; Ghahary, Aziz

doi:10.2337/db09-1560

Cited by 46 publications

(56 citation statements)

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“…Our research group conducted a series of novel studies showing the potential use of three-dimensional islet grafts equipped with IDO-expressing dermal fibroblasts to prevent islet allograft rejection without systemic immunosuppressive agents. We showed that IDO genetically modified islets transplanted into mouse kidney capsules survive longer than those islets transplanted without IDO expressing fibroblasts (Jalili et al 2010). This prolongation was due to the expression of IDO preventing T cell proliferation and infiltration into transplanted allogeneic islets (Jalili et al 2010).…”

Section: Role Of Ido Expression In Allogeneic Islet Transplantationmentioning

confidence: 91%

“…We showed that IDO genetically modified islets transplanted into mouse kidney capsules survive longer than those islets transplanted without IDO expressing fibroblasts (Jalili et al 2010). This prolongation was due to the expression of IDO preventing T cell proliferation and infiltration into transplanted allogeneic islets (Jalili et al 2010).…”

Section: Role Of Ido Expression In Allogeneic Islet Transplantationmentioning

confidence: 91%

“…Tryptophan starvation also causes naïve CD4+ T lymphocyte conversion to immunosuppressive regulatory T cells (Tregs) (Fallarino et al 2006) and activation of mature CD4+ CD25+ Foxp3+ Tregs . An increase in the number of Tregs causes an antigen-specific impairment of T-cell priming (Jalili et al 2010). The IDO overexpression also induces a Th2 immune response shift and generates an anti-inflammatory cytokine profile (Jalili et al 2010).…”

Section: Ido and Immunosuppressionmentioning

confidence: 99%

“…An increase in the number of Tregs causes an antigen-specific impairment of T-cell priming (Jalili et al 2010). The IDO overexpression also induces a Th2 immune response shift and generates an anti-inflammatory cytokine profile (Jalili et al 2010). IDO has also been known to be an innate defense mechanism.…”

Section: Ido and Immunosuppressionmentioning

confidence: 99%

“…Later studies by our research group (Jalili et al 2010) investigated the potential use of composite 3-dimensional islet grafts. These grafts were engineered by embedding allogeneic mouse islets and adenoviral transduced IDO-expressing syngeneic bystander fibroblasts within collagen gel matrices (Jalili et al 2010).…”

Section: Role Of Ido Expression In Allogeneic Islet Transplantationmentioning

confidence: 99%

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Immuno-modulatory Role of Indoleamine 2, 3-Dioxygenase in Allogeneic Islet and Skin Transplantation

Gill¹,

Jalili²,

Ghahary³

2013

IMMU

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Indoleamine 2, 3-dioxygenase (IDO) is a naturally occurring immunomodulatory agent that has been found to play a key role in preventing rejection of the semi-allogeneic fetus during pregnancy. It is a cytosolic monomeric hemoprotein enzyme that degrades tryptophan, the least available essential amino acid in the body, through the kynurenine metabolic pathway. This causes a regulatory effect on T cells by, as it has been proposed, causing toxic tryptophan metabolites to accumulate and a tryptophan deficient microenvironment to form. By helping with the induction of T cell unresponsiveness, IDO has been shown to establish immune tolerance and control autoreactive immune responses. Thus, the application of IDO's ability to do this may have a huge potential in improving the rates of acceptance of insulin producing islet cell or skin graft transplants in patients suffering from conditions such as type I diabetes or burn injuries, respectively. The discovery of an agent able to do this is especially important since currently used systemic immunosuppressive drugs carry many side effects and cause complications that make the long term use of these agents problematic after transplantation. This review discusses the immunomodulatory role of IDO and the very promising results of studies done by our research group on the application of this enzyme in islet and skin transplantation.

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Section: Role Of Ido Expression In Allogeneic Islet Transplantationmentioning

confidence: 91%

Section: Role Of Ido Expression In Allogeneic Islet Transplantationmentioning

confidence: 91%

Section: Ido and Immunosuppressionmentioning

confidence: 99%

Section: Ido and Immunosuppressionmentioning

confidence: 99%

Section: Role Of Ido Expression In Allogeneic Islet Transplantationmentioning

confidence: 99%

See 3 more Smart Citations

Immuno-modulatory Role of Indoleamine 2, 3-Dioxygenase in Allogeneic Islet and Skin Transplantation

Gill¹,

Jalili²,

Ghahary³

2013

IMMU

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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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Diabetes and Tryptophan Metabolism

Ünlütürk

Erbaş

2015

Molecular and Integrative Toxicology

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Tryptophan, an essential amino acid, can be metabolized to several kinds of physiologically active metabolites. Accumulating data indicate that an altered metabolism of tryptophan and its active metabolites have important roles for the pathogenesis and development of complications of diabetes mellitus. Changes in tryptophan-kynurenine and tryptophan-methoxyindole pathways are related to several pathophysiological mechanisms of type 1 or type 2 diabetes. Particularly, serotonin, melatonin, and their receptors would be novel targets not only to better understand the pathogenesis of diabetes but also to develop new antidiabetic agents. Keywords IntroductionIn addition to the traditional knowledge, recent studies show that amino acids are also among the regulators of the phosphorylation cascade of proteins and expression of genes. Moreover, they are crucial precursors of hormones and nitrogenous substances with outstanding biological importance. Even though physiological concentrations of amino acids and their metabolites are necessary for physiological processes, their elevated levels might be pathogenic in several disorders. Several

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Local Expression of Indoleamine 2,3 Dioxygenase in Syngeneic Fibroblasts Significantly Prolongs Survival of an Engineered Three-Dimensional Islet Allograft

Cited by 46 publications

References 50 publications

Immuno-modulatory Role of Indoleamine 2, 3-Dioxygenase in Allogeneic Islet and Skin Transplantation

Immuno-modulatory Role of Indoleamine 2, 3-Dioxygenase in Allogeneic Islet and Skin Transplantation

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

Diabetes and Tryptophan Metabolism

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