In vivo infusion of anti-CD11a/LFA-1 antibody for prevention and treatment of severe GVHD in HLA-nonidentical bone marrow transplantation : Its serum concentrations and biological effects.

对于仅有的治疗方法是异基因骨髓移植，但不能提供人类白细胞抗原相合的供者，人类白细胞抗原不相合骨髓移植(BMT)仍然是唯一可行的方法。在此背景下，未经治疗的骨髓移植中的严重移植物抗宿主病(GVHD)和T细胞耗尽的骨髓移植中的移植物排斥反应是主要的障碍。为了克服这些障碍，一种抗CD11a/LFA-1的单抗已经被使用，并取得了良好的效果。在这项研究中，1例Fanconi贫血患者接受了人类白细胞抗原不相合、T细胞耗尽的骨髓移植，并用抗CD11a/LFA-1单抗(25.3)预防移植物排斥反应，但未能成功重建造血。另一例接受了人类白细胞抗原相合的骨髓移植，但发生了激素耐药的严重急性移植物抗宿主病，给予CD11a/LFA-1单抗治疗。连续滴注7天后，严重的胃肠道症状得到改善，但皮疹的变化不大。用本研究建立的酶联免疫吸附试验(ELASA)测定单抗的血清浓度。单次输注6h，血清抗体水平在8h达到高峰，然后下降，半衰期估计为40h，每日输注可使血清mAb累积升高，在第5天达到最大值。停药后血清mAb水平迅速下降。在治疗过程中，白细胞减少和中性粒细胞减少逐渐发展，但淋巴细胞计数基本保持不变。CD_4~+T细胞减少，导致CD_4/CD_8比值异常低。淋巴细胞对有丝分裂原(PHA、conA、PWM)的促分裂反应在治疗过程中有缺陷，但在停止输注后完全恢复。结果提示，抗CD11a/LFA-1单抗是控制GVHD的一种替代策略。

HLA-nonidentical bone marrow transplantation (BMT) remains the only possiblility for patients for whom allogeneic BMT in the only curative approach but a HLA-identical donor can not be offered. In this context, severe graft-versus-host disease (GVHD) in case of untreated marrow transplant and graft rejection in case of T-cell depleted BMT are major obstracles. To overcome these obstrucles an anti-CD11a/LFA-1 monoclonal antibody (mAb) has been used with promising results. In this study, a patient with Fanconi's anemia underwent HLA-nonidentical, T-cell depleted BMT and an anti-CD11a/LFA-1 mAb (25.3) was used to prevent graft rejection without success to reconstitute hematopoiesis. In another patient who underwent HLA-identical BMT but suffered from steroid-resistant severe acute GVHD, the CD11a/LFA-1 mAb was given to treat the illness. With 7-day successive infusions of the antibody severe gastrointestinal illness was improved, but skin eruption was not much changed. Serum concentrations of the mAb were assayed by enzyme-linked immunosorbent assay (ELASA) established in this study. With a single 6-h infusion the serum antibody level reached a peak at 8h and then declined with an estimated half-life of 40 h. Daily infusion caused a cumulative increase of serum mAb concentration reaching a maximum at the 5th day. After discontinuation the serum mAb levels droped rapidly. During the treatment leukopenia and neutropenia developed gradually but lylmpyocyte counts remained unchanged much. CD4+ T-cell population decreased resulting in abnormally low CD4/CD8 ratios. Blastogenic responses of lymphocytes to mitogens (PHA, con A, PWM) were defective during the treatment but completely restored after stopping the infusion. The results obtained suggest that infusion of anti-CD11a/LFA-1 mAb is an alternative strategy in controlling stroid-resistant GVHD.