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首页> 外文期刊>Clinical immunology: The official journal of the Clinical Immunology Society >Therapeutic antibody targeting of indoleamine-2,3-dioxygenase (IDO2) inhibits autoimmune arthritis
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Therapeutic antibody targeting of indoleamine-2,3-dioxygenase (IDO2) inhibits autoimmune arthritis

机译：indoleamine-2,3-二氧化酶（IDO2）的治疗抗体靶向抑制自身免疫性关节炎

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Abstract 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. In this study, we develop a novel monoclonal antibody (mAb)-based approach to therapeutically target IDO2. Treatment with IDO2-specific mAb alleviated arthritis in two independent preclinical arthritis models, reducing autoreactive T and B cell activation and recapitulating the strong anti-arthritic effect of genetic IDO2 deficiency. Mechanistic investigations identified FcγRIIb as necessary for mAb internalization, allowing targeting of an intracellular antigen traditionally considered inaccessible to mAb therapy. Taken together, our results offer preclinical proof of concept for antibody-mediated targeting of IDO2 as a new therapeutic strategy to treat RA and other autoantibody-mediated diseases. Graphical abstract Display Omitted Highlights ? IDO2-specific Ig treatment alleviates arthritis in two preclinical arthritis models. ? IDO2 Ig inhibits autoreactive T and B cells, recapitulating genetic IDO2 deficiency. ? IDO2 Ig uses FcγRIIb to internalize and access its intracellular target. ? FcγRIIb on B cells is necessary for IDO2 Ig function in vivo .
机译：摘要类风湿性关节炎（RA）是一种衰弱的炎症性自身免疫病，没有已知治愈。最近，我们将免疫调节酶吲哚胺-2,3-二氧合酶2（IDO2）鉴定为自身反应性B和T细胞响应驱动Ra的必需介体。然而，鉴于缺乏特异性抑制IDO2的小分子而没有影响密切相关的IDO1，治疗靶向IDO2一直挑战。在这项研究中，我们开发一种新的单克隆抗体（MAB）的治疗靶标IO2。用IDO2特异性MAB治疗缓解关节炎在两个独立的临床前关节炎模型中，减少自身反应性T和B细胞活化，重新承诺遗传IDO2缺乏的强抗关节炎效应。机械研究确定了MAb内化必要的FcγRIIB，允许靶向MAB治疗无法访问的细胞内抗原。我们的结果一起提供突出的抗体介导的IDO2靶向概念概念作为一种治疗RA和其他自身癌症介导的疾病的新治疗策略。图形抽象显示省略了亮点？ IDO2特异性Ig治疗减轻了两个临床前关节炎模型中的关节炎。还IDO2 Ig抑制自身反应性T和B细胞，重新承载遗传IDO2缺乏。还IDO2 IG使用FCγRIIB内化并访问其细胞内目标。还B细胞上的FcγRIIB对于体内IDO2 IG函数是必要的。

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