Effect of T-cell-epitope matching at HLA-DPB1 in recipients of unrelated-donor haemopoietic-cell transplantation: a retrospective study

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• 作者：Katharina Fleischhauer ; MD^a ; ^&Dagger ; ; Dr Bronwen E Shaw ; MD^b ; ^c ; ^&Dagger ; ; ^{bshaw@doctors.org.uk} ; Prof Theodore Gooley ; PhD^d ; Mari Malkki ; PhD^d ; Peter Bardy ; MD^e ; ^f ; Jean-Denis Bignon ; MD^g ; Valé ; rie Dubois ; BSc^h ; Prof Mary M Horowitz ; MDⁱ ; Prof J Alejandro Madrigal ; MD^c ; Prof Yasuo Morishima ; MD^k ; ^l ; Machteld Oudshoorn ; PhD^m ; ⁿ ; Prof Olle Ringden ; MD^o ; Stephen Spellman ; MBS^j ; Prof Andrea Velardi ; MD^p ; Elisabetta Zino ; BSc^a ; Prof Effie W Petersdorf ; MD^d ; on behalf of the International Histocompatibility Working Group in Hematopoietic Cell Transplantation
• 刊名：Lancet Oncology
• 出版年：2012
• 期刊代码：184_14702045
• 类别：med
• 出版时间：April, 2012
• 卷：13
• 期：4
• 页码：366-374
• 文件大小：200 K

摘要

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Summary

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 related-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路15, 95%CI 1路05-1路25; p=0路002), non-relapse mortality (1路28, 1路14-1路42; p<0路0001), and severe aGvHD (odds ratio [OR] 1路31, 95%CI 1路11-1路54; p=0路001), but not relapse (HR 0路89, 95%CI 0路77-1路02; p=0路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路86, 0路75-0路98; p=0路03) and relapse (1路34, 1路17-1路54; p<0路0001), but not for overall mortality (0路96, 0路87-1路06; p=0路40) or aGvHD (OR 0路84, 95%CI 0路69-1路03; p=0路09). In the HLA 9/10 matched population, non-permissive HLA-DPB1 mismatches also increased the risk of overall mortality (HR 1路10, 95%CI 1路00-1路22; p=0路06), non-relapse mortality (1路19, 1路05-1路36; p=0路007), and severe aGvHD (OR 1路37, 95%CI 1路13-1路66; p=0路002) compared with permissive mismatches, but the risk of relapse was the same in both groups (HR 0路93, 95%CI 0路78-1路11; p=0路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.