Fischer A, Friedrich W, Fasth A, Blanche S, Le Deist F, Girault D, Veber F, Vossen J, Lopez M, Griscelli C
Department of Pediatrics, Hôpital des Enfants-Malades, Paris, France.
Blood. 1991 Jan 15;77(2):249-56.
Forty-six infants and children suffering from either inherited immunodeficiency disorders (Wiskott-Aldrich syndrome, functional T-cell immunodeficiency with or without HLA class II expression deficiency), malignant osteopetrosis, or Fanconi's anemia received HLA-nonidentical bone marrow transplantation (BMT) from related donors. Bone marrow was T-cell depleted to reduce the risk of graft-versus-host disease (GVHD). To prevent graft failure, a mouse monoclonal antibody specific for the CD11a-lymphocyte function-associated antigen 1 (LFA-1) molecule was infused into the patients. Eleven patients received five infusions of 0.1 mg/kg every other day from day -3 to +5. Thirty-five patients received 0.2 mg/kg daily from day -3 to +6. The overall sustained engraftment rate was 72% instead of 26.1% in a historical control group of 24 patients similarly treated except for the infusion of the anti-LFA-1 antibody. No late rejection occurred. The T-cell depletion method (E-rosetting or Campath IM plus complement) resulted in different rate of engraftment (83.3% v 57.9%, respectively, P = .05). Engraftment rate was slightly but not significantly influenced by the degree of HLA incompatibility between donor and recipient. Acute GVHD of grade II or more occurred in 35.5% of the patients and the rate of chronic GVHD was 12.9%. The overall actuarial survival rate with a functional graft is 47.3% with a mean follow-up of 28.0 months for patients with immunodeficiency and osteopetrosis, while none of the four patients with Fanconi's anemia survived. The development of full T-cell functions took on the average 6 months and of full B-cell functions 10 months. Significant infectious problems developed in the majority of the patients during the posttransplant course. Epstein-Barr virus-induced B-cell proliferative syndromes were observed in seven patients, six of whom had Wiskott-Aldrich syndrome. Correction of immunodeficiency was comparable in terms of kinetics and quality with that observed in patients with severe combined immunodeficiency undergoing HLA-nonidentical BMT. Correction of osteopetrosis appears not to be different from what has been observed after HLA-identical BMT. The in vivo use of an anti-CD11a-LFA-1 antibody as an additional immunosuppressive therapy in HLA-nonidentical BMT may thus promote engraftment and survival with correction of the primary disease in a significant number of patients with life-threatening immunodeficiency and osteopetrosis, but not with Fanconi's anemia.
46例患有遗传性免疫缺陷疾病（威斯科特-奥尔德里奇综合征、功能性T细胞免疫缺陷伴或不伴HLA II类表达缺陷）、恶性骨质石化症或范科尼贫血的婴幼儿及儿童接受了来自相关供体的HLA配型不合的骨髓移植（BMT）。对骨髓进行T细胞去除以降低移植物抗宿主病（GVHD）的风险。为防止移植失败，向患者输注了一种针对CD11a淋巴细胞功能相关抗原1（LFA-1）分子的小鼠单克隆抗体。11例患者从第-3天至+5天每隔一天接受5次0.1mg/kg的输注。35例患者从第-3天至+6天每天接受0.2mg/kg的输注。总体持续植入率为72%，而在一个24例接受类似治疗（除输注抗LFA-1抗体外）的历史对照组中，该比率为26.1%。未发生晚期排斥反应。T细胞去除方法（E花环法或Campath IM加补体）导致不同的植入率（分别为83.3%和57.9%，P = 0.05）。植入率受供体与受体之间HLA不相容程度的影响较小，但不显著。35.5%的患者发生了II级或更高级别的急性GVHD，慢性GVHD的发生率为12.9%。对于免疫缺陷和骨质石化症患者，功能性移植物的总体精算生存率为47.3%，平均随访28.0个月，而4例范科尼贫血患者无一存活。T细胞功能完全恢复平均需要6个月，B细胞功能完全恢复平均需要10个月。在大多数患者的移植后过程中出现了严重的感染问题。在7例患者中观察到爱泼斯坦-巴尔病毒诱导的B细胞增殖综合征，其中6例患有威斯科特-奥尔德里奇综合征。免疫缺陷的纠正在动力学和质量方面与严重联合免疫缺陷患者接受HLA配型不合的BMT时观察到的情况相当。骨质石化症的纠正似乎与HLA配型相同的BMT后观察到的情况没有差异。因此，在HLA配型不合的BMT中，体内使用抗CD11a-LFA-1抗体作为额外的免疫抑制治疗可能会促进大量患有危及生命的免疫缺陷和骨质石化症（但不包括范科尼贫血）的患者实现植入和存活，并纠正原发性疾病。
