Feto‐maternal microchimaerism does not indicate the existence of feto‐maternal immunological tolerance in human leucocyte antigen haploidentical haematopoietic stem cell transplantation from mother to offspring
Feto‐maternal microchimaerism does not indicate the existence of feto‐maternal immunological tolerance in human leucocyte antigen haploidentical haematopoietic stem cell transplantation from mother to offspring
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母婴微嵌合并不表明人白细胞抗原半相合造血干细胞母体移植中存在母婴免疫耐受
DOI：
10.1046/j.1365-2141.2003.04507.x
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发表时间：
2003
影响因子：
6.5
通讯作者：
C. Shimazaki
中科院分区：
文献类型：
--
作者：
N. Ochiai;T. Inaba;E. Maruya;H. Saji;M. Nakagawa;C. Shimazaki
母体血液中存在胎儿造血细胞，反之亦然，称为胎儿-母体微嵌合体，支持存在胎儿-母体免疫耐受性（Evans et al，1999; Ichinohe et al，2002）。最近在同种异体造血干细胞移植（HSCT）中证实了胎儿-母体免疫耐受的作用（Ochiai et al，2002;货车Rood et al，2002; Maruya et al，2003; Shimazaki et al，2003）。目前还不清楚是否存在胎-母微嵌合体是一个指标，胎-母免疫耐受异基因造血干细胞移植。我们报告一例T细胞淋巴母细胞性淋巴瘤（T-LBL）成功移植自人类白细胞抗原（HLA）半相合的3个位点不匹配的母亲，其中HLA巢式聚合酶链反应与序列特异性引物分型（PCR-SSP）未显示母亲外周血（PB）和外周血干细胞（PBSC）中的受体嵌合细胞（Ichinohe等人，2002; Maruya等人，2003）。一名17岁的男性于1999年7月入院，诊断为T-LBL IV期（安阿伯分类）。患者接受了联合化疗，并进行了自体外周血干细胞移植（PBSCT），但未达到完全缓解。家系成员、无关骨髓供者和脐血库中均无HLA相合供者。该患者与其母亲的HLA 3基因座不匹配（表I）。HLANested PCR-SSP在母亲外周血和外周血干细胞中均未检测到患者的遗传性父系抗原（IPA）。患者全身多处淋巴结肿大迅速恶化。在征得我院伦理委员会的同意和患者的书面知情同意书后，我们基于母胎免疫耐受的假设，采用粒细胞集落刺激因子诱导的外周血干细胞，在不选择TCD或CD 34细胞的情况下，进行了HLA半相合HSCT。患者接受了由阿糖胞苷、环磷酰胺和8 × 0戈伊全身照射组成的预处理方案。移植物抗宿主病（GVHD）预防包括他克莫司和小剂量甲氨蝶呤，如前所述（Ochiai et al，2002; Shimazaki et al，2003）。2002年7月，共输注了3 × 8· 10 ⁄ kg CD 34细胞。供者造血干细胞的植入是快速和持续的。第10天发生1级急性GVHD，泼尼松龙2 mg/kg/d后迅速改善。荧光原位杂交分析每30天骨髓单个核细胞显示完全嵌合。第89天，患者主诉复视和视力障碍。Gd增强磁共振成像（MRI）显示双侧第三神经异常增强。减少他克莫司和泼尼松龙以诱导移植物抗白血病效应。在第115天，他出现严重的全身性皮疹伴高热，令人惊讶的是，复视和视力障碍改善。他于2002年12月出院。最近，在同种异体HSCT中，母亲和胎儿之间存在免疫耐受已变得清楚（Ochiai et al，2002;货车Rood et al，2002; Maruya et al，2003; Shimazaki et al，2003）。我们在5例晚期血液系统恶性肿瘤患者中进行了HLA半相合HSCT，未使用TCD，基于胎儿-母体微嵌合体（Shimazaki et al，2003）。尽管这些病例均为2或3位点HLA错配，但除1例发生他克莫司脑病外，所有患者均发生了2级急性GVHD。Maruya et al（2003）调查了33例接受非TCD HLA半相合HSCT的日本患者，报告母亲的重度GVHD发生率高于非遗传性母体抗原不匹配的同胞或后代供体（60% vs 0%）。这些报道表明，严重急性GVHD的发生率不能简单地通过母亲传给后代的HSCT中存在的HLA 3位点不匹配的母胎微嵌合体来预测，我们的病例表明表I.患者（受者）与其母亲之间的HLA配型关系。
The existence of fetal haematopoietic cells in the maternal blood and vice versa, which is called feto-maternal microchimaerism, supports the existence of feto-maternal immunological tolerance (Evans et al, 1999; Ichinohe et al, 2002). The role of feto-maternal immunological tolerance was demonstrated recently in allogeneic haematopoietic stem cell transplantation (HSCT) (Ochiai et al, 2002; van Rood et al, 2002; Maruya et al, 2003; Shimazaki et al, 2003). It is unclear whether the existence of feto-maternal microchimaerism is an indicator of feto-maternal immunological tolerance in allogeneic HSCT. We report a case of T-cell lymphoblastic lymphoma (T-LBL) successfully transplanted from a human leucocyte antigen (HLA) haploidentical 3-loci mismatched mother without T-cell depletion (TCD), in which an HLA-nested polymerase chain reaction with sequence-specific primer typing (PCR-SSP) did not demonstrate recipient chimaeric cells in the peripheral blood (PB) and peripheral blood stem cells (PBSC) of the mother (Ichinohe et al, 2002; Maruya et al, 2003). A 17-year-old male was admitted to hospital in July 1999 with a diagnosis of T-LBL in stage IV (Ann Arbor classification). The patient received combination chemotherapy, and autologous peripheral blood stem cell transplantation (PBSCT) was performed, but he did not achieve a complete remission. There were no available HLAmatched donors among family members, unrelated bone marrow donors and cord blood banks. The patient was HLA 3-loci mismatched from his mother (Table I). HLAnested PCR-SSP did not detect the inherited paternal antigens (IPA) of the patient in the PB and PBSC of the mother. The patient’s multiple systemic lymph node swelling deteriorated rapidly. After obtaining the agreement of the ethical committee of our hospital and written informed consent from the patient, we performed an HLA haploidentical HSCT using PBSC induced by granulocyte colony-stimulating factor without TCD or CD34 cell selection, based on the hypothesis of fetomaternal immunological tolerance. The patient received a conditioning regimen consisting of cytarabine, cyclophosphamide and total body irradiation at 8Æ0 Gy. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and minidose methotrexate as described previously (Ochiai et al, 2002; Shimazaki et al, 2003). A total of 3Æ8 · 10 ⁄ kg CD34 cells were infused in July 2002. The engraftment of donor haematopoietic stem cells was rapid and sustained. An acute GVHD of grade 1 occurred on d 10, which improved rapidly with prednisolone at 2 mg ⁄ kg ⁄ d. Fluorescence in situ hybridization analysis of bone marrow mononuclear cells every 30 d showed complete chimaerism. On d 89, the patient complained of diplopia and visual disturbance. Gd-enhanced magnetic resonance imaging (MRI) revealed an abnormal enhancement of bilateral third nerves. Tacrolimus and prednisolone were reduced to induce a graft-versus-leukaemia effect. On d 115, he had severe systemic eruption with high fever and, surprisingly, the diplopia and visual disturbance improved. He was discharged in December 2002. The existence of immunological tolerance between mother and fetus has become clear in allogeneic HSCT recently (Ochiai et al, 2002; van Rood et al, 2002; Maruya et al, 2003; Shimazaki et al, 2003). We performed an HLA haploidentical HSCT without TCD based on the feto-maternal microchimaerism in five patients with advanced haematological malignancies (Shimazaki et al, 2003). Although these cases were 2or 3-loci HLA mismatched, an acute GVHD of £ grade 2 developed in all patients except one, who developed tacrolimus encephalopathy. Maruya et al (2003) surveyed 33 Japanese patients who received non-TCD HLA haploidentical HSCT and reported a higher incidence of severe GVHD from the mother compared with those from donors who were either non-inherited maternal antigenmismatched siblings or offspring (60% versus 0%). These reports suggested that the incidence of severe acute GVHD could not simply be predicted by the existence of fetomaternal microchimaerism in HLA 3-loci-mismatched HSCT from mother to offspring, and our case suggests that Table I. HLA-match relationship between the patient (recipient) and his mother.
影响因子：
20.3
作者：
Evans, PC;Lambert, N;Nelson, JL
通讯作者：
Nelson, JL