Petersdorf Effie W, Gooley Theodore A, Malkki Mari, Bacigalupo Andrea P, Cesbron Anne, Du Toit Ernette, Ehninger Gerhard, Egeland Torstein, Fischer Gottfried F, Gervais Thibaut, Haagenson Michael D, Horowitz Mary M, Hsu Katharine, Jindra Pavel, Madrigal Alejandro, Oudshoorn Machteld, Ringdén Olle, Schroeder Marlis L, Spellman Stephen R, Tiercy Jean-Marie, Velardi Andrea, Witt Campbell S, O'Huigin Colm, Apps Richard, Carrington Mary
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Medicine, University of Washington School of Medicine, Seattle, WA;
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA;
Blood. 2014 Dec 18;124(26):3996-4003. doi: 10.1182/blood-2014-09-599969. Epub 2014 Oct 16.
Life-threatening graft-versus-host disease (GVHD) limits the use of HLA-C-mismatched unrelated donors in transplantation. Clinicians lack criteria for donor selection when HLA-C-mismatched donors are a patient's only option for cure. We examined the role for HLA-C expression levels to identify permissible HLA-C mismatches. The median fluorescence intensity, a proxy of HLA-C expression, was assigned to each HLA-C allotype in 1975 patients and their HLA-C-mismatched unrelated transplant donors. The association of outcome with the level of expression of patients' and donors' HLA-C allotypes was evaluated in multivariable models. Increasing expression level of the patient's mismatched HLA-C allotype was associated with increased risks of grades III to IV acute GVHD, nonrelapse mortality, and mortality. Increasing expression level among HLA-C mismatches with residue 116 or residue 77/80 mismatching was associated with increased nonrelapse mortality. The immunogenicity of HLA-C mismatches in unrelated donor transplantation is influenced by the expression level of the patient's mismatched HLA-C allotype. HLA-C expression levels provide new information on mismatches that should be avoided and extend understanding of HLA-C-mediated immune responses in human disease.
危及生命的移植物抗宿主病（GVHD）限制了人类白细胞抗原C（HLA-C）错配的无关供者在移植中的应用。当HLA-C错配的供者是患者唯一的治愈选择时，临床医生缺乏供者选择标准。我们研究了HLA-C表达水平在识别可允许的HLA-C错配中的作用。将1975例患者及其HLA-C错配的无关移植供者的每个HLA-C同种异型的中位荧光强度（作为HLA-C表达的替代指标）进行赋值。在多变量模型中评估患者和供者HLA-C同种异型表达水平与预后的相关性。患者错配的HLA-C同种异型表达水平增加与III至IV级急性GVHD、非复发死亡率和死亡率增加相关。在第116位残基或第77/80位残基错配的HLA-C错配中，表达水平增加与非复发死亡率增加相关。无关供者移植中HLA-C错配的免疫原性受患者错配的HLA-C同种异型表达水平影响。HLA-C表达水平提供了关于应避免的错配的新信息，并扩展了对人类疾病中HLA-C介导的免疫反应的理解。
