Indoleamine 2,3 dioxygenase contributes to transferable tolerance in rat red blood cell inducible model of experimental autoimmune haemolytic anaemia

Dahal, Lekh N.; Hall, Lindsay S; Barker, Robert N.; Ward, Frank J.

doi:10.1111/cei.12091

Cited by 8 publications

(6 citation statements)

References 35 publications

(52 reference statements)

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“…Erythrocyte autoantibodies are detectable within 5–6 weeks and correlate with a shortened RBC lifespan and a significant drop in hematocrit and hemoglobin [ 29 ]. Similar to observations with the NZB murine model, predisposition to AIHA involves genetics, gender, and dysregulation of cytokines [ 30 – 33 ]. Distinctly, findings in this model have elucidated that T cell immune responses to RBC-derived antigens are cross-reactive between species and that linked recognition of foreign rat RBC-derived epitopes provide help to murine RBC autoreactive B cells and can induce AIHA [ 34 – 36 ].…”

Section: Playfair and Marshall–clarke Model: Experimentally Induced Asupporting

confidence: 60%

Murine models of autoimmune hemolytic anemia

Howie

Hudson

2018

Current Opinion in Hematology

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Purpose of reviewPathogenic autoantibodies directed against red blood cells (RBCs) may lead to autoimmune hemolytic anemia (AIHA), a severe and sometimes fatal disease. Much of what is known about the etiology and pathogenesis of AIHA has been learned from observations made in human patients and murine models, but many questions remain; importantly, it is still unclear why some people generate RBC-specific autoantibodies. The combination of technological advancements applied to existing models and the development of new AIHA murine models will continue to provide considerable insight into the initiation of AIHA and provide a platform for the design of more effective therapies.Recent findingsAdvancements in well described murine models of AIHA show that reticulocytes are preferentially targeted by anti-RBC autoantibodies and an increase in oxidative stress may trigger autoantibody production. Additionally, a new murine model of erythrocyte autoreactivity demonstrates that T cell tolerance is the stopgap for autoimmunity. Moreover, unlike many self-antigens, data suggest that RBC self-antigens are not presented in the thymus thereby escaping the scrutiny of T cell central tolerance mechanisms and placing emphasis on peripheral tolerance instead. Information gained from this new model provide novel insight into how the immune system responds to RBC autoantigens and provides a tractable platform to discover new therapies for AIHA.SummaryMurine models of AIHA have provided significant understanding into the risk factors for AIHA. The application of new technologies and models of erythrocyte autoreactivity is a pathway with the potential to elucidate how tolerance to RBC autoantigens is established, maintained, and broken down.

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Section: Playfair and Marshall–clarke Model: Experimentally Induced Asupporting

confidence: 60%

Murine models of autoimmune hemolytic anemia

Howie

Hudson

2018

Current Opinion in Hematology

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“…Pharmacological inhibition of IDO has been shown to break maternal immune tolerance in pregnancy, spontaneously aborting fetus, and precipitate autoimmunity in susceptible strains in mice ( 42 , 43 ). Such findings provided proof-of-concept that breaking tolerance to tumor antigens in cancers where IDO is used as a route to immune escape may hold promise for cancer immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

Investigating the Role of Indoleamine 2,3-Dioxygenase in Acute Myeloid Leukemia: A Systematic Review

2021

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Background: The immunomodulatory enzyme, indoleamine 2,3-dioxygenase (IDO) facilitates tryptophan catabolism at the rate-limiting step of the kynurenine (Kyn) pathway. IDO expression and elevations in Kyn metabolites are associated with immunosuppressive tumor microenvironment including T cell proliferative arrest and generation of regulatory T cells (Tregs) which can favor tumor progression. However, the extent of the role of IDO in acute myeloid leukemia (AML) is currently ill-defined. This study reviews the role of IDO-driven Treg function in AML and evaluates the current body of evidence implicating IDO in AML pathogenesis.Method: Studies related to IDO in AML were identified through a systematic review of PubMed and Scopus. Data extracted described sample analysis, IDO expression, IDO in prognosis, techniques used in Treg phenotypic studies, and the effect of IDO inhibitors.Results: Twenty studies were included in the systematic review. Expression of IDO was identified in a range of cells in AML, both inducible and constitutive. Seven studies indicated an association between elevated expression and poor clinical prognosis. Six studies suggested a positive correlation between IDO expression and Treg induction, with FoxP3 being the prominent Treg phenotypic marker. Of eight studies investigating IDO inhibition, some reported reductions in Treg frequency and enhanced effector T cell proliferation.Conclusion: This review highlights that IDO expression in AML is associated with poor prognosis and measurement of IDO and its Kyn metabolites may offer utility as prospective prognostic markers. Pharmacological inhibition of IDO using novel drugs may hold promise for the treatment of AML.

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“…It is well established that IDO has the ability of catabolizing the essential amino acid, tryptophan, to kynurenine metabolites and thereby generating an immune tolerance in different physiological and pathological conditions such as that seen in mammalian pregnancy (Munn et al, ; Kudo, ), autoimmunity (Yan et al, ; Dahal et al, ), and transplantation (Luan et al, ; Suarez‐Fuentetaja et al, ). Based on this body of evidence, we further investigated the underlying immunological mechanisms by which our 15M IDO‐expressing fibroblasts altered the progression of T1D in NOD mice.…”

Section: Discussionmentioning

confidence: 99%

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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Indoleamine 2,3 dioxygenase contributes to transferable tolerance in rat red blood cell inducible model of experimental autoimmune haemolytic anaemia

Cited by 8 publications

References 35 publications

Murine models of autoimmune hemolytic anemia

Murine models of autoimmune hemolytic anemia

Investigating the Role of Indoleamine 2,3-Dioxygenase in Acute Myeloid Leukemia: A Systematic Review

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

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