Chaves Daniel Gonçalves, da Silva Santos Brendon Ayala, Zucherato Luciana Werneck, Dias Maíse Moreira, Lorenzato Claudia Santos, de Oliveira Andrea Gonçalves, Cerqueira Mônica Hermida, de Albuquerque Ribeiro Rosângela, Etto Leina Yukari, Franco Vivian Karla Brognoli, Roberti Maria do Rosário Ferraz, de Araújo Callado Fábia Michelle Rodrigues, de Cerqueira Maria Aline Ferreira, Pinto Ieda, Camelo Ricardo Mesquita, Rezende Suely Meireles
Fundação Centro de Hematologia e Hemoterapia do Estado de Minas Gerais (HEMOMINAS), Belo Horizonte, Brazil.
Faculty of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Res Pract Thromb Haemost. 2024 May 6;8(4):102436. doi: 10.1016/j.rpth.2024.102436. eCollection 2024 May.
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.
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.
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.
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; < .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; < .0001 for both). Plasma cytokines, chemokines, and anti-FVIII IgG1 were not associated with ITI outcome.
Our results show that high levels of plasma anti-FVIII IgG4 and IgG total are associated with ITI failure.
免疫耐受诱导（ITI）是根除遗传性血友病A患者体内中和性抗凝血因子（F）VIII同种抗体（抑制剂）的首选治疗方法。然而，在10%至40%的病例中并不成功。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不清楚。
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结果之间的关联。
在巴西免疫耐受研究的这项横断面分析中，我们使用酶联免疫吸附测定法，以血浆来源的FVIII和重组FVIII作为固定在微孔板中的靶抗原，评估抗FVIII IgG的血浆水平。
在完成首个ITI疗程后，我们检测了98例中度严重和严重（FVIII活性<2%）血友病A患者的血浆样本。ITI治疗失败的血友病A患者的抗重组FVIII IgG总量和IgG4水平（IgG总量光密度[OD]，0.37；四分位间距[IQR]，0.15 - 0.73；IgG4 OD，2.19；IQR，0.80 - 2.52）高于部分成功（IgG总量OD，0.03；IQR，0.00 - 0.14；IgG4 OD，0.39；IQR，0.09 - 1.11；两者均P <.0001）或完全成功（IgG总量OD，0.04；IQR，0.00 - 0.07；IgG4 OD，0.07；IQR，0.06 - 0.40；两者均P <.0001）的患者。血浆细胞因子、趋化因子和抗FVIII IgG1与ITI结果无关。
我们的结果表明，血浆中高水平的抗FVIII IgG4和IgG总量与ITI治疗失败相关。
