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.

  • Letter to the Editor
  • Published:

Graft-versus-host driven graft-versus-leukemia effect of minor histocompatibility antigen HA-1 in chronic myeloid leukemia patients

Leukemia volume 24, pages 1388–1392 (2010)Cite this article

Subjects

Numerous clinical and experimental studies in human leukocyte antigen (HLA)-matched stem cell transplantation (SCT) provide evidence that both the graft versus leukemia (GvL) effect and graft versus host disease (GvHD) develop as a result of cellular allo-immune responses evoked by disparity of minor histocompatibility antigens (mHags) between recipient and donor.1 The mHags are polymorphic peptides that are presented on the cell surface by HLA molecules and can induce allo-immune T-cell responses from mHag-negative donors. The mHags are derived from polymorphic cellular proteins expressed either ubiquitously or in a hematopoietic system-specific manner.1 Among hematopoietic mHags, the HLA-A2 restricted mHag HA-1 receives most attention; it is highly immunogenic, is frequent in Caucasians, shows high expression in all types of hematological malignancies and aberrant expression on various epithelial tumors with no expression in normal epithelial cells.2 HA-1-specific cytotoxic T lymphocytes (CTLs) lyse all hematopoietic cells including leukemia and myeloma cells in vitro and inhibit human lymphoblastoid leukemia cell outgrowth in a xenogeneic non obese diabetic/severe combined immunodeficient murine model,3 suggesting a significant contribution of mHag HA-1 to the GvL effect. Nonetheless, the only clinical evidence suggesting the involvement of HA-1 in GvL and in graft versus myeloma is the emergence of HA-1-specific CTLs in circulation coinciding with tumor regression in chronic myeloid leukemia (CML) and multiple myeloma patients after donor lymphocyte infusions (DLI).4 Therefore, we here evaluated the putative clinical importance of HA-1 by correlating HA-1 disparity with relapse incidence (RI), overall survival (OS), relapse-free survival (RFS) and non-relapse mortality (NRM) in a relatively large cohort of 285 HLA-A2-positive CML patients who received myeloablative allo-SCT from HLA-identical sibling donors.

The cohort included 156 male and 129 female patients with a median age of 39 (range 14–65). At the time of SCT, 226 (82%) patients presented the CML at chronic phase, 42 (15%) patients showed accelerated phase, 7 (3%) patients showed blast crisis and 12 of them had an unknown phase of the disease. In 54 (23%) cases, recipients received a sex-mismatched transplantation, defined as recipient male-donor female. Other gender combinations were regarded as no sex-mismatch. For all patients and their donors, we determined the HA-1 allelic expression by genomic HA-1 typing using established and verified techniques.2, 5 As only one of the two HA-1 alleles (HA-1H) is immunogenic,1 HA-1 disparity is defined as the presence of the HA-1H in the recipient and its absence in the donor. The analyses were carried out only in this defined HA-1-mismatch direction. As expected on the basis of the HA-1 alleles phenotype frequency, 36 of the 285 (13.3%) pairs were HA-1 incompatible. GvHD prophylaxis involved either T-cell depletion (alone or combined with cyclosporine), or cyclosporine (alone or combined with methotrexate). Acute(a) GvHD was graded according to the standard criteria.6 The occurrence of relapse was based on the information reported by the individual team. In most instances, solely hematological relapse were reported with no further detailed information on cytogenetic and molecular relapse because the international study design within the European Group for Blood and Marrow Transplantation does not provide more detailed information.

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

Relevant articles

Open Access articles citing this article.

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

References

  1. Mutis T, Goulmy E . Hematopoietic system-specific antigens as targets for cellular immunotherapy of hematological malignancies. Semin Hematol 2002; 39: 23–31.

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  3. Hambach L, Nijmeijer BA, Aghai Z, Schie ML, Wauben MH, Falkenburg JH et al. Human cytotoxic T lymphocytes specific for a single minor histocompatibility antigen HA-1 are effective against human lymphoblastic leukaemia in NOD/scid mice. Leukemia 2006; 20: 371–374.

    Article  CAS  Google Scholar 

  4. Marijt WA, Heemskerk MH, Kloosterboer FM, Goulmy E, Kester MG, van der Hoorn MA et al. Hematopoiesis-restricted minor histocompatibility antigens HA-1- or HA- 2-specific T cells can induce complete remissions of relapsed leukemia. Proc Natl Acad Sci USA 2003; 100: 2742–2747.

    Article  CAS  Google Scholar 

  5. 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  Google Scholar 

  6. Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation 1974; 18: 295–304.

    Article  CAS  Google Scholar 

  7. 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  Google Scholar 

  8. Stelljes M, Strothotte R, Pauels HG, Poremba C, Milse M, Specht C et al. Graft-versus-host disease after allogeneic hematopoietic stem cell transplantation induces a CD8+ T cell-mediated graft-versus-tumor effect that is independent of the recognition of alloantigenic tumor targets. Blood 2004; 104: 1210–1216.

    Article  CAS  Google Scholar 

  9. Carnevale-Schianca F, Cignetti A, Capaldi A, Vitaggio K, Vallario A, Ricchiardi A et al. Allogeneic nonmyeloablative hematopoietic cell transplantation in metastatic colon cancer: tumor-specific T-cells directed to a tumor-associated antigen are generated in vivo during GVHD. Blood 2006; 107: 3795–3803.

    Article  CAS  Google Scholar 

  10. Morita Y, Heike Y, Kawakami M, Miura O, Nakatsuka S, Ebisawa M et al. Monitoring of WT1-specific cytotoxic T lymphocytes after allogeneic hematopoietic stem cell transplantation. Int J Cancer 2006; 119: 1360–1367.

    Article  CAS  Google Scholar 

  11. Jaffee EM, Hruban RH, Biedrzycki B, Laheru D, Schepers K, Sauter PR et al. Novel allogeneic granulocyte-macrophage colony-stimulating factor-secreting tumor vaccine for pancreatic cancer:a phase I trial of safety and immune activation. J Clin Oncol 2001; 19: 145–156.

    Article  CAS  Google Scholar 

  12. Nabel GJ, Gordon D, Bishop DK, Nickoloff BJ, Yang ZY, Aruga A et al. Immune response in human melanoma after transfer of an allogeneic class I major histocompatibility complex gene with DNA-liposome complexes. Proc Natl Acad Sci USA 1996; 93: 15388–15393.

    Article  CAS  Google Scholar 

  13. Stopeck AT, Jones A, Hersh EM, Thompson JA, Finucane DM, Gutheil JC et al. Phase II study of direct intralesional gene transfer of allovectin-7, an HLA-B7/beta2-microglobulin DNA-liposome complex, in patients with metastatic melanoma. Clin Cancer Res 2001; 7: 2285–2291.

    CAS  PubMed  Google Scholar 

  14. Rubio MT, Kim YM, Sachs T, Mapara M, Zhao G, Sykes M . Antitumor effect of donor marrow graft rejection induced by recipient leukocyte infusions in mixed chimeras prepared with non-myeloablative conditioning: critical role for recipient-derived IFN-γ. Blood 2003; 102: 2300–2307.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by the Leiden University Medical Center and the Netherlands Organization of Scientific Research (NWO). We thank Prof Dr A Brand and Dr L Hambach for critically reading the paper.

Author information

Authors and Affiliations

  1. Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands

    T Mutis & E Goulmy

  2. Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, The Netherlands

    T Mutis

  3. Department of Medical Statistics & Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands

    R Brand & A van Biezen

  4. Department of Hematology, Institut Català d’Oncologia, Hospital Josep Trueta., Girona, Spain

    D Gallardo

  5. Department of Hematology, Leipzig University, Leipzig, Germany

    D Niederwieser

Authors
  1. T Mutis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R Brand
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D Gallardo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A van Biezen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D Niederwieser
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. E Goulmy
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

for the collaborative study of the Chronic Leukemia Working Party of European Group for Blood and Marrow Transplantation (EBMT) and Spanish Group of hematopoietic Transplant (GETH)

Corresponding author

Correspondence to T Mutis.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mutis, T., Brand, R., Gallardo, D. et al. Graft-versus-host driven graft-versus-leukemia effect of minor histocompatibility antigen HA-1 in chronic myeloid leukemia patients. Leukemia 24, 1388–1392 (2010). https://doi.org/10.1038/leu.2010.115

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2010.115

This article is cited by

Search

Advanced search

Quick links