A High Degree of HLA Disparity Arises From Limited Allelic Diversity: Analysis of 1775 Unrelated Bone Marrow Transplant Donor-Recipient Pairs Carolyn Katovich Hurley, Marcelo Fernandez-Vina, William H. Hildebrand, Harriet J. Noreen, Elizabeth Trachtenberg, Thomas M. Williams, Lee Ann Baxter-Lowe, Ann B. Begovich Effie Petersdorf, Annamalai Selvakumar, Peter Stastny, Janet Hegland, Robert J. Hartzman, Michael Carston, Sharavi Gandham, Craig Kollman, Gene Nelson, Stephen Spellman, and Michelle Setterholm ABSTRACT: The allelic diversity and associated human leukocyte antigen (HLA) disparity of 1775 bone marrow recipients and their unrelated donors, matched for six of six (1361/1775,77%), five of six (397/1775, 22%), or four of six (17/1775, 1%) HLA-A, -B, -DR antigens, were retrospectively evaluated. The comprehensive HLA anal- ysis included the class I (A, B, C) and II (DRB1, DQA1, DQB1, DPA1, DPB1) loci. Most (66%) of the predom- inantly Caucasian study population carried one or two of five to seven common alleles at each HLA locus. In spite of this limited diversity, 29% of the six of six antigen- matched transplants carried allele mismatches at HLA-A, -B, and/or -DRB1, and 92% carried at least one allele mismatch at one of the eight HLA loci tested. Of the 968 HLA-A,-B,-DRB1 allele-matched pairs, 89% carried mis- matches at other HLA loci, predominantly at DP loci. The substantially greater than expected HLA allelic disparity between donor and recipient suggests extensive haplo- typic diversity and underscores the importance of enhanc- ing approaches to mitigate the deleterious effect of HLA mismatches. Human Immunology 68, 30 – 40 (2007). © American Society for Histocompatibility and Immunoge- netics, 2007. Published by Elsevier Inc. KEYWORDS: Bone marrow transplantation; HLA ABBREVIATIONS HLA human leukocyte antigen From the Department of Oncology, Georgetown University, Washington, DC, USA (C.K.H.); American Red Cross-National, Baltimore, MD, USA and M. D. Anderson Cancer Center, Houston, TX, USA (M.F.-V.); University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA (W.H.H.); Immunology/Histocompatibility Laboratory, University of Min- nesota Medical Center, Fairview, Minneapolis, MN, USA (H.J.N.); Chil- dren’s Hospital Oakland Research Institute, Oakland, CA, USA (E.T., A.B.B.); Department of Pathology, University of New Mexico, Albuquerque, NM, USA (T.M.W.); Department of Surgery, University of California San Francisco, San Francisco, CA, USA (L.A.B.-L.); Roche Molecular Systems, Alameda, CA, USA and Celera Diagnostics, Alameda, CA, USA (A.B.B.); Fred Hutchinson Cancer Research Center, Seattle, WA, USA (E.P.); Sloan-Kettering Institute for Cancer Research, New York, NY, USA (A.S.); University of Texas Southwestern, Dallas, TX, USA (P.S.); Na- tional Marrow Donor Program, Minneapolis, MN, USA (J.H., M.C., S.G., C.K., G.N., S.S., M.S.); and Naval Medical Research Center, Bethesda, MD, USA (R.J.H.). Address reprint requests to: Dr. Carolyn Katovich Hurley, E404 Re- search Building, Georgetown University Medical Center, 3970 Reservoir Rd NW, Washington, DC 20057; Tel: (202) 687-2157; Fax: (202) 687- 6440; E-mail: hurleyc@georgetown.edu. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the Office of Naval Research, the Department of Defense, or the U.S. government. Received June 30, 2006; revised September 12, 2006; accepted September 28, 2006. Human Immunology 68, 30 – 40 (2007) © American Society for Histocompatibility and Immunogenetics, 2007 0198-8859/07/$–see front matter Published by Elsevier Inc. doi:10.1016/j.humimm.2006.09.004