Ghobrial R R, Boublik M, Winn H J, Auchincloss H
Department of Surgery, Massachusetts General Hospital, Boston 02114.
Clin Immunol Immunopathol. 1989 Sep;52(3):486-506. doi: 10.1016/0090-1229(89)90162-1.
Experiments were performed seeking conditions for the optimum use of anti-T cell monoclonal antibodies in vivo in mice. Anti-L3T4 (CD4) and anti-Lyt2 (CD8) antibodies of different subclasses (IgG2b, IgG2a, and IgM) and species (rat or mouse) were used. The results showed that (i) intraperitoneal compared to intravenous administration of the different antibodies achieved the same serum levels whether in the presence or absence of the recipient's thymus; (ii) repeated treatment with a rat IgM anti-L3T4 or a rat IgG2b anti-Lyt2 antibody was followed by inability to detect serum levels of each antibody; (iii) in vivo treatment with these antibodies caused target cell lysis, target antigen masking without cell destruction, or target antigen modulation without cell destruction and the particular effect of a given antibody could not be predicted by its isotype or specificity; (iv) neither the C5 component of complement nor antibody-dependent cell-mediated cytotoxicity mediated the action of GK1.5 antibody in vivo; (v) dose-response curves of in vivo potency of a given antibody could not be predicted by in vitro assays; (vi) thymocytes were depleted by monoclonal antibody treatment by using 1000-fold more antibody than needed to deplete peripheral lymphocytes; (vii) the rate of return of target T cells after depletion in nonthymectomized mice depended on the dose of the antibody; and (viii) thymectomy prolonged the effect of most, but not all antibodies. In thymectomized mice, CD8+ cells remained almost undetectable for prolonged periods of time after depletion while CD4+ cells returned to approximately 30% of their original level and remained constant over time after initial complete depletion. These results provide useful data for the effective use of monoclonal anti-T cell antibodies in mice. They stress the difficulty of predicting the in vivo effects of monoclonal antibodies without actually testing them in vivo. They include new insights into mechanisms of action of monoclonal antibodies and the role of thymectomy in prolonging their effect. They describe the unrecognized ability of antibodies to deplete thymocytes.
进行了实验以探寻在小鼠体内最佳使用抗T细胞单克隆抗体的条件。使用了不同亚类（IgG2b、IgG2a和IgM）和物种（大鼠或小鼠）的抗L3T4（CD4）和抗Lyt2（CD8）抗体。结果表明：（i）无论受体胸腺是否存在，与静脉注射不同抗体相比，腹腔注射可达到相同的血清水平；（ii）用大鼠IgM抗L3T4或大鼠IgG2b抗Lyt2抗体重复治疗后，无法检测到每种抗体的血清水平；（iii）用这些抗体进行体内治疗会导致靶细胞裂解、靶抗原被掩盖但细胞未被破坏，或靶抗原发生调节但细胞未被破坏，且无法通过给定抗体的同种型或特异性预测其特定效果；（iv）补体的C5成分和抗体依赖性细胞介导的细胞毒性均未介导GK1.5抗体在体内的作用；（v）体外试验无法预测给定抗体体内效力的剂量反应曲线；（vi）通过单克隆抗体治疗使胸腺细胞耗竭时，所需抗体量比耗尽外周淋巴细胞所需量多1000倍；（vii）未切除胸腺的小鼠中，靶T细胞耗竭后恢复的速率取决于抗体剂量；（viii）胸腺切除术延长了大多数但并非所有抗体的作用效果。在切除胸腺的小鼠中，CD8 +细胞在耗竭后很长一段时间内几乎检测不到，而CD4 +细胞在最初完全耗竭后恢复到其原始水平的约30%，并随时间保持恒定。这些结果为在小鼠中有效使用单克隆抗T细胞抗体提供了有用的数据。它们强调了在未实际进行体内测试的情况下预测单克隆抗体体内效果的困难。它们包括对单克隆抗体作用机制以及胸腺切除术在延长其效果中的作用的新见解。它们描述了抗体耗尽胸腺细胞的未被认识到的能力。
