Down-regulation of HLA-A and HLA-Bw6, but not HLA-Bw4, allospecificities in leukemic cells: an escape mechanism from CTL and NK attack?
Down-regulation of HLA-A and HLA-Bw6, but not HLA-Bw4, allospecificities in leukemic cells: an escape mechanism from CTL and NK attack?
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DOI：
10.1182/blood-2003-07-2500
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发表时间：
2004-04-15
期刊：
影响因子：
20.3
通讯作者：
Ferrone, S
中科院分区：
文献类型：
--
作者：
Demanet, C;Mulder, A;Ferrone, S
人类白细胞抗原（HLA）I类抗原缺陷可能对T细胞免疫治疗白血病策略的日益广泛应用产生负面影响。因此，在本研究中，利用一个大面板的HLA I类等位基因特异性的人单克隆抗体，我们比较了HLA I类抗原表达白血病细胞与自体和同种异体正常细胞。HLA-A和/或-B同种特异性的下调存在于大多数研究的患者中。然而，下调并不影响所有的HLA I类等位基因一致，但几乎完全限于HLA-A同种异体特异性和HLA-B同种异体特异性，属于HLA-Bw 6组。后者的同种异体特异性，属于HLA-Bw 4组的差异，不调节白血病细胞与自然杀伤（NK）细胞的相互作用。因此，我们的研究结果表明，选择性下调HLA-A和HLABw 6同种特异性与HLABw 4保存提供了一个逃避机制，不仅从细胞毒性T淋巴细胞（CTL），但也从NK细胞白血病细胞。因此，基于T细胞的白血病免疫策略应利用HLA-Bw 4同种抗原作为限制性元件，因为选择性HLA-Bw 4等位基因丢失将为白血病细胞提供从CTL逃逸的机制，但会增加它们对NK细胞介导的裂解的易感性。
Human leukocyte antigen (HLA) class I antigen defects may have a negative impact on the growing application of T-cell-based immunotherapeutic strategies for treatment of leukemia. Therefore in the present study, taking advantage of a large panel of HLA class I allele-specific human monoclonal antibodies, we have compared HLA class I antigen expression on leukemic cells with that on autologous and allogeneic normal cells. Downregulation of HLA-A and/or -B allo-specificities was present in the majority of the patients studied. However, downregulation did not affect all HLA class I alleles uniformly, but was almost exclusively restricted to HLA-A allospecificities and to HLA-B allospecificities; which belong to the HLA-Bw6 group. The latter allospecificities, at variance from those that belong to the HLA-Bw4 group, do not modulate the interactions of leukemic cells with natural killer (NK) cells. Therefore, our results suggest that the selective down-regulation of HLA-A and HLABw6 allospecificities associated with HLABw4 preservation provides leukemic cells with an escape mechanism not only from cytotoxic T lymphocytes (CTLs), but also from NK cells. As a result T-cell-based immunotherapeutic strategies for leukemia should utilize HLA-Bw4 alloantigens as restricting elements since a selective HLA-Bw4 allele loss would provide leukemic cells with an escape mechanism from CTLs, but would increase their susceptibility to NK cell-mediated lysis.