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The induction mechanism of anti-idiotypic antibodies in patients with Hemophilia A and inhibitors

甲型血友病患者抗独特型抗体及其抑制剂的诱导机制

基本信息

批准号：
15591127
负责人：
TANAKA Ichiro
金额：
$ 2.37万
依托单位：
Nara Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591127/
关键词：
factor VIII inhibitor anti-idiotypic antibody 免疫寛容療法

项目摘要

In order to clarify the induction mechanism of anti-idiotypic antibodies by immune tolerance induction(ITI) for hemophiliacs with inhibitors, we studied the mode of FVIII:C inactivation in the presence of high-titer anti-FVIII antibodies. We used 7 kinds of alloantibodies and 4 kinds of monoclonal antibodies against human FVIII. The former contains 3 alloantibodies recognizing A2 domain in the heavy chain and 4 alloantibodies recognizing C2 domain in the light chain. The latter contains each monoclonal antibody recognizing A1 and A2 domain, and 2 monoclonal antibodies recognizing C2 domain. Ten or twenty Bethesda units(BU)/ml of inhibitor IgG diluted with FVIII deficient plasma were mixed with normal plasma. The mixture was removed after incubation for 120 min, and then maximum coagulation acceleration (|min2|) and FVIII:C were measured by MDAII. In the presence of 10 BU/ml inhibitors, FVIII:C were detected in 4 alloantibodies (0.4-1.1 U/dl) and 3 monoclonal antibodies (0.2-5.7 U/dl), whereas |min2| were detected in 3 alloantibodies (0.128-0.152) and 4 monoclonal antibodies (0.102-0.367). In the presence of 20 BU/ml inhibitors, FVIII:C was detected in an alloantibody (0.8 U/dl) and 2 monoclonal antibodies (0.3-3.2 U/dl), whereas |min2| were detected in 3 alloantibodies (0.111-0.131) and a monoclonal antibody (0.329). Especially, the low levels of FVIII:C were detected in the alloantibodies and monoclonal antibody recognizing A2 domain in the heavy chain. These findings suggested that residual FVIII:C after FVIII infusion during ITI treatment may result in the prophylactic effect even in the presence of high responding inhibitor, and may result from the induction of anti-idiotypic antibody.

为了阐明免疫耐受诱导（ITI）对血友病患者抗独特型抗体的诱导机制，我们研究了高滴度抗FVIII抗体存在下FVIII:C的失活模式。采用7种同种异体抗体和4种单克隆抗体抗人FVIII。前者含有3个识别重链A2结构域的同种异体抗体和4个识别轻链C2结构域的同种异体抗体。后者包含识别A1和A2结构域的单克隆抗体，以及2个识别C2结构域的单克隆抗体。用FVIII缺陷血浆稀释10或20个Bethesda单位(BU)/ml的抑制剂IgG与正常血浆混合。孵育120 min后取出混合物，用mdai测定最大凝血加速（|min2|）和FVIII:C。在10个BU/ml抑制剂存在的情况下，4个同种异体抗体（0.4 ~ 1.1 U/dl）和3个单克隆抗体（0.2 ~ 5.7 U/dl）检测到FVIII:C， 3个同种异体抗体（0.128 ~ 0.152）和4个单克隆抗体（0.102 ~ 0.367）检测到|min2|。在20个BU/ml抑制剂存在时，FVIII:C在1个同种异体抗体（0.8 U/dl）和2个单克隆抗体（0.3 ~ 3.2 U/dl）中检测到，|min2|在3个同种异体抗体（0.111 ~ 0.131）和1个单克隆抗体（0.329）中检测到。特别是在识别重链A2结构域的同种抗体和单克隆抗体中检测到低水平的FVIII:C。这些发现提示ITI治疗过程中FVIII输注后残留的FVIII:C可能在存在高反应抑制剂的情况下仍有预防作用，可能是由于诱导抗独特型抗体所致。