Impact of highly conserved HLA haplotype on acute graft-versus-host disease (original) (raw)

Abstract

Although the effects of human leukocyte antigen (HLA) locus matching on clinical outcome in unrelated hematopoietic stem cell transplantations have been characterized, the biologic implications of HLA haplotypes have not been defined. We demonstrated the genetic fixity of Japanese conserved extended haplotypes by multi-single nucleotide polymorphism analysis in 1810 Japanese donor-recipient pairs matching with HLA-A,-B,-C,-DRB1, and-DQB1 alleles. Three major Japanese conserved extended haplotypes (named HP-P1, HP-P2, and HP-P3) were essentially completely conserved at least in the 3.3-Mb HLA region from HLA-A to-DPB1, and extended far beyond HLA-A. The risk of acute graft-versus-host disease (GVHD) of these HLA haplotypes was assessed with multivariate Cox regression in 712 patients transplanted from HLA fully (HLA-A, B, C, DRB1, DQB1, and DPB1) matched unrelated donors. HP-P2 itself reduced the risk of grade 2 to 4 acute GVHD (hazard ratio [HR] ‫؍‬ 0.63; P ‫؍‬ .032 compared with HP-P2-negative), whereas HP-P3 tended to increase the risk (HR ‫؍‬ 1.38; P ‫؍‬ .07). Among 381 patients with HP-P1, HP-P1/P3 (HR ‫؍‬ 3.35; P ‫؍‬ .024) significantly increased the risk of acute GVHD compared with homozygous HP-P1. This study is the first to demonstrate that a genetic difference derived from HLA haplotype itself is associated with acute GVHD in allogeneic hematopoietic stem cell transplantation. (Blood. 2010;115(23): 4664-4670)

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References (30)

  1. Sasazuki T, Juji T, Morishima Y, et al. Effect of matching of class I HLA alleles on clinical out- come after transplantation of hematopoietic stem cells from an unrelated donor: Japan Marrow Do- nor Program. N Engl J Med. 1998;339(17):1177- 1185.
  2. Morishima Y, Sasazuki T, Inoko H, et al. The clini- cal significance of human leukocyte antigen (HLA) allele compatibility in patients receiving a marrow transplant from serologically HLA-A, HLA-B, and HLA-DR matched unrelated donors. Blood. 2002;99(11):4200-4206.
  3. Lee SJ, Klein J, Haagenson M, et al. High- resolution donor-recipient HLA matching contrib- utes to the success of unrelated donor marrow transplantation. Blood. 2007;110(13):4576-4583.
  4. Kawase T, Morishima Y, Matsuo K, et al. High-risk HLA allele mismatch combinations responsible for severe acute graft-versus-host disease and implication for its molecular mechanism. Blood. 2007;110(7):2235-2241.
  5. Petersdorf EW, Malkki M, Gooley TA, Martin PJ, Guo Z. MHC haplotype matching for unrelated hematopoietic cell transplantation. PLoS Med. 2007;4(1):e8.
  6. Tay GK, Witt CS, Christiansen FT, et al. Matching for MHC haplotypes results in improved survival following unrelated bone marrow transplantation. Bone Marrow Transplant. 1995;15(3):381-385.
  7. Kitcharoen K, Witt CS, Romphruk AV, Christiansen FT, Leelayuwat C. MICA, MICB, and MHC beta block matching in bone marrow trans- plantation: relevance to transplantation outcome. Hum Immunol. 2006;67(3):238-246.
  8. Alper CA, Awdeh Z, Yunis EJ. Conserved, ex- tended MHC haplotypes. Exp Clin Immunogenet. 1992;9(2):58-71.
  9. Degli-Esposti MA, Leaver AL, Christiansen FT, Witt CS, Abraham LJ, Dawkins RL. Ancestral haplotypes: conserved population MHC haplo- types. Hum Immunol. 1992;34(4):242-252.
  10. Price P, Witt C, Allcock R, et al. The genetic basis for the association of the 8.1 ancestral haplotype (A1, B8, DR3) with multiple immunopathological diseases. Immunol Rev. 1999;167:257-274.
  11. Tokunaga K, Ishikawa Y, Ogawa A, et al. Sequence-based association analysis of HLA class I and II alleles in Japanese supports con- servation of common haplotypes. Immunogenet- ics. 1997;46(3):199-205.
  12. Saito S, Ota S, Yamada E, Inoko H, Ota M. Allele frequencies and haplotypic associations defined by allelic DNA typing at HLA class I and class II loci in the Japanese population. Tissue Antigens. 2000;56(6):522-529.
  13. Shiina T, Ota M, Shimizu S, et al. Rapid evolution of major histocompatibility complex class I genes in primates generates new disease alleles in hu- mans via hitchhiking diversity. Genetics. 2006; 173(3):1555-1570.
  14. Bilbao JR, Calvo B, Aransay AM, et al. Conserved extended haplotypes discriminate HLA-DR3-ho- mozygous Basque patients with type 1 diabetes mellitus and celiac disease. Genes Immun. 2006; 7(7):550-554.
  15. Romero V, Larsen CE, Duke-Cohan JS, et al. Ge- netic fixity in the human major histocompatibility complex and block size diversity in the class I re- gion including HLA-E. BMC Genet. 2007;8:14.
  16. Aly TA, Baschal EE, Jahromi MM, et al. Analysis of single nucleotide polymorphisms identifies ma- jor type 1A diabetes locus telomeric of the major histocompatibility complex. Diabetes. 2008;57(3): 770-776.
  17. Worwood M, Raha Chowdhury R, Robson KJ, Pointon J, Shearman JD, Darke C. The HLA A1-B8 haplotype extends 6 Mb beyond HLA-A: associations between HLA-A, B, F and 15 micro- satellite markers. Tissue Antigens. 1997;50(5): 521-526.
  18. Yunis EJ, Larsen CE, Fernandez-Vina M, et al. Inheritable variable sizes of DNA stretches in the human MHC: conserved extended haplotypes and their fragments or blocks. Tissue Antigens. 2003;62(1):1-20.
  19. Akatsuka Y, Morishima Y, Kuzushima K, Kodera Y, Takahashi T. Minor histocompatibility antigens as targets for immunotherapy using allogeneic immune reactions. Cancer Sci. 2007;98(8):1139- 1146.
  20. McCarroll SA, Bradner JE, Turpeinen H, et al. Donor-recipient mismatch for common gene dele- tion polymorphisms in graft-versus-host disease. Nat Genet. 2009;41(12):1341-1344.
  21. Kaplan DH, Anderson BE, McNiff JM, Jain D, Shlomchik MJ, Shlomchik WD. Target antigens determine graft-versus-host disease phenotype. J Immunol. 2004;173(9):5467-5475.
  22. Battiwalla M, Hahn T, Radovic M, et al. Human leukocyte antigen (HLA) DR15 is associated with reduced incidence of acute GVHD in HLA- matched allogeneic transplantation but does not impact chronic GVHD incidence. Blood. 2006; 107(5):1970-1973.
  23. Stern M, Passweg J, Tiercy JM, et al. Human leu- kocyte antigen DR15 is associated with reduced relapse rate and improved survival after human leukocyte antigen-identical sibling hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2006;12(11):1169-1175.
  24. Davidson JA, Tate DG, Poulton KV, et al. HLA- DR15, reduced relapse rate and improved sur- vival after HLA-identical sibling hemopoietic stem cell transplantation. Biol Blood Marrow Trans- plant. 2007;13(4):493-494.
  25. Maciejewski JP, Follmann D, Nakamura R, et al. Increased frequency of HLA-DR2 in patients with paroxysmal nocturnal hemoglobinuria and the PNH/aplastic anemia syndrome. Blood. 2001; 98(13):3513-3519.
  26. Saunthararajah Y, Nakamura R, Nam JM, et al. HLA-DR15 (DR2) is overrepresented in myelo- dysplastic syndrome and aplastic anemia and predicts a response to immunosuppression in myelodysplastic syndrome. Blood. 2002;100(5): 1570-1574.
  27. Ishikawa Y, Kashiwase K, Akaza T, et al. Polymor- phisms in TNFA and TNFR2 affect outcome of unrelated bone marrow transplantation. Bone Marrow Transplant. 2002;29(7):569-575.
  28. Hansen JA, Petersdorf EW, Lin MT, et al. Genet- ics of allogeneic hematopoietic cell transplanta- tion: role of HLA matching, functional variation in immune response genes. Immunol Res. 2008; 41(1):56-78.
  29. Trowsdale J, Ragoussis J, Campbell RD. Map of the human MHC. Immunol Today. 1991;12(12): 443-446.
  30. York IA, Rock KL. Antigen processing and pre- sentation by the class I major histocompatibility complex. Annu Rev Immunol. 1996;14:369-396.