Tan R, Xu X, Ogg G S, Hansasuta P, Dong T, Rostron T, Luzzi G, Conlon C P, Screaton G R, McMichael A J, Rowland-Jones S
Molecular Immunology Group, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK.
Blood. 1999 Mar 1;93(5):1506-10.
Human immunodeficiency virus (HIV)-specific cytotoxic T lymphocytes (CTL) probably play the major role in controlling HIV replication. However, the value of adoptive transfer of HIV-specific CTL expanded in vitro to HIV+ patients has been limited: this contrasts with the success of CTL therapy in treating or preventing Epstein-Barr virus and cytomegalovirus disease after bone marrow transplantation (BMT). We investigated the fate of expanded HIV-specific CTL clones in vivo following adoptive transfer to a patient with acquired immunodeficiency syndrome (AIDS). Two autologous CTL clones specific for HIV Gag and Pol were expanded to large numbers (>10(9)) in vitro and infused into an HIV-infected patient whose viral load was rising despite antiretroviral therapy. The fate of one clone was monitored by staining peripheral blood mononuclear cells (PBMCs) with T-cell receptor-specific tetrameric major histocompatibility complex (MHC)-peptide complexes. Although the CTL transfer was well tolerated, there were no significant changes in CD4 and CD8 lymphocyte counts and virus load. By tracking an infused clone using soluble MHC-peptide complexes, we show that cells bearing the Gag-specific T-cell receptors were rapidly eliminated within hours of infusion through apoptosis. Thus, the failure of adoptively transferred HIV-specific CTL to reduce virus load in AIDS may be due to rapid apoptosis of the infused cells, triggered by a number of potential mechanisms. Further trials of adoptive transfer of CTL should take into account the susceptibility of infused cells to in vivo apoptosis.
人类免疫缺陷病毒（HIV）特异性细胞毒性T淋巴细胞（CTL）可能在控制HIV复制中起主要作用。然而，将体外扩增的HIV特异性CTL过继转移给HIV阳性患者的价值有限：这与CTL疗法在治疗或预防骨髓移植（BMT）后爱泼斯坦-巴尔病毒和巨细胞病毒疾病方面的成功形成对比。我们研究了过继转移给一名获得性免疫缺陷综合征（AIDS）患者后，体内扩增的HIV特异性CTL克隆的命运。两个针对HIV Gag和Pol的自体CTL克隆在体外扩增至大量（>10⁹），并注入一名尽管接受抗逆转录病毒治疗但病毒载量仍在上升的HIV感染患者体内。通过用T细胞受体特异性四聚体主要组织相容性复合体（MHC）-肽复合物对外周血单个核细胞（PBMC）进行染色，监测其中一个克隆的命运。尽管CTL转移耐受性良好，但CD4和CD8淋巴细胞计数以及病毒载量均无显著变化。通过使用可溶性MHC-肽复合物追踪注入的克隆，我们发现携带Gag特异性T细胞受体的细胞在注入后数小时内通过凋亡迅速被清除。因此，过继转移的HIV特异性CTL未能降低AIDS患者的病毒载量，可能是由于注入细胞因多种潜在机制引发的快速凋亡。CTL过继转移的进一步试验应考虑注入细胞对体内凋亡的易感性。
