IDO2 Drives Autoantibody Production and Joint Inflammation in a Preclinical Model of Arthritis by Repressing Runx1 Function in B Cells.

The immunomodulatory enzyme IDO2 is an essential mediator of autoantibody production and joint inflammation in preclinical models of autoimmune arthritis. Although originally identified as a tryptophan-catabolizing enzyme, we recently discovered a previously unknown nonenzymatic pathway is essential for the proarthritic function of IDO2. We subsequently identified Runx1 (Runt-related transcription factor 1) as a potential component of the nonenzymatic pathway IDO2 uses to drive arthritis.

Off-target depletion of plasma tryptophan by allosteric inhibitors of BCKDK.

The activation of branched chain amino acid (BCAA) catabolism has garnered interest as a potential therapeutic approach to improve insulin sensitivity, enhance recovery from heart failure, and blunt tumor growth. Evidence for this interest relies in part on BT2, a small molecule that promotes BCAA oxidation and is protective in mouse models of these pathologies. BT2 and other analogs allosterically inhibit branched chain ketoacid dehydrogenase kinase (BCKDK) to promote BCAA oxidation, which is presumed to underlie the salutary effects of BT2.

Microbiota-mediated skewing of tryptophan catabolism modulates CD4 T cells in lupus-prone mice.

A skewed tryptophan metabolism has been reported in patients with lupus. Here, we investigated the mechanisms by which it occurs in lupus-susceptible mice, and how tryptophan metabolites exacerbate T cell activation. Metabolomic analyses demonstrated that tryptophan is differentially catabolized in lupus mice compared to controls and that the microbiota played a role in this skewing.

Impact of IDO1 and IDO2 on the B Cell Immune Response.

Indoleamine-2,3-dioxygenase (IDO)1 and IDO2 are closely related tryptophan catabolizing enzymes that have immunomodulatory properties. Although initially studied as modifiers of T cell activity, emerging evidence suggests IDO1 and IDO2 also have important roles as modulators of B cell function. In this context, IDO1 and IDO2 appear to play opposite roles, with IDO1 inhibiting and IDO2 driving inflammatory B cell responses.

The Immunomodulatory Enzyme IDO2 Mediates Autoimmune Arthritis through a Nonenzymatic Mechanism.

IDO2 is one of two closely related tryptophan catabolizing enzymes induced under inflammatory conditions. In contrast to the immunoregulatory role defined for IDO1 in cancer models, IDO2 has a proinflammatory function in models of autoimmunity and contact hypersensitivity. In humans, two common single-nucleotide polymorphisms have been identified that severely impair IDO2 enzymatic function, such that <25% of individuals express IDO2 with full catalytic potential.

IDO1 Signaling through GCN2 in a Subpopulation of Gr-1 Cells Shifts the IFNγ/IL6 Balance to Promote Neovascularization.

In addition to immunosuppression, it is generally accepted that myeloid-derived suppressor cells (MDSC) also support tumor angiogenesis. The tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO1) has been implicated in promoting neovascularization through its positioning as a key regulatory node between the inflammatory cytokines IFNγ and IL6. Here, we report that within the heterogeneous expanse of Gr-1 MDSCs, both IDO1 expression and the ability to elicit neovascularization were associated with a minor subset of autofluorescent, CD11b cells.

Differential Roles of IDO1 and IDO2 in T and B Cell Inflammatory Immune Responses.

Indoleamine-2,3-dioxygenase (IDO)1 and IDO2 are two closely related tryptophan catabolizing enzymes encoded by linked genes. The IDO pathway is also immunomodulatory, with IDO1 well-characterized as a mediator of tumor immune evasion. Due to its homology with IDO1, IDO2 has been proposed to have a similar immunoregulatory function.

B-Cell-Targeted 3DNA Nanotherapy Against Indoleamine 2,3-Dioxygenase 2 (IDO2) Ameliorates Autoimmune Arthritis in a Preclinical Model.

The tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase 2 (IDO2) has been identified as an immunomodulatory agent promoting autoimmunity in preclinical models. As such, finding ways to target the expression of IDO2 in B cells promises a new avenue for therapy for debilitating autoimmune disorders such as rheumatoid arthritis. IDO2, like many drivers of disease, is an intracellular protein expressed in a range of cells, and thus therapeutic inhibition of IDO2 requires a mechanism for targeting this intracellular protein in specific cell types.

Peptide vaccination directed against IDO1-expressing immune cells elicits CD8 and CD4 T-cell-mediated antitumor immunity and enhanced anti-PD1 responses.

Background: The tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1), which subverts T-cell immunity at multiple levels, is itself subject to inherent T-cell reactivity. This intriguing deviation from central tolerance has been interpreted as counterbalancing IDO1-mediated immunosuppression. Based on this hypothesis, clinical studies employing an IDO1 peptide-based vaccine approach for cancer treatment have been initiated, but there remains a pressing need to further investigate the immunological ramifications of stimulating the anti-IDO1 T-cell response in this manner.

Host Gene Status Influences Tumor Progression and Radiotherapy Response in -Driven Sporadic Pancreatic Cancers.

Purpose: Heritable genetic variations can affect the inflammatory tumor microenvironment, which can ultimately affect cancer susceptibility and clinical outcomes. Recent evidence indicates that IDO2, a positive modifier in inflammatory disease models, is frequently upregulated in pancreatic ductal adenocarcinoma (PDAC). A unique feature of in humans is the high prevalence of two inactivating single-nucleotide polymorphisms (SNP), which affords the opportunity to carry out loss-of-function studies directly in humans.

RhoB blockade selectively inhibits autoantibody production in autoimmune models of rheumatoid arthritis and lupus.

During the development of autoimmune disease, a switch occurs in the antibody repertoire of B cells so that the production of pathogenic rather than non-pathogenic autoantibodies is enabled. However, there is limited knowledge concerning how this pivotal step occurs. Here, we present genetic and pharmacological evidence of a positive modifier function for the vesicular small GTPase RhoB in specifically mediating the generation of pathogenic autoantibodies and disease progression in the K/BxN preclinical mouse model of inflammatory arthritis.

Therapeutic antibody targeting of indoleamine-2,3-dioxygenase (IDO2) inhibits autoimmune arthritis.

Rheumatoid arthritis (RA) is a debilitating inflammatory autoimmune disease with no known cure. Recently, we identified the immunomodulatory enzyme indoleamine-2,3-dioxygenase 2 (IDO2) as an essential mediator of autoreactive B and T cell responses driving RA. However, therapeutically targeting IDO2 has been challenging given the lack of small molecules that specifically inhibit IDO2 without also affecting the closely related IDO1.

IDO2: A Pathogenic Mediator of Inflammatory Autoimmunity.

Indoleamine 2,3-dioxygenase 2 (IDO2), a homolog of the better-studied tryptophan-catabolizing enzyme IDO1, is an immunomodulatory molecule with potential effects on various diseases including cancer and autoimmunity. Here, we review what is known about the direct connections between IDO2 and immune function, particularly in relationship to autoimmune inflammatory disorders such as rheumatoid arthritis and lupus. Accumulating evidence indicates that IDO2 acts as a pro-inflammatory mediator of autoimmunity, with a functional phenotype distinct from IDO1.

IDO2 Modulates T Cell-Dependent Autoimmune Responses through a B Cell-Intrinsic Mechanism.

Mechanistic insight into how adaptive immune responses are modified along the self-nonself continuum may offer more effective opportunities to treat autoimmune disease, cancer, and other sterile inflammatory disorders. Recent genetic studies in the KRN mouse model of rheumatoid arthritis demonstrate that the immunomodulatory molecule IDO2 modifies responses to self-antigens; however, the mechanisms involved are obscure. In this study, we show that IDO2 exerts a critical function in B cells to support the generation of autoimmunity.

IDO2 in Immunomodulation and Autoimmune Disease.

IDO2 is a relative of IDO1 implicated in tryptophan catabolism and immune modulation but its specific contributions to normal physiology and pathophysiology are not known. Evolutionary genetic studies suggest that IDO2 has a unique function ancestral to IDO1. In mice, IDO2 gene deletion does not appreciably affect embryonic development or hematopoiesis, but it leads to defects in allergic or autoimmune responses and in the ability of IDO1 to influence the generation of T regulatory cells.

1-Methyl-tryptophan synergizes with methotrexate to alleviate arthritis in a mouse model of arthritis.

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease with no known cure. Current strategies to treat RA, including methotrexate (MTX), target the later inflammatory stage of disease. Recently, we showed that inhibiting indoleamine-2,3-dioxygenase (IDO) with 1-methyl-tryptophan (1MT) targets autoantibodies and cytokines that drive the initiation of the autoimmune response.

Indoleamine 2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer.

Genetic and pharmacological studies of indoleamine 2,3-dioxygenase (IDO) have established this tryptophan catabolic enzyme as a central driver of malignant development and progression. IDO acts in tumor, stromal and immune cells to support pathogenic inflammatory processes that engender immune tolerance to tumor antigens. The multifaceted effects of IDO activation in cancer include the suppression of T and NK cells, the generation and activation of T regulatory cells and myeloid-derived suppressor cells, and the promotion of tumor angiogenesis.

IDO2 is a critical mediator of autoantibody production and inflammatory pathogenesis in a mouse model of autoimmune arthritis.

Rheumatoid arthritis and other autoimmune disorders are associated with altered activity of the immunomodulatory enzyme IDO. However, the precise contributions of IDO function to autoimmunity remain unclear. In this article, we examine the effect of two different IDO enzymes, IDO1 and IDO2, on the development of autoimmune arthritis in the KRN preclinical model of rheumatoid arthritis.

IDO2 is critical for IDO1-mediated T-cell regulation and exerts a non-redundant function in inflammation.

IDO2 is implicated in tryptophan catabolism and immunity but its physiological functions are not well established. Here we report the characterization of mice genetically deficient in IDO2, which develop normally but exhibit defects in IDO-mediated T-cell regulation and inflammatory responses. Construction of this strain was prompted in part by our discovery that IDO2 function is attenuated in macrophages from Ido1 (-/-) mice due to altered message splicing, generating a functional mosaic with implications for interpreting findings in Ido1 (-/-) mice.

IDO is a nodal pathogenic driver of lung cancer and metastasis development.

Unlabelled: Indoleamine 2,3-dioxygenase (IDO) enzyme inhibitors have entered clinical trials for cancer treatment based on preclinical studies, indicating that they can defeat immune escape and broadly enhance other therapeutic modalities. However, clear genetic evidence of the impact of IDO on tumorigenesis in physiologic models of primary or metastatic disease is lacking. Investigating the impact of Ido1 gene disruption in mouse models of oncogenic KRAS-induced lung carcinoma and breast carcinoma-derived pulmonary metastasis, we have found that IDO deficiency resulted in reduced lung tumor burden and improved survival in both models.

Addition of an indoleamine 2,3,-dioxygenase inhibitor to B cell-depletion therapy blocks autoreactive B cell activation and recurrence of arthritis in K/BxN mice.

Objective: To define the role of indoleamine 2,3-dioxygenase (IDO) in driving pathogenic B cell responses that lead to arthritis and to determine if inhibitors of the IDO pathway can be used in conjunction with therapeutic B cell depletion to prevent the reemergence of autoantibodies and arthritis following reconstitution of the B cell repertoire.

Methods: Immunoglobulin-transgenic mice were treated with the IDO inhibitor 1-methyltryptophan (1-MT) and monitored for the extent of autoreactive B cell activation. Arthritic K/BxN mice were treated with B cell depletion alone or in combination with 1-MT.

Non-hematopoietic expression of IDO is integrally required for inflammatory tumor promotion.

Indoleamine 2,3-dioxygenase (IDO) is generally considered to be immunosuppressive but recent findings suggest this characterization oversimplifies its role in disease pathogenesis. Recently, we showed that IDO is essential for tumor outgrowth in the classical two-stage model of inflammatory skin carcinogenesis. Here, we report that IDO loss did not exacerbate classical inflammatory responses.

The immunoregulatory enzyme IDO paradoxically drives B cell-mediated autoimmunity.

Rheumatoid arthritis (RA) is a chronic and debilitating inflammatory autoimmune disease of unknown etiology. As with a variety of autoimmune disorders, evidence of elevated tryptophan catabolism has been detected in RA patients indicative of activation of the immunomodulatory enzyme IDO. However, the role that IDO plays in the disease process is not well understood.