Abstract
We evaluated the influence of gene polymorphisms of TLR9 (T1237C; T1486C), IL23R (A1142G), and NOD2 SNP8 (R702W), SNP12 (G908R) and SNP13 (1007fs) on outcome of hematopoietic SCT in a homogenous group of 142 AML patients after non-T-cell-depleted myeloablative transplantation from HLA-identical sibling donors. In our retrospective study, we found that TLR9 gene variant at 1486 influenced transplant outcome. Estimated 5-year OS in patients with the CC gene variant of TLR9 was 70.2% compared with 44.8% (P<0.027) in patients with TC/TT of TLR9 gene. No significant influences on 5-year OS were found for gene polymorphisms of NOD2 or IL23R (A1142G) in this study group. The 5-year treatment-related mortality was lowest in patients with CC gene variant of TLR9 (7.8 vs 23.1%; NS). Acute GVHD grade III–IV was higher in patients with NOD2 gene variants (28 vs 12.8%; P=0.065). In contrast, patients transplanted from donors with the gene variant of IL23R had no occurrence of severe acute GVHD grade III–IV (0 vs 18.4%; P<0.048). However, multivariate analysis confirmed the influence of NOD2 gene variants on the occurrence of acute GVHD grade II–IV after transplant. These results suggest that the gene variants of TLR9, NOD2 and Il23R had influence on the outcome of transplant.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Elmaagacli AH, Koldehoff M, Hindahl H, Trenschel R, Peceny R, Ottinger H et al. Mutations in innate immune system NOD2/CARD 15 and TLR-4 (Thr399Ile) genes influence the risk for severe acute GVHD in patients who underwent an allogeneic transplantation. Transplantation 2006; 81: 247–254.
Granell M, Urbano-Ispizua A, Aróstegui JI, Fernández-Avilés F, Martínez C, Rovira M et al. Effect of NOD2/CARD15 variants in T-cell depleted allogeneic stem cell transplantation. Haematologica 2006; 91: 1372–1376.
Hildebrandt GC, Granell M, Urbano-Ispizua A, Wolff D, Hertenstein B, Greinix HT et al. Recipient NOD2/CARD15 variants: a novel independent risk factor for the development of bronchiolitis obliterans after allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2008; 14: 67–74.
Ditschkowski M, Elmaagacli AH, Trenschel R, Peceny R, Koldehoff M, Schulte C et al. T-cell depletion prevents from bronchiolitis obliterans and bronchiolitis obliterans with organizing pneumonia after allogeneic hematopoietic stem cell transplantation with related donors. Haematologica 2007; 92: 558–561.
Holler E, Rogler G, Herfarth H, Brenmoehl J, Wild PJ, Hahn J et al. Both donor and patient NOD2/CARD15 mutations associate with transplant-related mortality and GvHD following allogeneic stem cell transplantation. Blood 2004; 104: 889–994.
Gruhn B, Intek J, Pfaffendorf N, Zell R, Corbacioglu S, Zintl F et al. Polymorphism of interleukin-23 receptor gene but not of NOD2/CARD15 is associated with graft-versus-host disease after hematopoietic stem cell transplantation in children. Biol Blood Marrow Transplant 2009; 15: 1571–1577.
van der Velden WJ, Blijlevens NM, Maas FM, Schaap NP, Jansen JH, van der Reijden BA et al. NOD2 polymorphisms predict severe acute graft-versus-host and treatment-related mortality in T-cell-depleted haematopoietic stem cell transplantation. Bone Marrow Transplant 2009; 44: 243–248.
Sairafi D, Uzunel M, Remberger M, Ringdén O, Mattsson J . No impact of NOD2/CARD15 on outcome after SCT. Bone Marrow Transplant 2008; 41: 961–964.
Mayor NP, Shaw BE, Hughes DA, Maldonado-Torres H, Madrigal JA, Keshav S et al. Single nucleotide polymorphisms in the NOD2/CARD15 gene are associated with an increased risk of relapse and death for patients with acute leukemia after hematopoietic stem-cell transplantation with unrelated donors. J Clin Oncol 2007; 25: 4262–4269.
Elmaagacli AH, Koldehoff M, Landt O, Beelen DW . Relation of an Interleukin-23 Receptor gene polymorphism to graft-versus-host disease after hematopoietic-cell transplantation. Bone Marrow Transplant 2008; 41: 821–826.
Elmaagacli AH, Koldehoff M, Beelen DW . Improved outcome of hematopoietic SCT in patients with homozygous gene variant of Toll-like receptor 9. Bone Marrow Transplant 2009; 44: 295–302.
Medzhitov R . Toll-like receptors and innate immunity. Nat Rev Immunol 2001; 1: 135–145 (review).
Medzhitov R, Janeway Jr C . The Toll receptor family and microbial recognition. Trends Microbiol 2000; 8: 452–456.
Chiffoleau E, Heslan J-M, Heslan M, Louvet C, Condamine T, Cuturi M-C . TLR9 ligand enhances proliferation of rat CD4+ T cell and modulates suppressive activity mediated by CD4+ CD25+ T cell. Int Immunol 2007; 19: 193–201.
Latz E, Verma A, Visintin A, Gong M, Sirois CM, Klein DCG et al. Ligand-induced conformational changes allosterically activate Toll-like receptor 9. Nat Immunol 2007; 8: 772–779.
Ashman RF, Goeken JA, Drahos J, Lenert P . Sequence requirements for oligodeoxyribonucleotide inhibitory activity. Int Immunol 2005; 17: 411–420.
Parham C, Chirica M, Timans J, Vaisberg E, Travis M, Cheung J et al. A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rβ1 and a novel cytokine receptor subunit, IL-23R. J Immunol 2002; 168: 5699–5708.
Eijnden SV, Goriely S, De Wit D, Willems F, Goldman M . IL-23 up-regulates IL-10 and induces IL-17 sythesis by polyconally activated naïve T cells in human. Eur J Immunol 2005; 35: 469–475.
Ottinger HD, Ferencik S, Beelen DW, Lindemann M, Peceny R, Elmaagacli AH et al. Hematopoietic stem cell transplantation: contrasting the outcome of transplantations from HLA-identical siblings, partially HLA-mismatched unrelated donors. Blood 2003; 102: 1131–1137.
Elmaagacli AH, Basoglu S, Peceny R, Trenschel R, Ottinger H, Lollert A et al. Improved disease-free-survival after transplantation of peripheral blood stem cells as compared to bone marrow from HLA-identical unrelated donors in patients with first chronic phase chronic myeloid leukemia. Blood 2002; 99: 1130–1135.
Prezpiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J et al. 1994 Consensus conference on acute GVHD grading. Bone Marrow Transplant 1995; 15: 825–828.
Sullivan KM, Agura E, Anasetti C, Appelbaum D, Badger C, Barman S et al. Chronic graft-versus-host-disease and other late complications of bone marrow transplantation. Semin Hematol 1991; 28: 250–259.
Kaplan EL, Meier P . Non-parametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–481.
Li J, Song W, Czerwinski DK, Varghese B, Uematsu S, Akira S et al. Lymphoma immunotherapy with CpG oligodeoxynucleotides requires TLR9 either in the host or in the tumor itself. J Immunol 2007; 179: 2493–2500.
Duramad O, Fearon KL, Chang B, Chan JH, Gregorio J, Coffman RL et al. Inhibitors of TLR-9 act on multiple cell subsets in mouse and man in vitro and prevent death in vivo from systemic inflammation. J Immunol 2005; 174: 5193–5200.
Tao K, Fujii M, Tsukumo S-I, Maekawa Y, Kishihara K, Kimoto Y et al. Genetic variations of Toll-like receptor 9 predispose to systemic lupus erythematosus in Japanese population. Ann Rheum Dis 2007; 66: 905–909.
Berghöfer B, Frommer T, König IR, Ziegler A, Chakrabortyz T, Bein G et al. Common human Toll-like receptor 9 polymorphisms and haplotypes: association with atopy and functional relevance. Clin Exp Allergy 2005; 35: 1147–1154.
Novak N, Yu C-F, Bussmann C, Maintz L, Peng W-M, Hart J et al. Putative association of a TLR9 promoter polymorphism with atopic eczema. Allergy 2007; 62: 766–772.
Calcaterra C, Sfondrini L, Rossigni A, Sommaria M, Rumio C, Ménard S et al. Critical role of TLR9 in acute graft-versus-host disease. J Immunol 2008; 181: 6132–6139.
Krieg AM . Toll-like receptor 9 (TLR9) agonists in the treatment of cancer. Oncogene 2008; 27: 161–167.
Blazar BR, Krieg AM, Taylor PA . Synthetic unmethylated cytosine-phosphate-guanosine oligodeoxynucleotides are potent stimulators of antileukemia responses in naive and bone marrow transplant recipients. Blood 2001; 98: 1217–1225.
Beelen DW, Elmaagacli A, Müller KD, Hirche H, Schaefer UW . Influence of intestinal bacterial decontamination using metronidazol and ciprofloxacin or ciprofloxacin alone on the development of acute graft-versus-host disease after marrow transplantation in patients with hematologic malignancies: final results and long-term follow-up of an open-label prospective randomized trial. Blood 1999; 93: 3267–3272.
Duerr RH, Taylor KD, Brant SR, Rioux JP, Silverberg MS, Daly MJ et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 2006; 314: 1461–1463.
Hugot JP, Chamaillard M, Zouali H, Lesage S, Cézard JP, Belaiche J et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 2001; 411: 599.
Acknowledgements
We thank Silke Gottwald, Christiane Schary (all Essen, Germany) for their excellent technical assistance with genotyping analyses. This work was supported by grants from the Deutsche Krebshilfe 70-3093-El4 and Kulturstiftung Essen (05 032 Elmaagacli).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Elmaagacli, A., Steckel, N., Ditschkowski, M. et al. Toll-like receptor 9, NOD2 and IL23R gene polymorphisms influenced outcome in AML patients transplanted from HLA-identical sibling donors. Bone Marrow Transplant 46, 702–708 (2011). https://doi.org/10.1038/bmt.2010.166
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/bmt.2010.166
Keywords
This article is cited by
-
Genetic polymorphism related to monocyte-macrophage function is associated with graft-versus-host disease
Scientific Reports (2017)
-
Sensing danger: toll-like receptors and outcome in allogeneic hematopoietic stem cell transplantation
Bone Marrow Transplantation (2017)
-
Intestinal barrier loss as a critical pathogenic link between inflammatory bowel disease and graft-versus-host disease
Mucosal Immunology (2015)
-
Identification and Utilization of Donor and Recipient Genetic Variants to Predict Survival After HCT: Are We Ready for Primetime?
Current Hematologic Malignancy Reports (2015)
-
A non-interventional study of the genetic polymorphisms of NOD2 associated with increased mortality in non-alcoholic liver transplant patients
BMC Gastroenterology (2014)