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Anti-human LFA-1 monoclonal antibodies for prevention of graft failure in HLA-mismatched bone marrow transplantation.

抗人 LFA-1 单克隆抗体，用于预防 HLA 不匹配骨髓移植中的移植失败。

基本信息

批准号：
63480233
负责人：
KONNO Tasuke
金额：
$ 3.9万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1988
资助国家：
日本
起止时间：
1988 至 1989
项目状态：
已结题

项目摘要

1. Use of the anti-LFA-1 antibody to prevent graft failure in HLA-haplotype mismatched bone marrow transplantation (BMT). A patient with Fanconi anemia underwent T cell- devpleted HLA-haplotype mismatched maternal BMT because of the lack of HLA-identical donor. To prevent graft failure a murine monoclonal antibody (mAb) directed against the alpha chain of human LFA-1 was used. The mAb (25.3) was kindly supplied by Immunotech (Marseille, France). The antibody preparations were checked for sterility and lack of pyrogenicity. The mAb was given in a 6-h iv infusion m dosis of 0.1 mg/kg for consecutive days from-3 to +6 without any signs of adverse reactions. Partial;hematological reconstitution was achieved but finally resulted in graft failure. The result in Fanconi anemia is in accord with experiences in other institutions. However, no adverse reactions in the use of the anti-LFA-1 mAb encourage to continue further clinical studies in patients selected.2. Production of mAb against human LFA-1. To obtain anti-LFA-1 mAb capable of inducing immune tolerance and available for clinical use spleen cells from BALB/C mice immunized with K4 cells were fused with SP2/0 cells. Hybridoma supernatants obtained were screened for the capability of inhibiting the aggregation of K4 cells stimulated by phorbol ester.Three hybridoma clones secreting anti-LFA-1 antibodies were obtained; one clone was determined by flowcytometry and biochemical analysis to produce the antibody directed at a chain (MAY-035) and other two the antibodies directed at 8 chain (MAY-017, and MAY-044). The isotype of the mAbs obtained was all IgGl. The three antibodies strongly inhibited lymphocyte proliferation in response to alloantigens and mitogens.

1.应用抗LFA-1抗体预防HLA半相合骨髓移植(BMT)移植失败。1例Fanconi贫血患者因缺乏相合的供者而接受了T细胞全血单倍型不匹配母体骨髓移植。为防止移植失败，使用了针对人LFA-1α链的鼠源性单抗。单抗(25.3)由法国马赛免疫技术公司提供。抗体制剂被检查是否无菌和缺乏致热性。单抗静脉滴注6h，剂量为0.1 mg/kg，-3~+6天连续给药，未见不良反应。部分；实现了血液学重建，但最终导致移植失败。Fanconi贫血的结果与其他机构的经验一致。然而，抗LFA-1单抗的使用没有不良反应，鼓励在选定的患者中继续进行进一步的临床研究。抗人LFA-1单抗的制备为获得可诱导免疫耐受并可用于临床的抗LFA-1单抗，将K4细胞免疫的BALB/C小鼠的脾细胞与SP2/0细胞融合。对获得的杂交瘤细胞上清液进行抑制佛波酯刺激的K4细胞聚集作用的筛选，获得3株分泌抗LFA-1抗体的杂交瘤细胞克隆，其中1株经流式细胞仪和生化分析鉴定为针对一链(MAY-035)的抗体，另两株针对8链(MAY-017和MAY-044)。获得的单抗的亚型均为IgG1。这三种抗体强烈抑制淋巴细胞对同种异体抗原和有丝分裂原的反应。