针对 HLA-DQ2.5 谷蛋白肽的双特异性抗体能有效阻断乳糜泻患者因摄入谷蛋白而诱导的谷蛋白特异性 t 细胞。

IF 4.5 3区 医学 Q2 IMMUNOLOGY Clinical immunology Pub Date : 2024-05-18 DOI:10.1016/j.clim.2024.110259
M.Y. Hardy , L.M. Henneken , A.K. Russell , Y. Okura , A. Mizoroki , Y. Ozono , S. Kobayashi , Y. Murakami , J.A. Tye-Din
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引用次数: 0

摘要

治疗乳糜泻(Ceeliac disease,CeD)的无麸质饮食是一种限制性饮食,往往不能诱导症状和/或粘膜疾病的完全缓解。麸质过敏症发病机制的核心是麸质特异性 CD4+ T 细胞,85% 以上的麸质过敏症患者的 CD4+ T 细胞受到 HLA-DQ2.5 的限制,这使得 HLA-DQ2.5 成为抑制麸质依赖性免疫的一个有吸引力的靶点。最近,一种新型抗HLA-DQ2.5抗体(DONQ52)被开发出来,它能特异性识别HLA-DQ2.5和多个麸质表位的复合物:目的:评估DONQ52抑制CeD患者T细胞对包含免疫优势T细胞表位的最具免疫原性的麸质多肽反应的能力:方法:我们在CeD患者中采用了体内麸质挑战模型,该模型可定量读出与疾病相关的麸质特异性T细胞反应。HLA-DQ2.5+ CeD 患者食用含有小麦、大麦或黑麦的食物 3 天,并在开始挑战前(D1)和挑战后 6 天(D6)采集血液。分离外周血单核细胞,并用干扰素(IFN)-γ 酶联免疫吸附点测定法(ELISpot)评估其对包含一系列免疫优势 T 细胞表位的麸质肽的反应。评估了 DONQ52(4 或 40 μg/mL)的抑制作用,并与泛 HLA-DQ 阻断(SPVL3 抗体)进行了比较:结果:在HLA-DQ2.5+ CeD患者中,DONQ52能降低T细胞对所有麦麸肽的反应,其效果等同于或高于泛HLA-DQ抗体阻断。它能将T细胞对最具有免疫优势的小麦表位的反应降低87.3%(IQR 72.4-92.4)。值得注意的是,DONQ52 还大大降低了 T 细胞对优势大麦角蛋白和黑麦鞘氨醇衍生肽的反应。DONQ52 对非麸质抗原的 T 细胞反应没有影响:结论:DONQ52 能显著阻断 HLA-DQ2.5 限制的 T 细胞对 CeD 中免疫原性最强的麸质多肽的反应。我们的研究结果支持体外数据,即 DONQ52 对多种谷蛋白肽:HLA-DQ2.5 复合物具有选择性和广泛的交叉反应性。这项工作提供了多特异性抗体阻断可能有效抑制 CeD 中致病性麸质特异性 T 细胞反应的概念证明,并为正在进行的治疗开发提供了支持。
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A bispecific antibody targeting HLA-DQ2.5-gluten peptides potently blocks gluten-specific T cells induced by gluten ingestion in patients with celiac disease

The gluten-free diet for celiac disease (CeD) is restrictive and often fails to induce complete symptom and/or mucosal disease remission. Central to CeD pathogenesis is the gluten-specific CD4+ T cell that is restricted by HLA-DQ2.5 in over 85% of CeD patients, making HLA-DQ2.5 an attractive target for suppressing gluten-dependent immunity. Recently, a novel anti-HLA-DQ2.5 antibody that specifically recognizes the complexes of HLA-DQ2.5 and multiple gluten epitopes was developed (DONQ52).

Objective

To assess the ability of DONQ52 to inhibit CeD patient-derived T-cell responses to the most immunogenic gluten peptides that encompass immunodominant T cell epitopes.

Methods

We employed an in vivo gluten challenge model in patients with CeD that affords a quantitative readout of disease-relevant gluten-specific T-cell responses. HLA-DQ2.5+ CeD patients consumed food containing wheat, barley, or rye for 3 days with collection of blood before (D1) and 6 days after (D6) commencing the challenge. Peripheral blood mononuclear cells were isolated and assessed in an interferon (IFN)-γ enzyme-linked immunosorbent spot assay (ELISpot) testing responses to gluten peptides encompassing a series of immunodominant T cell epitopes. The inhibitory effect of DONQ52 (4 or 40 μg/mL) was assessed and compared to pan-HLA-DQ blockade (SPVL3 antibody).

Results

In HLA-DQ2.5+ CeD patients, DONQ52 reduced T cell responses to all wheat gluten peptides to an equivalent or more effective degree than pan-HLA-DQ antibody blockade. It reduced T cell responses to a cocktail of the most immunodominant wheat epitopes by a median of 87% (IQR 72–92). Notably, DONQ52 also substantially reduced T-cell responses to dominant barley hordein and rye secalin derived peptides. DONQ52 had no effect on T-cell responses to non-gluten antigens.

Conclusion

DONQ52 can significantly block HLA-DQ2.5-restricted T cell responses to the most highly immunogenic gluten peptides in CeD. Our findings support in vitro data that DONQ52 displays selectivity and broad cross-reactivity against multiple gluten peptide:HLA-DQ2.5 complexes. This work provides proof-of-concept multi-specific antibody blockade has the potential to meaningfully inhibit pathogenic gluten-specific T-cell responses in CeD and supports ongoing therapeutic development.

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来源期刊
Clinical immunology
Clinical immunology 医学-免疫学
CiteScore
12.30
自引率
1.20%
发文量
212
审稿时长
34 days
期刊介绍: Clinical Immunology publishes original research delving into the molecular and cellular foundations of immunological diseases. Additionally, the journal includes reviews covering timely subjects in basic immunology, along with case reports and letters to the editor.
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