Donor killer immunoglobulin-like receptor genes and reactivation of cytomegalovirus after HLA-matched hematopoietic stem-cell transplantation: HLA-C allotype is an essential cofactor.
Donor killer immunoglobulin-like receptor genes and reactivation of cytomegalovirus after HLA-matched hematopoietic stem-cell transplantation: HLA-C allotype is an essential cofactor.
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DOI：
10.3389/fimmu.2013.00036
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发表时间：
2013
影响因子：
7.3
通讯作者：
Zaia JA
中科院分区：
文献类型：
--
作者：
Behrendt CE;Nakamura R;Forman SJ;Zaia JA
其杀伤免疫球蛋白样受体（KIR）识别人类白细胞抗原（HLA）配体的自然杀伤（NK）细胞被“许可”具有活性。相比之下，非许可NK细胞显示自身基因型中不存在配体的KIR，并且通常是低应答的。令人惊讶的是，非许可细胞在造血干细胞移植（HSCT）后的肿瘤控制中是活跃的，并且主导对鼠巨细胞病毒（CMV）感染的NK应答。根据这些报道，我们假设HSCT后早期人CMV的控制受到供体KIR基因的影响，其HLA配体在HLA匹配的供体和受体的基因型中缺失。为了调查，我们研究了CMV血清阳性供体和/或受体移植后100天的CMV再激活。一个多变量比例比率模型控制了监测的变异性，并建立了包括急性移植物抗宿主病在内的协变量;调整了具有确定的HLA I类配体（2DL 1、2DL 2/3、2DS 1、2DS 2、全长2DS 4、3DL 1/3DS 1、3DL 2）的多个KIR的统计学显著性。在HSCT受者中（n = 286），CMV无再激活生存时间随HLA-C进化特异性KIR基因个体供体而变化：当供体/受体基因型中不存在配体时，抑制性KIR 2DL 2 2DL 1（P = 0.015）预测的预后较差，而激活KIR的2DS 2（P <0.0001）、2DS 1（P = 0.016）和2DS 4（P = 0.016）预测的预后较上级。另外，配体基因型中存在的供体KIR基因没有影响。总之，HLA匹配的HSCT后早期，单个抑制性和激活性KIR基因对CMV再激活风险具有质的不同影响;出乎意料的是，供体/受体基因型中HLA-C配体的缺失构成了这些关联中的重要辅助因子。作为KIR和HLA-C特异性，这些发现独立于通过识别HLA-E的替代NK细胞受体（NKG 2A，NKG 2C）的许可。
Natural killer (NK) cells whose killer immunoglobulin-like receptors (KIRs) recognize human leukocyte antigen (HLA) ligand are “licensed” for activity. In contrast, non-licensed NK cells display KIRs for which ligand is absent from the self genotype and are usually hyporesponsive. Surprisingly, non-licensed cells are active in tumor control after hematopoietic stem-cell transplantation (HSCT) and dominate NK response to murine cytomegalovirus (CMV) infection. From those reports, we hypothesized that control of human CMV early after HSCT is influenced by donor KIR genes whose HLA ligand is absent-from-genotype of HLA-matched donor and recipient. To investigate, we studied CMV reactivation through Day 100 after grafts involving CMV-seropositive donor and/or recipient. A multivariate proportional rates model controlled for variability in surveillance and established covariates including acute graft-versus-host disease; statistical significance was adjusted for testing of multiple KIRs with identified HLA class I ligand (2DL1, 2DL2/3, 2DS1, 2DS2, full-length 2DS4, 3DL1/3DS1, 3DL2). Among HSCT recipients (n = 286), CMV reactivation-free survival time varied with individual donor KIR genes evolutionarily specific for HLA-C: when ligand was absent from the donor/recipient genotype, inhibitory KIRs 2DL2 (P < 0.0001) and 2DL1 (P = 0.015) each predicted inferior outcome, and activating KIRs 2DS2 (P < 0.0001), 2DS1 (P = 0.016), and 2DS4 (P = 0.016) each predicted superior outcome. Otherwise, with ligand present-in-genotype, donor KIR genes had no effect. In conclusion, early after HLA-matched HSCT, individual inhibitory and activating KIR genes have qualitatively different effects on risk of CMV reactivation; unexpectedly, absence of HLA-C ligand from the donor/recipient genotype constitutes an essential cofactor in these associations. Being KIR- and HLA-C-specific, these findings are independent of licensing via alternate NK cell receptors (NKG2A, NKG2C) that recognize HLA-E.
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影响因子：
8.8
作者：
Hadaya, K.;de Rham, C.;Villard, J.
通讯作者：
Villard, J.
影响因子：
4.4
作者：
Ljungman, Per;Hakki, Morgan;Boeckh, Michael
通讯作者：
Boeckh, Michael
DOI：
10.1016/j.bbmt.2011.04.008
发表时间：
2011-11
期刊：
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation
影响因子：
--
作者：
Gallez-Hawkins GM;Franck AE;Li X;Thao L;Oki A;Gendzekhadze K;Dagis A;Palmer J;Nakamura R;Forman SJ;Senitzer D;Zaia JA
通讯作者：
Zaia JA
影响因子：
4.3
作者：
Guerrero, Abraham;Riddell, Stanley R.;Boeckh, Michael
通讯作者：
Boeckh, Michael
影响因子：
20.3
作者：
Miller, Jeffery S.;Cooley, Sarah;Weisdorf, Daniel J.
通讯作者：
Weisdorf, Daniel J.