Fleischhauer, K., Shaw, B. E., Gooley, T., Malkki, M., Bardy, P., Bignon, J. D., Dubois, V., Horowitz, M. M., Madrigal, J. A., Morishima, Y., Oudshoorn, M., Ringden, O., Spellman, S., Velardi, A., Zino, E., Petersdorf, E. W., Int Histocompatibility Working, Grp (2012) Effect of T-cell-epitope matching at HLA-DPB1 in recipients of unrelated-donor haemopoietic-cell transplantation: a retrospective study. LANCET ONCOLOGY, 13 (4). pp. 366-374. ISSN 1470-2045

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Abstract

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 trans plantation. Methods HLA and clinical data for unrelated-donor transplantations submitted to the International Histo compatibility 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 u 06), non-relapse mortality (1 u 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 trans plantations 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.

Item Type:	Article
Authors (ICR Faculty only):	Shaw, Bronwen
All Authors:	Fleischhauer, K., Shaw, B. E., Gooley, T., Malkki, M., Bardy, P., Bignon, J. D., Dubois, V., Horowitz, M. M., Madrigal, J. A., Morishima, Y., Oudshoorn, M., Ringden, O., Spellman, S., Velardi, A., Zino, E., Petersdorf, E. W., Int Histocompatibility Working, Grp
Additional Information:	ISI Document Delivery No.: 918YG Times Cited: 2 Cited Reference Count: 34 Fleischhauer, Katharina Shaw, Bronwen E. Gooley, Theodore Malkki, Mari Bardy, Peter Bignon, Jean-Denis Dubois, Valerie Horowitz, Mary M. Madrigal, J. Alejandro Morishima, Yasuo Oudshoorn, Machteld Ringden, Olle Spellman, Stephen Velardi, Andrea Zino, Elisabetta Petersdorf, Effie W. National Institutes of Health, USA[AI069197, CA18029]; Associazione Italiana per la Ricerca sul Cancro (AIRC); Cariplo Foundation[GGP08201]; Public Health Service; National Cancer Institute (NCI), National Heart, Lung and Blood Institute (NHLBI), National Institute of Allergy and Infectious Diseases[U24-CA76518, HHSH234200637015C]; Health Resources and Services Administration (HRSA/DHHS)[N00014-10-1-0204]; Office of Naval Research[N00014-1-1-0339]; IRGHET-Paris; Swedish Cancer Society[CAN 2008/562, 10 0333]; Children's Cancer Foundation[PROJ09/093]; Swedish Research Council[K2008-64X-05971-28-3]; Cancer Society in Stockholm; Karolinska Institutet; Leukemia and Lymphoma Society[6260-11 (AV)]; Telethon Foundation; Italian Ministry of Health The members of the IHWG haemopoietic-cell transplantation component who contributed data to this publication are listed in the appendix. We acknowledge support from the following funding agencies: grants AI069197, CA18029 from National Institutes of Health, USA (EWP, TG, and MM); Associazione Italiana per la Ricerca sul Cancro (AIRC), GGP08201 Telethon Foundation, Ricerca Finalizzata RF2007 Italian Ministry of Health, Cariplo Foundation (KF); Public Health Service grant or cooperative agreement U24-CA76518 from National Cancer Institute (NCI), National Heart, Lung and Blood Institute (NHLBI), National Institute of Allergy and Infectious Diseases (MMH); contract HHSH234200637015C with Health Resources and Services Administration (HRSA/DHHS), grant N00014-10-1-0204 and N00014-1-1-0339 from the Office of Naval Research, and other grants (MMH and SS); IRGHET-Paris (JDB); Swedish Cancer Society (CAN 2008/562, 10 0333), Children's Cancer Foundation (PROJ09/093), Swedish Research Council (K2008-64X-05971-28-3), Cancer Society in Stockholm, and Karolinska Institutet (OR); Leukemia and Lymphoma Society Grant number 6260-11 (AV). The views expressed in this article are those of the authors and do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, or any other agency of the US government. Elsevier science inc New york
Uncontrolled Keywords:	versus-host-disease amino-acid difference hla-dp marrow transplantation allograft-rejection molecular-mechanism crucial role mismatches disparities leukemia
Research teams:	Closed research groups > Translational studies in Haematopoietic Stem Cell Transplantation
Depositing User:	Users 11 not found.
Date Deposited:	08 May 2012 14:40
Last Modified:	25 Sep 2014 11:42
URI:	http://publications.icr.ac.uk/id/eprint/11572

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