Kozak R W, Fitzgerald D P, Atcher R W, Goldman C K, Nelson D L, Gansow O A, Pastan I, Waldmann T A
Division of Cytokine Biology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892.
J Immunol. 1990 May 1;144(9):3417-23.
The human allogeneic mixed lymphocyte reaction is the in vitro correlate of graft rejection. Cytotoxic effector cells generated during an allogeneic mixed lymphocyte reaction were previously shown to express the human p55 IL-2 receptor subunit, whereas resting cells do not express this receptor peptide. In this study, we asked whether Pseudomonas exotoxin or bismuth-212 (an alpha-particle emitting radionuclide) coupled to the anti-IL-2 receptor mAb, anti-Tac, were able to selectively eliminate alloresponsive cells generated during an allogeneic mixed lymphocyte reaction. After assembly, anti-Tac immunoconjugates retained their binding integrity, specificity, and selectivity. Deletion of alloresponsive cells was shown by the removal of alloproliferating cells as assessed by quantitating cell recovery and by measurement of thymidine incorporation into newly synthesized DNA. Both toxin and radionuclide immunoconjugates eliminated established cytotoxic effector cells generated in an allogeneic mixed lymphocyte reaction, while leaving intact the PHA-inducible mitogenic response of the nonactivated cells. The addition of excess anti-Tac blocked all of the effects of these cytotoxic reagents. The therapeutic reagents in vitro were most effective when added just prior to the peak of the alloproliferative response, when receptor expression would be close to maximum. Thus, anti-Tac conjugated either with toxin or radionuclide is effective in vitro in specifically eliminating cytotoxic effector cells.
人类同种异体混合淋巴细胞反应是移植排斥反应在体外的对应反应。先前研究表明，在同种异体混合淋巴细胞反应过程中产生的细胞毒性效应细胞表达人p55白细胞介素-2受体亚基，而静息细胞不表达这种受体肽。在本研究中，我们探究了与抗白细胞介素-2受体单克隆抗体抗Tac偶联的铜绿假单胞菌外毒素或铋-212（一种发射α粒子的放射性核素）是否能够选择性清除同种异体混合淋巴细胞反应过程中产生的同种反应性细胞。组装后，抗Tac免疫缀合物保持其结合完整性、特异性和选择性。通过定量细胞回收率评估以及通过测量胸苷掺入新合成DNA来评估，同种反应性细胞的缺失表现为同种异体增殖细胞的清除。毒素和放射性核素免疫缀合物均能清除同种异体混合淋巴细胞反应中产生的已建立的细胞毒性效应细胞，同时不影响未活化细胞对PHA诱导的有丝分裂反应。加入过量抗Tac可阻断这些细胞毒性试剂的所有效应。当在同种异体增殖反应达到峰值之前添加体外治疗试剂时最为有效，此时受体表达接近最大值。因此，与毒素或放射性核素偶联的抗Tac在体外能够有效特异性清除细胞毒性效应细胞。
