Induction of tolerance to factor VIII inhibitors by gene therapy with immunodominant A2 and C2 domains presented by B cells as Ig fusion proteins
Induction of tolerance to factor VIII inhibitors by gene therapy with immunodominant A2 and C2 domains presented by B cells as Ig fusion proteins
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DOI：
10.1182/blood-2004-11-4274
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发表时间：
2005-06-15
期刊：
影响因子：
20.3
通讯作者：
Scott, DW
中科院分区：
文献类型：
--
作者：
Lei, TC;Scott, DW
高达30%的血友病A患者给予治疗因子VIII（fVIII）可以产生抑制性抗体，其中大多数与其C2和A2结构域反应。我们以前已经证明，抗原特异性耐受几种抗原可以诱导脂多糖（LPS）激活的B细胞母细胞转导免疫球蛋白（IgG）抗原融合结构。为了将该系统应用于血友病A抑制剂的形成，我们创建了与IgG重链骨架同框表达Will氨基酸S2173-Y2332（C2结构域）和S373-R740（A2结构域）的逆转录病毒载体。将这些载体转导到B细胞母细胞中，以在幼稚和fVIII致敏的血友病（E16 fVIII（-/-））小鼠中诱导耐受性。因此，用表达fVIII C2和A2结构域的B细胞治疗E16 fVIII（-/-）小鼠，导致对Will及其C2或A2结构域的特异性体液反应（包括抑制性抗体滴度）和细胞反应方面的耐受性。此外，在具有现有抗I-fVIII滴度的免疫血友病小鼠中可以实现对fVIII的免疫应答的显著降低。这种低反应状态持续了至少2个月，并经受住了威尔的额外挑战。进一步的实验，其中小鼠用消耗性单克隆抗-CD 25处理，表明调节性T细胞可能是转导的B细胞的致耐受性作用所必需的。这些发现表明，B细胞呈递IG骨架上的Will结构域特异性地防止或减少血友病A小鼠中现有的抗体。(c)2005年，美国血液学会。
Up to 30% of patients with hemophilia A given therapeutic factor VIII (fVIII) can make inhibitory antibodies, the majority of which are reactive with its C2 and A2 domains. We have previously demonstrated that anti gen-specific tolerance to several antigens can be induced by lipopolysaccharide (LPS)-activated B-cell blasts transduced with immunoglobulln (IgG)-antigen fusion constructs. To apply this system to hemophilia A inhibitor formation, we created retroviral vectors expressing Will amino acids S2173-Y2332 (C2 domain) and S373-R740 (A2 domain) in frame with an IgG heavy chain backbone. These vectors were transduced into B-cell blasts to induce tolerance in both naive and fVIII-primed hemophilic (E16 fVIII(-/-)) mice. Thus, treatment of E16 fVIII(-/-) mice with B cells expressing fVIII C2 and A2 domains led to tolerance in terms of specific humoral response (including inhibitory antibody titers) and cellular responses to Will and its C2 or A2 domains. Moreover, a significant reduction in immune responses to fVIII could be achieved in immunized hemophilic mice with existing antI-fVIII titers. This hyporesponsive state persisted for at least 2 months and withstood additional challenge with Will. Further experiments, in which mice were treated with a depleting monoclonal anti-CD25, suggested that a regulatory T cell may be required for the tolerogenic effect of transduced B cells. These findings demonstrate that B-cell presentation of Will domains on an Ig backbone specifically prevents or decreases existing antibodies in hemophilia A mice. (c) 2005 by The American Society of Hematology.