Effect of T-cell-epitope matching at HLA-DPB1 in recipients of unrelated-donor haemopoietic-cell transplantation: a retrospective study.
Effect of T-cell-epitope matching at HLA-DPB1 in recipients of unrelated-donor haemopoietic-cell transplantation: a retrospective study.
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DOI：
10.1016/s1470-2045(12)70004-9
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发表时间：
2012-04
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通讯作者：
International Histocompatibility Working Group in Hematopoietic Cell Transplantation
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作者：
Fleischhauer K;Shaw BE;Gooley T;Malkki M;Bardy P;Bignon JD;Dubois V;Horowitz MM;Madrigal JA;Morishima Y;Oudshoorn M;Ringden O;Spellman S;Velardi A;Zino E;Petersdorf EW;International Histocompatibility Working Group in Hematopoietic Cell Transplantation
背景供受者HLA-A、HLA-B、HLA-C、HLA-DRB 1、HLA-DQB 1等位基因匹配（10/10匹配）的非亲缘供者造血细胞移植后的风险可通过选择HLA-DPB 1也匹配的非亲缘供者来降低;然而，这样的供者很难找到。基于T细胞表位组的HLA-DPB 1错配的分类可以识别移植后可能耐受的错配（允许的）和将增加风险的错配（非允许的）。我们做了一项回顾性研究，比较非亲缘供者造血细胞移植中允许和非允许HLA-DPB 1错配的结局。方法回顾性分析国际造血细胞移植组织相容性工作组提交的非亲缘供者移植的HLA和临床资料。根据基于同种异体反应性T细胞交叉反应性模式的功能算法分配HLA-DPB 1 T细胞表位组。受体和无关供体匹配状态分为HLA-DPB 1匹配、非允许性HLA-DPB 1错配（具有错配的T细胞表位组的那些）或允许性HLA-DPB 1错配（具有匹配的T细胞表位组的那些）。评估的临床结局为总死亡率、非复发死亡率、复发和重度（3-4级）急性移植物抗宿主病（aGvHD）。在8539例移植中，5428例（64%）与10个HLA等位基因中的10个（HLA 10/10匹配）匹配，3111例（36%）与10个等位基因中的9个（HLA 9/10匹配）匹配。在整个组中，1719例（20%）为HLA-DPB 1匹配，2670例（31%）为非允许HLA-DPB 1错配，4150例（49%）为允许HLA-DPB 1错配。在HLA 10/10匹配的移植中，非允许性错配与总体死亡风险显著增加相关（风险比[HR] 1.15，95% CI 1.05 - 1.25; p= 0.002），非复发死亡率（1.28，1.14 - 1.42; p<0.0001）和重度aGvHD（比值比[OR] 1.31，95%CI 1.11 - 1.54; p= 0.001），但与允许性错配相比，未复发（HR 0.89，95%CI 0.77 - 1.02; p= 0.10）。在非复发死亡率方面，允许性HLA-DPB 1错配与HLA-DPB 1匹配之间存在显著差异（0.86，0.75 - 0.98; p= 0.03）和复发（1·34，1·17-1·54; p<0·0001），但总体死亡率（0·96，0·87-1·06; p=0·40）或aGvHD（OR 0·84，95% CI 0·69-1·03; p=0·09）则无此差异。在HLA 9/10匹配人群中，非允许性HLA-DPB 1错配也增加了总体死亡率的风险（HR 1.10，95% CI 1.00 - 1.22; p= 0.06），非复发死亡率（1.19，1.05 - 1.36; p= 0.007），重度aGvHD（OR 1.37，95%CI 1.13 - 1.66; p= 0.002），但两组复发风险相同（HR 0.93，95%CI 0.78 - 1.11; p= 0.44）。HLA 10/10匹配的移植与非允许性HLA-DPB 1错配的结果与HLA 9/10匹配的移植与允许性HLA-DPB 1错配或HLA-DPB 1匹配的结果没有实质性差异。解释T细胞表位匹配定义了允许性和非允许性HLA-DPB 1错配。避免与HLA-DPB 1非允许性T细胞表位错配无关的供体可能为降低无关供体造血细胞移植后死亡风险提供了一种实用的临床策略。资助国家卫生研究所;意大利癌症研究协会; Telethon基金会;意大利卫生部; Cariplo基金会;国家癌症研究所;国家心脏、肺和血液研究所;国家过敏和传染病研究所;海军研究办公室; IRGHET巴黎;瑞典癌症协会;儿童癌症基金会;瑞典研究理事会;斯德哥尔摩癌症协会; Karolinska研究所;白血病和淋巴瘤协会。
Background The risks after unrelated-donor haemopoietic-cell transplantation with matched HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1 alleles between donor and recipient (10/10 matched) can be decreased by selection of unrelated donors who also match for HLA-DPB1; however, such donors are difficult to find. Classification of HLA-DPB1 mismatches based on T-cell-epitope groups could identify mismatches that might be tolerated (permissive) and those that would increase risks (non-permissive) after transplantation. We did a retrospective study to compare outcomes between permissive and non-permissive HLA-DPB1 mismatches in unrelated-donor haemopoietic-cell transplantation. Methods HLA and clinical data for unrelated-donor transplantations submitted to the International Histocompatibility Working Group in haemopoietic-cell transplantation were analysed retrospectively. HLA-DPB1 T-cell-epitope groups were assigned according to a functional algorithm based on alloreactive T-cell crossreactivity patterns. Recipients and unrelated donors matching status were classified as HLA-DPB1 match, non-permissive HLA-DPB1 mismatch (those with mismatched T-cell-epitope groups), or permissive HLA-DPB1 mismatch (those with matched T-cell-epitope groups). The clinical outcomes assessed were overall mortality, non-relapse mortality, relapse, and severe (grade 3–4) acute graft-versus-host disease (aGvHD). Findings Of 8539 transplantations, 5428 (64%) were matched for ten of ten HLA alleles (HLA 10/10 matched) and 3111 (36%) for nine of ten alleles (HLA 9/10 matched). Of the group overall, 1719 (20%) were HLA-DPB1 matches, 2670 (31%) non-permissive HLA-DPB1 mismatches, and 4150 (49%) permissive HLA-DPB1 mismatches. In HLA 10/10-matched transplantations, non-permissive mismatches were associated with a significantly increased risk of overall mortality (hazard ratio [HR] 1·15, 95% CI 1·05–1·25; p=0·002), non-relapse mortality (1·28, 1·14–1·42; p<0·0001), and severe aGvHD (odds ratio [OR] 1·31, 95% CI 1·11–1·54; p=0·001), but not relapse (HR 0·89, 95% CI 0·77–1·02; p=0·10), compared with permissive mismatches. There were significant differences between permissive HLA-DPB1 mismatches and HLA-DPB1 matches in terms of non-relapse mortality (0·86, 0·75–0·98; p=0·03) and relapse (1·34, 1·17–1·54; p<0·0001), but not for overall mortality (0·96, 0·87–1·06; p=0·40) or aGvHD (OR 0·84, 95% CI 0·69–1·03; p=0·09). In the HLA 9/10 matched population, non-permissive HLA-DPB1 mismatches also increased the risk of overall mortality (HR 1·10, 95% CI 1·00–1·22; p=0·06), non-relapse mortality (1·19, 1·05–1·36; p=0·007), and severe aGvHD (OR 1·37, 95% CI 1·13–1·66; p=0·002) compared with permissive mismatches, but the risk of relapse was the same in both groups (HR 0·93, 95% CI 0·78–1·11; p=0·44). Outcomes for HLA 10/10-matched transplantations with non-permissive HLA-DPB1 mismatches did not differ substantially from those for HLA 9/10-matched transplantations with permissive HLA-DPB1 mismatches or HLA-DPB1 matches. Interpretation T-cell-epitope matching defines permissive and non-permissive HLA-DPB1 mismatches. Avoidance of an unrelated donor with a non-permissive T-cell-epitope mismatch at HLA-DPB1 might provide a practical clinical strategy for lowering the risks of mortality after unrelated-donor haemopoietic-cell transplantation. Funding National Institutes of Health; Associazione Italiana per la Ricerca sul Cancro; Telethon Foundation; Italian Ministry of Health; Cariplo Foundation; National Cancer Institute; National Heart, Lung and Blood Institute; National Institute of Allergy and Infectious Diseases; Office of Naval Research; IRGHET Paris; Swedish Cancer Society; Children's Cancer Foundation; Swedish Research Council; Cancer Society in Stockholm; Karolinska Institutet; and Leukemia and Lymphoma Society.