Treatment of Post‐Transfusion Graft‐versus‐Host Disease with Nafmostat Mesilate, a Serine Protease Inhibitor
Treatment of Post‐Transfusion Graft‐versus‐Host Disease with Nafmostat Mesilate, a Serine Protease Inhibitor
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用丝氨酸蛋白酶抑制剂甲磺酸萘莫司他治疗输血后移植物抗宿主病
DOI：
10.1046/j.1423-0410.1999.7640241.x
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发表时间：
1999
期刊：
影响因子：
2.7
通讯作者：
T. Juji
中科院分区：
文献类型：
--
作者：
R. Ryo;K. Saigo;M. Hashimoto;M. Kohsaki;M. Yasufuku;Norihisa Watanabe;Masayoshi Okada;K. Tadokoro;T. Juji
背景：在输血后移植物抗宿主病(PT-GVHD)中，来自供者的细胞毒性T淋巴细胞被认为是通过对依赖于酶和Fas的细胞的杀伤来损伤靶器官。所涉及的酶是一种丝氨酸蛋白酶，甲磺酸那福坦(NM)是一种丝氨酸蛋白酶抑制剂，已被发现抑制从PT-GVHD患者建立的T细胞克隆的体外异位细胞毒作用，从而表明NM在治疗PT-GVHD方面是有用的。病例报告：1例47岁男性食道癌患者，接受来自5个无关供者的3单位红细胞和20单位浓缩血小板，根据典型的临床特征、患者和供者的HLA配型以及微卫星DNA多态性分析CD8+淋巴细胞的混合嵌合体被诊断为PT-GVHD。使用NM抑制被认为是颗粒酶的丝氨酸蛋白酶的活性；肝功能障碍和血小板减少与白细胞减少同时得到改善。随后，应用大剂量甲基强的松龙冲击疗法和抗CD3单抗减少供者淋巴细胞的增殖，导致淋巴细胞减少，并伴随供者淋巴细胞的消除和CD4/CD8比值的正常化。然而，负责任的供者淋巴细胞的增殖在停止给药后复发，可能是由于类固醇和抗CD3的单抗引起的过度免疫抑制。结论：在致死性PT-GVHD中，给予丝氨酸蛋白酶抑制剂可能通过抑制细胞毒性T细胞介导的靶细胞杀伤而改善PT-GVHD症状。激素和抗CD3单抗可能是一过性临床改善的原因。然而，关于清除捐献者淋巴细胞的机制还需要更多的研究。
Background: Cytotoxic T lymphocytes from donors are thought to injure the target organs in post‐transfusion graft‐versus‐host disease (PT‐GVHD) through perforingranzyme‐ and Fas‐dependent cell killings. The protease involved is a serine protease, and nafmostat mesilate (NM), a serine protease inhibitor, has been found to inhibit the in vitro allocytotoxicity of the T cell clone established from a patient with PT‐GVHD, thus suggesting the usefulness of NM for treatment of PT‐GVHD. Case Report: A 47‐year‐old male with esophageal cancer, who received 3 units of packed red cells and 20 units of platelet concentrates from 5 unrelated donors, was diagnosed as having PT‐GVHD on the basis of typical clinical features, HLA typing of the patient and the responsible donor, and a mixed chimera of CD8+ lymphocytes on microsatellite DNA polymorphism analysis. NM was administered to inhibit the activity of the serine proteases, thought to be granzymes; a liver dysfunction and thrombocytopenia with leukocytopenia simultaneously improved. Subsequently, a high‐dose methylprednisolone pulse therapy and monoclonal anti‐CD3 were administered to reduce the donor's proliferating lymphocytes, which resulted in lymphopenia accompanied by elimination of the donor's lymphocytes and normalization of the CD4/CD8 ratio. However, recurrence of the proliferation of the responsible donor's lymphocytes developed after cessation of NM administration, probably because of excessive immunosuppression caused by steroids and the monoclonal anti‐CD3. Conclusion: This case indicates that administration of a serine protease inhibitor may improve PT‐GVHD symptoms by inhibiting cytotoxic T‐cell‐mediated killing of target cells in fatal PT‐GVHD. Steroids and monoclonal anti‐CD3 were probably responsible for the transient clinical improvements. More studies are required, however, on mechanisms to eliminate the donor's lymphocytes.