Role of the inhibitory KIR ligand HLA-Bw4 and HLA-C expression levels in the recognition of leukemic cells by Natural Killer cells.
Role of the inhibitory KIR ligand HLA-Bw4 and HLA-C expression levels in the recognition of leukemic cells by Natural Killer cells.
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DOI：
10.1007/s00262-008-0601-7
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发表时间：
2009-06
影响因子：
5.8
通讯作者：
Demanet, Christian
中科院分区：
文献类型：
--
作者：
Verheyden, Sonja;Ferrone, Soldano;Mulder, Arend;Claas, Frans H.;Schots, Rik;De Moerloose, Barbara;Benoit, Yves;Demanet, Christian
关键词：
急性髓系白血病(AML)患者与相关半相合供者的移植物移植已被证明具有强大的移植物抗白血病效应。这种作用是由NK细胞介导的，因为缺乏识别HLA-Bw4和HLA-C等位基因的抑制性杀伤细胞免疫球蛋白样受体(KIRS)的激活。然而，关于KIR配体不匹配对白血病患者进行非亲缘关系的人类白细胞抗原不匹配的造血干细胞移植(HSCT)结局的影响，有相互矛盾的结果报道。白血病细胞上人类白细胞抗原I类等位基因表达水平的信息很少，这阻碍了对这些相互矛盾的结果的解释，尽管这一变量可能影响抑制性KIR的激活。因此，在本研究中，我们利用大量的人类单抗，检测了20份B-CLL细胞标本、16份B-ALL细胞标本和19份AML细胞标本的HLA-A、-B和-C等位基因的表达水平。比较白血病细胞和自体正常T细胞的HLA-I类抗原表达水平，发现20例B-CLL中15例和14例、16例B-ALL中2例和5例、19例AML患者中7例和11例分别选择性下调了HLA-A和HLA-B等位基因。最有趣的是，人类白细胞抗原-C等位基因在所有三种类型的白血病细胞上都显着下调；这种下调在急性髓系白血病细胞中最为明显。通过在表达NK细胞激活配体的白血病细胞表面包被单抗，以剂量依赖的方式增强NK细胞活性，提示了这些异常的潜在功能相关性。我们的结果表明，除了人类白细胞抗原和KIR基因外，白血病细胞上KIR配体的表达水平也应包括在选择供受者组合的标准中。
Transplantation of acute myeloid leukemia (AML) patients with grafts from related haploidentical donors has been shown to result in a potent graft-versus-leukemia effect. This effect is mediated by NK cells because of the lack of activation of inhibitory killer cell immunoglobulin-like receptors (KIRs) which recognize HLA-Bw4 and HLA-C alleles. However, conflicting results have been reported about the impact of KIR ligand mismatching on the outcome of unrelated HLA-mismatched hematopoietic stem cells transplants (HSCT) to leukemic patients. The interpretation of these conflicting results is hampered by the scant information about the level of expression of HLA class I alleles on leukemic cells, although this variable may affect the activation of inhibitory KIRs. Therefore in the present study, utilizing a large panel of human monoclonal antibodies we have measured the level of expression of HLA-A, -B and -C alleles on 20 B-chronic lymphoid leukemic (B-CLL) cell preparations, on 16 B-acute lymphoid leukemic (B-ALL) cell preparations and on 19 AML cell preparations. Comparison of the level of HLA class I antigen expression on leukemic cells and autologous normal T cells identified selective downregulation of HLA-A and HLA-B alleles on 15 and 14 of the 20 B-CLL, on 2 and 5 of the 16 B-ALL and on 7 and 11 of the 19 AML patients tested, respectively. Most interestingly HLA-C alleles were markedly downregulated on all three types of leukemic cells; the downregulation was most pronounced on AML cells. The potential functional relevance of these abnormalities is suggested by the dose-dependent enhancement of NK cell activation caused by coating the HLA-HLA-Bw4 epitope with monoclonal antibodies on leukemic cells which express NK cell activating ligands. Our results suggest that besides the HLA and KIR genotype, expression levels of KIR ligands on leukemic cells should be included among the criteria used to select the donor-recipient combinations for HSCT.
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影响因子：
4.4
作者：
Almeida, Catarina R.;Davis, Daniel M.
通讯作者：
Davis, Daniel M.
影响因子：
6.5
作者：
Vollmer, M;Li, L;Schmitt, M
通讯作者：
Schmitt, M
影响因子：
20.3
作者：
Demanet, C;Mulder, A;Ferrone, S
通讯作者：
Ferrone, S
DOI：
10.1084/jem.181.3.1133
发表时间：
1995-03-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Gumperz JE;Litwin V;Phillips JH;Lanier LL;Parham P
通讯作者：
Parham P
影响因子：
20.3
作者：
Ruggeri, Loredana;Mancusi, Antonella;Velardi, Andrea
通讯作者：
Velardi, Andrea