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:

Graft-Versus-Host Disease

Lack of IFN-gamma 2/2 homozygous genotype independently of recipient age and intensity of conditioning regimen influences the risk of aGVHD manifestation after HLA-matched sibling haematopoietic stem cell transplantation

Summary:

A total of 110 patients (71 adults and 39 children) who received allogeneic haematopoietic stem cell transplantation from HLA-matched sibling donors were studied for the incidence of acute graft-versus-host disease (aGvHD) in relation to IFN-gamma gene microsatellite polymorphism. A strong tendency was observed towards the lower incidence of grades II–IV aGvHD in patients having an IFN-gamma 2/2 genotype as compared to the recipients with other IFN-gamma genotypes (0.12 vs 0.33, P=0.06). This relationship was independent of the intensity of conditioning regimen and diagnosis. IFN-gamma polymorphic features, together with other clinical and biological factors (patient's age, donor–recipient gender, diagnosis, conditioning regimen, transplant material and GvHD prophylaxis), were subjected to multivariate analysis for aGvHD manifestation in order to exclude indirect association of the IFN-gamma 2/2 genotype. In multivariate analysis, myeloablative therapy (OR=11.462, P=0.013), recipient age (OR=4.896, P=0.009) and lack of IFN-gamma 2/2 genotype (OR=4.311, P=0.048) were found to significantly contribute to the development of grade II–IV aGvHD, while type of GvHD prophylaxis showed less-strong influence (OR=2.963, P=0.066). Thus, it appeared that the IFN-gamma 2/2 genotype constituted an independent and protective factor associated with a decreased risk of grade II–IV aGvHD. However, this genotype was not found to be associated with the risk of cGvHD or survival.

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

Access options

Buy this article

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

Figure 1

Similar content being viewed by others

References

  1. Holler E . Cytokines, viruses, and graft-versus-host disease. Curr Opin Hematol 2002; 9: 479–484.

    Article  PubMed  Google Scholar 

  2. Pravica V, Perrey C, Stevens A et al. A single nucleotide polymorphism in the first intron of the human IFN-gamma gene: absolute correlation with a polymorphic CA microsatellite marker of high IFN-gamma production. Hum Immunol 2000; 61: 863–866.

    Article  CAS  PubMed  Google Scholar 

  3. Pravica V, Asderakis A, Perrey C et al. In vitro production of IFN-gamma correlates with CA repeat polymorphism in the human IFN-gamma gene. Eur J Immunogenet 1999; 26: 1–3.

    Article  CAS  PubMed  Google Scholar 

  4. Warle MC, Farhan A, Metselaar HJ et al. Are cytokine gene polymorphisms related to in vitro cytokine production profiles? Liver Transplant 2003; 9: 170–181.

    Article  Google Scholar 

  5. Vandenbroeck K, Goris A . Cytokine gene polymorphisms in multifactorial diseases: gateways to novel targets for immunotherapy? Trends Pharmacol Sci 2003; 24: 284–289.

    Article  CAS  PubMed  Google Scholar 

  6. Socié G, Loiseau P, Tamouza R 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  PubMed  Google Scholar 

  7. Cavet J, Dickinson AM, Norden J et al. Interferon-gamma and interleukin-6 gene polymorphisms associate with graft-versus-host disease in HLA-matched sibling bone marrow transplantation. Blood 2001; 98: 1594–1600.

    Article  CAS  PubMed  Google Scholar 

  8. Lange A, Bogunia-Kubik K, Karabon L, Polak M . An evidence that while differences in polymorphism in TNF-β and IL-6 genes are associated with toxic complications after bone marrow transplantation, differences in IFN-γ gene with a higher risk of GvHD. Blood 2000; 96: 398a (Abstr. 1716).

    Google Scholar 

  9. Przepiorka D, Weisdorf D, Martin P et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 1995; 15: 825–828.

    CAS  PubMed  Google Scholar 

  10. Awad M, Pravica V, Perrey C et al. CA repeat allele polymorphism in the first intron of the human interferon-gamma gene is associated with lung allograft fibrosis. Hum Immunol 1999; 60: 343–346.

    Article  CAS  PubMed  Google Scholar 

  11. Lange A, Moniewska A, Fetting R et al. rIL-2-activated killer cell generation is influenced by autologous TNF-alpha production. Nat Immun 1995; 14: 2–10.

    CAS  PubMed  Google Scholar 

  12. Dickinson AM, Sviland L, Dunn J et al. Demonstration of direct involvement of cytokines in graft-versus-host reactions using an in vitro human skin explant model. Bone Marrow Transplant 1991; 7: 209–216.

    CAS  PubMed  Google Scholar 

  13. Bogunia-Kubik K, Wang XN, Fallen P et al. Analysis of effector cells involved in graft versus host disease (GvHD) in bone marrow (BM) graft recipients using an in vitro skin explant model. Bone Marrow Transplant 2002; 29 (Suppl. 2): 168 (Abstr. P639).

    Google Scholar 

  14. Lange A, Klimczak A, Karabon L, Suchnicki K . Cytokines, adhesion molecules (E-selectin and VCAM-1) and graft-versus-host disease. Arch Immunol Ther Exp (Warsz) 1995; 43: 99–105.

    CAS  Google Scholar 

  15. Lange A, Karabon L, Klimczak A et al. Serum interferon-gamma and C-reactive protein levels as predictors of acute graft-vs-host disease in allogeneic hematopoietic precursor cell (marrow or peripheral blood progenitor cells) recipients. Transplant Proc 1996; 28: 3522–3525.

    CAS  PubMed  Google Scholar 

  16. Turner DM, Grant SC, Lamb WR et al. A genetic marker of high TNF-alpha production in heart transplant recipients. Transplantation 1995; 60: 1113–1117.

    Article  CAS  PubMed  Google Scholar 

  17. Fishman D, Faulds G, Jeffery R et al. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest 1998; 102: 1369–1376.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lange A, Klimczak A, Wysoczanska B et al. B-cell expansion post transplant is more frequent in patients receiving fludarabine and anti-T-lymphocyte globulin as a part of conditioning regimen and was associated with IFNgamma Intron I polymorphic features. Bone Marrow Transplant 2003; 31 (Suppl. 1): 89 (Abstr. P451).

    Google Scholar 

  19. Wysoczanska B, Bogunia-Kubik K, Suchnicki K et al. Combined association between IFN-gamma 3,3 homozygosity and DRB1*03 in Löfgren's syndrome patients. Immun Lett 2004; 91: 125–129.

    Article  Google Scholar 

  20. Middleton PG, Taylor PR, Jackson G et al. Cytokine gene polymorphisms associating with severe acute graft-versus-host disease in HLA-identical sibling transplants. Blood 1998; 92: 3943–3948.

    CAS  PubMed  Google Scholar 

  21. Karabon L, Lange A . IL-6, IL-10 and IFN-gamma gene polymorphisms acting in concert in patients undergoing HSCT. Genes Immun 2003; 4 (Suppl. 1): 44 (Abstr. 170).

    Google Scholar 

Download references

Acknowledgements

This work was supported by a grant from the Polish State Committee for Scientific Research (KBN; No. 6 P05B 056 20).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to A Lange.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mlynarczewska, A., Wysoczanska, B., Karabon, L. et al. Lack of IFN-gamma 2/2 homozygous genotype independently of recipient age and intensity of conditioning regimen influences the risk of aGVHD manifestation after HLA-matched sibling haematopoietic stem cell transplantation. Bone Marrow Transplant 34, 339–344 (2004). https://doi.org/10.1038/sj.bmt.1704581

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.bmt.1704581

Keywords

This article is cited by

Search

Quick links