Splenic marginal zone antigen-presenting cells are critical for the primary allo-immune response to therapeutic factor VIII in hemophilia A
Splenic marginal zone antigen-presenting cells are critical for the primary allo-immune response to therapeutic factor VIII in hemophilia A
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DOI：
10.1111/j.1538-7836.2009.03571.x
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发表时间：
2009-11-01
影响因子：
10.4
通讯作者：
Lacroix-Desmazes, S.
中科院分区：
文献类型：
--
作者：
Navarrete, A.;Dasgupta, S.;Lacroix-Desmazes, S.
背景资料：对静脉内给予的蛋白质治疗剂的同种免疫应答是内源性蛋白质水平有缺陷的患者中替代治疗失败的最常见原因。这种情况在一些血友病A患者中遇到，他们在给予FVIII治疗血管病变后产生抑制性抗因子（F）VIII同种抗体。目的：尚未研究参与对人类治疗剂的免疫应答启动的次级淋巴器官的性质。因此，我们在FVIII（一种自源性外源性蛋白质治疗剂）的情况下对此进行了研究。研究方法：在给FVIII缺陷小鼠注射放射性标记的FVIII后，使用免疫组织化学跟踪静脉内给药的FVIII的分布。脾和抗原呈递细胞（APC）在抗FVIII免疫应答的发作中的作用在脾切除术或用APC消耗化合物处理小鼠后进行分析。结果：FVIII在脾脏边缘区（MZ）的嗜金属巨噬细胞水平优先蓄积。手术切除脾脏或选择性体内清除巨噬细胞和CD11c阳性CD8 α阴性树突状细胞导致抗FVIII免疫应答急剧减少。结论：使用FVIII缺陷型小鼠作为血友病A患者的模型，和人促凝血因子FVIII作为免疫原性自身衍生蛋白质治疗的模型，我们的研究结果突出了脾脏和MZ APC在启动对蛋白质治疗的免疫应答中的重要性。鉴定与蛋白质治疗剂在MZ中的保留有关的受体可能为旨在降低其免疫原性的新策略铺平道路。
Background: Alloimmune responses to intravenously administered protein therapeutics are the most common cause of failure of replacement therapy in patients with defective levels of endogenous proteins. Such a situation is encountered in some patients with hemophilia A, who develop inhibitory anti-factor (F)VIII alloantibodies after administration of FVIII to treat hemorrhages. Objectives: The nature of the secondary lymphoid organs involved in the initiation of immune responses to human therapeutic has not been studied. We therefore investigated this in the case of FVIII, a self-derived exogenous protein therapeutic. Methods: The distribution of intravenously administered FVIII was followed after FVIII-deficient mice were injected with radiolabeled FVIII and using immunohistochemistry. The role of the spleen and antigen-presenting cells (APC) in the onset of the anti-FVIII immune response was analyzed upon splenectomy or treatment of the mice with APC-depleting compounds. Results: FVIII preferentially accumulated in the spleen at the level of metallophilic macrophages in the marginal zone (MZ). Surgical removal of the spleen or selective in vivo depletion of macrophages and CD11c-positive CD8 alpha-negative dendritic cells resulted in a drastic reduction in anti-FVIII immune responses. Conclusions: Using FVIII-deficient mice as a model for patients with hemophilia A, and human pro-coagulant FVIII as a model for immunogenic self-derived protein therapeutics, our results highlight the importance of the spleen and MZ APCs in the initiation of immune responses to protein therapeutics. Identification of the receptors implicated in retention of protein therapeutics in the MZ may pave the way towards novel strategies aimed at reducing their immunogenicity.