Skip to main content

Thank you for visiting 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.

Graft-Versus-Host Disease

NOD2 polymorphisms predict severe acute graft-versus-host and treatment-related mortality in T-cell-depleted haematopoietic stem cell transplantation


Single nucleotide polymorphisms (SNPs) in the NOD2 gene have significant impact on both treatment-related mortality (TRM) and acute GVHD (aGVHD) in haematopoietic stem cell transplantation (HSCT). The effect of these polymorphisms when using T-cell-depleted grafts has been poorly studied. We retrospectively analysed NOD2 polymorphisms in a cohort of 85 patients and donors who received an HLA-identical sibling partially T-cell-depleted HSCT (0.5 × 106 CD3+ T cells per kg) following idarubicin-containing conditioning regimens. NOD2 polymorphisms were present in 14 of 85 (16.5%) of patients and 18 of 85 (21%) of donors. The risk of severe aGVHD (grade III–IV) and the 1-year TRM was significantly higher in the presence of NOD2 polymorphisms (hazard ratio (HR) 6.0, P=0.02 for severe aGVHD and HR 3.3, P=0.02 for TRM, respectively) and was most prominent in cases where patient and donor both had a polymorphism (HR 10.5, P=0.002 and HR 3.9, P=0.002). There was also a trend towards increased risk of bacteraemia due to coagulase-negative staphylococci in patients with an NOD2 polymorphism. We conclude that NOD2 polymorphism screening should be used to optimize donor selection and antimicrobial prophylaxis to reduce the occurrence of aGVHD and TRM following allogeneic HSCT.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it


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

Figure 1
Figure 2


  1. Blijlevens NM . Implications of treatment-induced mucosal barrier injury. Curr Opin Oncol 2005; 17: 605–610.

    PubMed  Google Scholar 

  2. Hill GR, Ferrara JL . The primacy of the gastrointestinal tract as a target organ of acute graft-versus-host disease: rationale for the use of cytokine shields in allogeneic bone marrow transplantation. Blood 2000; 95: 2754–2759.

    CAS  PubMed  Google Scholar 

  3. Ferrara JL, Levy R, Chao NJ . Pathophysiologic mechanisms of acute graft-vs-host disease. Biol Blood Marrow Transplant 1999; 5: 347–356.

    Article  CAS  PubMed  Google Scholar 

  4. 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 

  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. Holler E, Rogler G, Herfarth H, Brenmoehl J, Wild PJ, Hahn J et al. Both donor and recipient NOD2/CARD15 mutations associate with transplant-related mortality and GvHD following allogeneic stem cell transplantation. Blood 2004; 104: 889–894.

    Article  CAS  PubMed  Google Scholar 

  7. Strober W, Murray PJ, Kitani A, Watanabe T . Signalling pathways and molecular interactions of NOD1 and NOD2. Nat Rev Immunol 2006; 6: 9–20.

    Article  CAS  PubMed  Google Scholar 

  8. Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 2001; 411: 599–603.

    Article  CAS  PubMed  Google Scholar 

  9. Voss E, Wehkamp J, Wehkamp K, Stange EF, Schroder JM, Harder J . NOD2/CARD15 mediates induction of the antimicrobial peptide human beta-defensin-2. J Biol Chem 2006; 281: 2005–2011.

    Article  CAS  PubMed  Google Scholar 

  10. Wehkamp J, Harder J, Weichenthal M, Schwab M, Schaffeler E, Schlee M et al. NOD2 (CARD15) mutations in Crohn's disease are associated with diminished mucosal alpha-defensin expression. Gut 2004; 53: 1658–1664.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Marks DJ, Harbord MW, MacAllister R, Rahman FZ, Young J, Al-Lazikani B et al. Defective acute inflammation in Crohn's disease: a clinical investigation. Lancet 2006; 367: 668–678.

    Article  CAS  PubMed  Google Scholar 

  12. Buhner S, Buning C, Genschel J, Kling K, Herrmann D, Dignass A et al. Genetic basis for increased intestinal permeability in families with Crohn's disease: role of CARD15 3020insC mutation? Gut 2006; 55: 342–347.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Watanabe T, Kitani A, Murray PJ, Strober W . NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses. Nat Immunol 2004; 5: 800–808.

    Article  CAS  PubMed  Google Scholar 

  14. Kullberg BJ, Ferwerda G, de Jong DJ, Drenth JP, Joosten LA, Van der Meer JW et al. Crohn's disease patients homozygous for the 3020insC NOD2 mutation have a defective NOD2/TLR4 cross-tolerance to intestinal stimuli. Immunology 2008; 123: 600–605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hedl M, Li J, Cho JH, Abraham C . Chronic stimulation of Nod2 mediates tolerance to bacterial products. Proc Natl Acad Sci USA 2007; 104: 19440–19445.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Watanabe T, Asano N, Murray PJ, Ozato K, Tailor P, Fuss IJ et al. Muramyl dipeptide activation of nucleotide-binding oligomerization domain 2 protects mice from experimental colitis. J Clin Invest 2008; 118: 545–559.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Netea MG, Kullberg BJ, de Jong DJ, Franke B, Sprong T, Naber TH et al. NOD2 mediates anti-inflammatory signals induced by TLR2 ligands: implications for Crohn's disease. Eur J Immunol 2004; 34: 2052–2059.

    Article  CAS  PubMed  Google Scholar 

  18. 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.

    Article  CAS  PubMed  Google Scholar 

  19. 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.

    Article  PubMed  Google Scholar 

  20. Schaap N, Schattenberg A, Bar B, Preijers F, Geurts van KA, van der MR et al. Outcome of transplantation for standard-risk leukaemia with grafts depleted of lymphocytes after conditioning with an intensified regimen. Br J Haematol 1997; 98: 750–759.

    Article  CAS  PubMed  Google Scholar 

  21. 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  PubMed  Google Scholar 

  22. Leisenring WM, Martin PJ, Petersdorf EW, Regan AE, Aboulhosn N, Stern JM et al. An acute graft-versus-host disease activity index to predict survival after hematopoietic cell transplantation with myeloablative conditioning regimens. Blood 2006; 108: 749–755.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. MacGregor RR, Beaty HN . Evaluation of positive blood cultures. Guidelines for early differentiation of contaminated from valid positive cultures. Arch Intern Med 1972; 130: 84–87.

    Article  CAS  PubMed  Google Scholar 

  24. van der Linde K, Boor PP, Houwing-Duistermaat JJ, Crusius BJ, Wilson PJ, Kuipers EJ et al. CARD15 mutations in Dutch familial and sporadic inflammatory bowel disease and an overview of European studies. Eur J Gastroenterol Hepatol 2007; 19: 449–459.

    Article  CAS  PubMed  Google Scholar 

  25. Granell M, Urbano-Ispizua A, Arostegui JI, Fernandez-Aviles F, Martinez C, Rovira M et al. Effect of NOD2/CARD15 variants in T-cell depleted allogeneic stem cell transplantation. Haematologica 2006; 91: 1372–1376.

    CAS  PubMed  Google Scholar 

  26. Rodriguez-Perez N, Aguinaga-Barrilero A, Gorrono-Echebarria MB, Perez-Blas M, Martin-Villa JM . Analysis of Crohn's disease-related CARD15 polymorphisms in Spanish patients with idiopathic uveitis. Dis Markers 2008; 24: 111–117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Holler E, Hahn J, Andreesen R, Rogler G, Brenmoehl J, Greinix H et al. NOD2/CARD15 polymorphisms in allogeneic stem-cell transplantation from unrelated donors: T depletion matters. J Clin Oncol 2008; 26: 338–339.

    Article  CAS  PubMed  Google Scholar 

  28. Uehara A, Fujimoto Y, Fukase K, Takada H . Various human epithelial cells express functional Toll-like receptors, NOD1 and NOD2 to produce anti-microbial peptides, but not proinflammatory cytokines. Mol Immunol 2007; 44: 3100–3111.

    Article  CAS  PubMed  Google Scholar 

  29. Herr C, Shaykhiev R, Bals R . The role of cathelicidin and defensins in pulmonary inflammatory diseases. Expert Opin Biol Ther 2007; 7: 1449–1461.

    Article  CAS  PubMed  Google Scholar 

  30. De SK, Contreras R . Human antimicrobial peptides: defensins, cathelicidins and histatins. Biotechnol Lett 2005; 27: 1337–1347.

    Article  Google Scholar 

  31. Costa SF, Miceli MH, Anaissie EJ . Mucosa or skin as source of coagulase-negative staphylococcal bacteraemia? Lancet Infect Dis 2004; 4: 278–286.

    Article  PubMed  Google Scholar 

  32. Ruescher TJ, Sodeifi A, Scrivani SJ, Kaban LB, Sonis ST . The impact of mucositis on alpha-hemolytic streptococcal infection in patients undergoing autologous bone marrow transplantation for hematologic malignancies. Cancer 1998; 82: 2275–2281.

    Article  CAS  PubMed  Google Scholar 

  33. Holler E, Rogler G, Brenmoehl J, Hahn J, Herfarth H, Greinix H et al. Prognostic significance of NOD2/CARD15 variants in HLA-identical sibling hematopoietic stem cell transplantation: effect on long term outcome is confirmed in 2 independent cohorts and may be modulated by the type of gastrointestinal decontamination. Blood 2006; 107: 4189–4193.

    Article  CAS  PubMed  Google Scholar 

  34. Fishbein T, Novitskiy G, Mishra L, Matsumoto C, Kaufman S, Goyal S et al. NOD2-expressing bone marrow-derived cells appear to regulate epithelial innate immunity of the transplanted human small intestine. Gut 2008; 57: 323–330.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations


Corresponding author

Correspondence to W J F M van der Velden.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

van der Velden, W., Blijlevens, N., Maas, F. 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 44, 243–248 (2009).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


  • NOD2/CARD15
  • single nucleotide polymorphisms
  • acute GVHD
  • TRM
  • idarubicin

This article is cited by


Quick links