Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Histocompatibility and Donor Selection

Immunogenic disparities of 11 minor histocompatibility antigens (mHAs) in HLA-matched unrelated allogeneic hematopoietic SCT

Bone Marrow Transplantation volume 43, pages 293–300 (2009)Cite this article

Abstract

We determined the alleles of 11 mHAs and investigated the association of immunogenic mHA mismatches between a donor and a recipient with a course of allogeneic hematopoietic SCT (allo-HSCT) from 10/10 alleles HLA-matched unrelated donors in 92 recipients after myeloablative conditioning between 2004 and 2006. The frequency analysis of mHA alleles, genotypes and phenotypes accompanied by appropriate restriction HLA Ags allowed for an estimation of the probability of immunogenic mismatches, which was the highest for HA-1, HA-8 and HY. GVH-directed disparity of mHAs with broad tissue distribution, especially of the sex-related HY Ag, influenced the results of allo-HSCT from HLA-matched unrelated donors by not only increasing the probability of chronic GVHD (cGVHD) but also by decreasing the relapse rate.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Mullighan CG, Bardy PG . New directions in the genomics of allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2007; 13: 127–144.

    Article  CAS  PubMed  Google Scholar 

  2. Kikuchi T, Naruse TK, Onizuka M, Li S, Kimura T, Oka A et al. Mapping of susceptibility and protective loci for acute GVHD in unrelated HLA-matched bone marrow transplantation donors and recipients using 155 microsatellite markers on chromosome 22. Immunogenetics 2007; 59: 99–108.

    Article  CAS  PubMed  Google Scholar 

  3. Dickinson AM, Middleton PG, Rocha V, Gluckman E, Holler E . Genetic polymorphisms predicting the outcome of bone marrow transplants. Br J Haematol 2004; 127: 479–490.

    Article  CAS  PubMed  Google Scholar 

  4. Bertinetto FE, Dall’Omo AM, Mazzola GA, Rendine S, Berrino M, Bertola L et al. Role of non-HLA genetic polymorphisms in graft-versus-host disease after haematopoietic stem cell transplantation. Int J Immunogenetics 2006; 33: 375–384.

    Article  CAS  Google Scholar 

  5. Mullally A, Ritz J . Beyond HLA: the significance of genomic variation for allogeneic hematopoietic stem cell transplantation. Blood 2007; 109: 1355–1362.

    Article  CAS  PubMed  Google Scholar 

  6. Spierings E, Drabbels J, Hendriks M, Pool J, Spruyt-Gerritse M, Claas F et al. A uniform genomic minor histocompatibility antigen typing methodology and database designed to facilitate clinical applications. PlosOne 2006; 1: 1–10.

    Article  Google Scholar 

  7. Kaplan EL, Meier P . Nonparametric estimation from incomplete observations. J Amer Stat Assoc 1958; 53: 457–481.

    Article  Google Scholar 

  8. Klein JP, Rizzo JD, Zhang MJ, Kleiding N . Statistical methods for the analysis and presentation of the results of bone marrow transplants. Part 1: Unadjusted analysis. Bone Marrow Transplant 2001; 28: 909–915.

    Article  CAS  PubMed  Google Scholar 

  9. Szydlo RM . Statistical evaluation of HSCT data. In: Red J Apperley, Carreras E, Gluckman E, Gratwohl A, Masszi T (eds). W: The EBMT Handbook. Haematopoietic stem cell transplantation. European School of Haematology: Paris, 2004, pp 342–350.

    Google Scholar 

  10. Gooley TA, Leisenring W, Crowley J, Storer BE . Estimation of failure probabilities in the presence of competing risk: new representations of old estimators. Stat Med 1999; 18: 695–706.

    Article  CAS  PubMed  Google Scholar 

  11. Spierings E, Hendriks M, Absi L, Canossi A, Chhaya S, Crowley J et al. Phenotype frequencies of autosomal minor Histocompatibility antigens display significant differences among ethnic populations. Plos Genetics 2007; 3: 1108–1119.

    Article  CAS  Google Scholar 

  12. Goulmy E . Minor histocompatibility antigens: from transplantation problems to therapy of cancer. Hum Immunol 2006; 67: 433–438.

    Article  CAS  PubMed  Google Scholar 

  13. Rice J, Dunn S, Piper K, Buchan SL, Moss PA, Stevenson FK . DNA fusion vaccines induce epitope-specific cytotoxic CD8(+) T cells against human leukemia-associated minor histocompatibility antigens. Cancer Res 2006; 66: 5436–5442.

    Article  CAS  PubMed  Google Scholar 

  14. Hambach L, Goulmy E . Immunotherapy of cancer through targeting of minor histocompatibility antigens. Curr Opin Immunol 2005; 17: 202–210.

    Article  CAS  PubMed  Google Scholar 

  15. Pietz BC, Warden MB, Duchateau BK, Ellis TM . Multiplex genotyping of human minor histocompatibility antigens. Hum Immunol 2005; 66: 1174–1182.

    Article  CAS  PubMed  Google Scholar 

  16. The International HapMap Consortium. The international HapMap project. Nature 2003; 426: 789–796.

    Article  Google Scholar 

  17. Siekiera U, Janusz J . Human minor histocompatibility antigens (mHAg) in HLA-ABC, DR, DQ matched sib-pairs. Transf Clin Biol 2001; 8 (suppl.1): 163s–164s (abstract).

    Google Scholar 

  18. Randolph SS, Gooley TA, Warren EH, Appelbaum FR, Riddell SR . Female donors contribute to a selective graft-versus-leukemia effect in male recipients of HLA-matched, related hematopoietic stem cell transplants. Blood 2004; 103: 347–352.

    Article  CAS  PubMed  Google Scholar 

  19. Mutis T, Gillespie G, Schrama E, Falkenburg JH, Moss P, Goulmy E . Tetrameric HLA class I- minor histocompatibility antigen- specific cytotoxic T lymphocytes in patients with graft-versus-host disease. Nat Med 1999; 5: 839–842.

    Article  CAS  PubMed  Google Scholar 

  20. Markiewicz M, Siekiera U, Wojnar J, Wyleżoł I, Karolczyk A, Giebel S et al. Influence of immunoreactive minor histocompatibility antigens mismatches on probability of graft-versus-host disease and relapse after hematopoietic stem cell transplantation from HLA-matched unrelated donors. Bone Marrow Transplant 2007; 39 (suppl.1): S310 (abstract).

    Google Scholar 

  21. Gahrton G . Risk assessment in haematopoietic stem cell transplantation: impact of donor-recipient sex combination in allogeneic transplantation. Best Pract Res Clin Haematol 2007; 20: 219–229.

    Article  PubMed  Google Scholar 

  22. Loren AW, Bunin GR, Boudreau C, Champlin RE, Cnaan A, Horowitz MM et al. Impact of donor and recipient sex and parity on outcomes of HLA-identical sibling allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2006; 12: 758–769.

    Article  PubMed  Google Scholar 

  23. Goulmy E, Schipper R, Pool J, Blokland E, Falkenburg JH, Vossen J et al. Mismatches of minor histocompatibility antigens between HLA-identical donors and recipients and the development of graft-versus-host disease after bone marrow transplantation. N Engl J Med 1996; 334: 281–285.

    Article  CAS  PubMed  Google Scholar 

  24. Tseng LH, Lin MT, Hansen JA, Gooley T, Pei J, Smith AG et al. Correlation between disparity for the minor histocompatibility antigen HA-1 and the development of acute graft-versus-host disease after allogeneic marrow transplantation. Blood 1999; 94: 2911–2914.

    CAS  PubMed  Google Scholar 

  25. Gallardo D, Arostegui JI, Balas A, Torres A, Caballero D, Carreras E et al. Disparity for the minor histocompatibility antigen HA-1 is associated with an increased risk of acute graft-versus-host disease (GvHD) but it does not affect chronic GvHD incidence, disease-free survival or overall survival after allogeneic human leucocyte antigen-identical sibling donor transplantation. Br J Haematol 2001; 114: 931–936.

    Article  CAS  PubMed  Google Scholar 

  26. Socie G, Loiseau P, Tamouza R, Janin A, Busson M, Gluckman E et al. Both genetic and clinical factors predict the development of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Transplantation 2001; 72: 699–706.

    Article  CAS  PubMed  Google Scholar 

  27. Perez-Garcia A, De la Camara R, Torres A, Gonzalez M, Jimenez A, Gallardo D . Minor histocompatibility antigen HA-8 mismatch and clinical outcome after HLA-identical sibling donor allogeneic stem cell transplantation. Haematologica 2005; 90: 1723–1724.

    CAS  PubMed  Google Scholar 

  28. Lin MT, Gooley T, Hansen JA, Tseng LH, Martin EG, Singleton K et al. Absence of statistically significant correlation between disparity for the minor histocompatibility antigen HA-1 and outcome after allogeneic hematopoietic cell transplantation. Blood 2001; 98: 3172–3173.

    Article  CAS  PubMed  Google Scholar 

  29. Murata M, Emi N, Hirabayashi N, Hamaguchi M, Goto S, Wakita A et al. No significant association between HA-1 incompatibility and incidence of acute graft-versus-host disease after HLA-identical sibling bone marrow transplantation in Japanese patients. Int J Hematol 2000; 72: 371–375.

    CAS  PubMed  Google Scholar 

  30. Tait BD, Maddison R, McCluskey J, Deayton S, Heatley S, Lester S et al. Clinical relevance of the minor histocompatibility antigen HA-1 in allogeneic bone marrow transplantation between HLA-identical siblings. Transplant Proc 2001; 33: 1760–1761.

    Article  CAS  PubMed  Google Scholar 

  31. Park MJ, Choi HB, Jang JP, Kim HJ, Kim YJ, Eom KS et al. Distribution of the minor histocompatibility antigens in Korean population and disparities in unrelated hematopoietic SCT. Bone Marrow Transplant 2007; 40: 723–728.

    Article  CAS  PubMed  Google Scholar 

  32. Teshima T, Ordemann R, Reddy P, Teshima T, Ordemann R, Reddy P et al. Acute graft-versus-host disease does not require alloantigen expression on host epithelium. Nat Med 2002; 8: 575–581.

    Article  CAS  PubMed  Google Scholar 

  33. Teshima T, Ferrara JL . Understanding the alloresponse: new approaches to graft-versus-host disease prevention. Semin Hematol 2002; 39: 15–22.

    Article  PubMed  Google Scholar 

  34. Antin JH . Approaches to graft-vs-host disease. Pediatr Transplant 2005; 9 (Suppl.7): 71–75.

    Article  CAS  PubMed  Google Scholar 

  35. Laylor R, Cannella L, Simpson E, Dazzi F . Minor histocompatibility antigens and stem cell transplantation. Vox Sanguinis 2004; 87 (suppl.2): S11–S14.

    Article  CAS  Google Scholar 

  36. Miklos DB, Kim HT, Miller KH, Guo L, Zorn E, Lee SJ et al. Antibody responses to H-Y minor histocompatibility antigens correlate with chronic graft versus host disease and disease remission. Blood 2005; 105: 2973–2978.

    Article  CAS  PubMed  Google Scholar 

  37. Ash RC, Horowitz MM, Gale RP, van Bekkum DW, Casper JT, Gordon-Smith EC et al. Bone marrow transplantation from related donors other than HLA-identical siblings: effect of T-cell depletion. Bone Marrow Transplant 1991; 7: 443–452.

    CAS  PubMed  Google Scholar 

  38. Voogt PJ, Fibbe WE, Marijt WA, Goulmy E, Veenhof WF, Hamilton M et al. Rejection of bone-marrow graft by recipient-derived cytotoxic T lymphocytes against minor histocompatibility antigens. Lancet 1990; 335: 131–134.

    Article  CAS  PubMed  Google Scholar 

  39. Marijt WA, Kernan NA, Diaz-Barrientos T, Veenhof WF, O’Reilly RJ, Willemze R et al. Multiple minor histocompatibility antigen-specific cytotoxic T lymphocyte clones can be generated during graft rejection after HLA-identical bone marrow transplantation. Bone Marrow Transplant 1995; 16: 125–132.

    CAS  PubMed  Google Scholar 

  40. Rotzschke O, Falk K, Wallny HJ, Faath S, Rammensee HG . Characterization of naturally occurring minor histocompatibility peptides including H-4 and H-Y. Science 1989; 249: 283–287.

    Article  Google Scholar 

  41. Goulmy E, Termijtelen A, Bradley BA, van Rood JJ . Alloimmunity to human H-Y. Lancet 1976; 2: 1206.

    Article  CAS  PubMed  Google Scholar 

  42. Stern M, Passweg JR, Locasciulli A, Socie G, Schrezenmeier H, Bekassy AN et al. Influence of donor/recipient sex matching on outcome of allogeneic hematopoietic stem cell transplantation for aplastic anemia. Transplantation 2006; 82: 218–226.

    Article  PubMed  Google Scholar 

  43. Pierce RA, Field ED, Mutis T, Golovina TN, Von Kap-Herr C, Wilke M et al. The HA-2 minor histocompatibility antigen is derived from a diallelic gene encoding a novel human class I myosin protein. J Immunol 2001; 167: 3223–3230.

    Article  CAS  PubMed  Google Scholar 

  44. Dolstra H, Fredrix H, Preijers F, Goulmy E, Figdor CG, de Witte TM et al. Recognition of B cell leukemia-associated minor histocompatibility antigen by CTL. J Immunol 1997; 158: 560–565.

    CAS  PubMed  Google Scholar 

  45. Falkenburg JHF, Goselink HM, van der Harst D, Falkenburg JH, Goselink HM, van der Harst D et al. Growth inhibition of clonogenic leukemic precursor cells by minor histocompatibility antigen-specific cytotoxic T-lymphocytes. J Exp Med 1991; 174: 27–33.

    Article  CAS  PubMed  Google Scholar 

  46. Gratwohl A, Stern M, Brand R, de Witte T, Sureda A, Rocha V et al. Impact of the donor recipient sex combination in hematopoietic stem cell transplantation: H-Y as a model for the interaction between major and minor histocompatibility antigens. Blood 2007; 110 (Part 1): 481 (abstract).

    Google Scholar 

  47. Katagiri T, Shiobara S, Nakao S, Wakano M, Muranaka E, Kuba N et al. Mismatch of minor histocompatibility antigen contributes to a graft-versus-leukemia effect rather than to acute GVHD, resulting in long-term survival after HLA-identical stem cell transplantation in Japan. Bone Marrow Transplant 2006; 38: 681–686.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Hematology and Bone Marrow Transplantation, Medical University of Silesia, Katowice, Poland

    M Markiewicz, A Karolczyk, G Helbig, J Wojnar, M Dzierzak-Mietla & S Kyrcz-Krzemien

  2. Department of Immunogenetics and HLA Laboratory, Regional Blood Center, Katowice, Poland

    U Siekiera

  3. Silesian Technical University, Katowice, Poland

    J Szymszal

Authors
  1. M Markiewicz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. U Siekiera
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Karolczyk
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J Szymszal
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G Helbig
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Wojnar
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Dzierzak-Mietla
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S Kyrcz-Krzemien
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M Markiewicz.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Markiewicz, M., Siekiera, U., Karolczyk, A. et al. Immunogenic disparities of 11 minor histocompatibility antigens (mHAs) in HLA-matched unrelated allogeneic hematopoietic SCT. Bone Marrow Transplant 43, 293–300 (2009). https://doi.org/10.1038/bmt.2008.326

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2008.326

Keywords

This article is cited by

Search

Advanced search

Quick links