高水平的抗 FVIII IgG4 和 IgG 总量与先天性血友病 A 和高应答抑制剂患者免疫耐受诱导失败有关

IF 3.4 3区医学 Q2 HEMATOLOGY Research and Practice in Thrombosis and Haemostasis Pub Date : 2024-05-01 DOI:10.1016/j.rpth.2024.102436

Daniel Gonçalves Chaves , Brendon Ayala da Silva Santos , Luciana Werneck Zucherato , Maíse Moreira Dias , Claudia Santos Lorenzato , Andrea Gonçalves de Oliveira , Mônica Hermida Cerqueira , Rosângela de Albuquerque Ribeiro , Leina Yukari Etto , Vivian Karla Brognoli Franco , Maria do Rosário Ferraz Roberti , Fábia Michelle Rodrigues de Araújo Callado , Maria Aline Ferreira de Cerqueira , Ieda Pinto , Ricardo Mesquita Camelo , Suely Meireles Rezende

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引用次数: 0

摘要

背景免疫耐受诱导（ITI）是消除遗传性 A 型血友病患者中和性抗因子 (F)VIII 异体抗体（抑制剂）的首选治疗方法。与 ITI 结果相关的生物学机制和生物标志物在很大程度上尚属未知。本研究旨在探讨血浆细胞因子（干扰素-γ、肿瘤坏死因子、白细胞介素 [IL]-2, IL-4, IL-5, IL-6, IL-10、和 IL-17A）、趋化因子（IL-8/CXCL8、RANTES/CCL5、MIG/CXCL9、MCP-1/CCL2 和 IP-10/CXCL10）以及抗 FVIII 免疫球蛋白 (Ig) G 总量、IgG1 和 IgG4 与 ITI 结果的关系。方法在这项巴西免疫耐受研究的横断面分析中，我们使用酶联免疫吸附试验评估了血浆中的抗 FVIII IgG 水平，该试验以固定在微孔板中的血浆衍生 FVIII 和重组 FVIII 为目标抗原。在 ITI 失败的 A 型血友病患者中，抗重组 FVIII IgG 总和 IgG4 的水平较高（IgG 总光密度 [OD]，0.37；IQR，0.15-0.73；IgG4 OD，2.19；IQR，0.80-2.52）。与部分成功（IgG 总光密度，0.03；IQR，0.00-0.14；IgG4 总光密度，0.39；IQR，0.09-1.11；两者均为 P <；.0001）或完全成功（IgG 总光密度，0.04；IQR，0.00-0.07；IgG4 总光密度，0.07；IQR，0.06-0.40；两者均为 P <；.0001）的患者相比，血浆细胞因子、IgG4 和 IgG 总光密度[OD]、IgG4 和 IgG4 总光密度[OD]的变化对患者的影响更大。血浆细胞因子、趋化因子和抗 FVIII IgG1 与 ITI 结果无关。

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High levels of anti–factor VIII immunoglobulin G4 and immunoglobulin G total are associated with immune tolerance induction failure in people with congenital hemophilia A and high-responding inhibitors

Background

Immune tolerance induction (ITI) is the treatment of choice to eradicate neutralizing anti–factor (F)VIII alloantibodies (inhibitors) in people with inherited hemophilia A. However, it is not successful in 10% to 40% of the cases. The biological mechanisms and biomarkers associated with ITI outcome are largely unknown.

Objectives

The aim of this study was to investigate the association of plasma cytokines (interferon-γ, tumor necrosis factor, interleukin [IL]-2, IL-4, IL-5, IL-6, IL-10, and IL-17A), chemokines (IL-8/CXCL8, RANTES/CCL5, MIG/CXCL9, MCP-1/CCL2, and IP-10/CXCL10), and anti-FVIII immunoglobulin (Ig) G total, IgG1, and IgG4 with ITI outcome.

Methods

In this cross-sectional analysis of the Brazilian Immune Tolerance Study, we assessed plasma levels of anti-FVIII IgGs using an enzyme-linked immunosorbent assay with plasma-derived FVIII and recombinant FVIII as target antigens, immobilized in microplates.

Results

We assayed 98 plasma samples of moderately severe and severe (FVIII activity, <2%) people with hemophilia A after completion of a first ITI course. Levels of anti–recombinant FVIII IgG total and IgG4 were higher in people with hemophilia A who failed ITI (IgG total optical density [OD], 0.37; IQR, 0.15-0.73; IgG4 OD, 2.19; IQR, 0.80-2.52) than in those who had partial (IgG total OD, 0.03; IQR, 0.00-0.14; IgG4 OD, 0.39; IQR, 0.09-1.11; P < .0001 for both) or complete success (IgG total OD, 0.04; IQR, 0.00-0.07; IgG4 OD, 0.07; IQR, 0.06-0.40; P < .0001 for both). Plasma cytokines, chemokines, and anti-FVIII IgG1 were not associated with ITI outcome.