Thrombocytopenia caused by the development of antibodies to thrombopoietin
Thrombocytopenia caused by the development of antibodies to thrombopoietin
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DOI：
10.1182/blood.v98.12.3241
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发表时间：
2001-12-01
期刊：
影响因子：
20.3
通讯作者：
Kuter, DJ
中科院分区：
文献类型：
--
作者：
Li, JZ;Yang, C;Kuter, DJ
在接受重组血小板素（TPO）、聚乙二醇化重组人巨核细胞生长发育因子（PEG-rHuMGDF）治疗的一些个体中发生血小板减少症。对发生重度血小板减少症的3例受试者进行了详细分析，以确定其血小板减少症的原因。除了容易瘀伤和月经量大，这些受试者没有大出血事件;没有人对静脉注射免疫球蛋白或泼尼松有反应。骨髓检查显示巨核细胞明显减少。所有3名血小板减少症受试者均具有抗PEG-rHuMGDF的抗体，该抗体与内源性TPO交叉反应并中和其生物活性。所有抗TPO抗体均为免疫球蛋白G（IgG），IgG 4含量增加;在任何时间均未检测到TPO IgM抗体。建立了血小板生成素IgG抗体的定量测定方法，结果表明抗体浓度与血小板计数呈负相关。抗TPO抗体识别TPO前163位氨基酸的表位，阻止TPO与其受体结合。在2例受试者中，内源性TPO水平升高，但TPO作为具有抗TPO IgG的生物学无活性免疫复合物循环;这些复合物中的内源性TPO的表观分子量为95 000，略大于全长重组TPO。没有一个受试者有非典型的HLA或血小板抗原，TPO cDNA在测序的两个都是正常的。1例受试者接受环孢菌素治疗后，抗体消除，血小板计数正常化。这些数据证明了血小板减少症的一种新机制，其中抗体发展为TPO;因为内源性TPO是组成性产生的，所以血小板减少症加剧。（血。2001;98：3241-3248）（C）2001由美国血液学学会。
Thrombocytopenia developed in some individuals treated with a recombinant thrombopoletin (TPO), pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF). Three of the subjects who developed severe thrombocytopenia were analyzed in detail to determine the cause of their thrombocytopenia. Except for easy bruising and heavy menses, none of these subjects had major bleeding episodes; none responded to intravenous immunoglobulin or prednisone. Bone marrow examination revealed a marked reduction in megakaryocytes. All 3 thrombocytopenic subjects had antibody to PEG-rHuMGDF that cross-reacted with endogenous TPO and neutralized its biological activity. All anti-TPO antibodies were immunoglobulin G (IgG), with increased amounts of IgG4; no IgM antibodies to TPO were detected at any time. A quantitative assay for IgG antibody to TPO was developed and showed that the antibody concentration varied inversely with the platelet count. Anti-TPO antibody recognized epitopes located in the first 163 amino acids of TPO and prevented TPO from binding to its receptor. In 2 subjects, endogenous TPO levels were elevated, but the TPO circulated as a biologically inactive immune complex with anti-TPO IgG; the endogenous TPO in these complexes had an apparent molecular weight of 95 000, slightly larger than the full-length recombinant TPO. None of the subjects had atypical HLA or platelet antigens, and the TPO cDNA was normal in both that were sequenced. Treatment of one subject with cyclosporine eliminated the antibody and normalized the platelet count. These data demonstrate a new mechanism for thrombocytopenia in which antibody develops to TPO; because endogenous TPO is produced constitutively, thrombocytopenia ensues. (Blood. 2001;98:3241-3248) (C) 2001 by The American Society of Hematology.