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Post-Transplant Events

Prognostic significance of genetic variants in the IL-23/Th17 pathway for the outcome of T cell-depleted allogeneic stem cell transplantation

Bone Marrow Transplantation volume 45, pages 1645–1652 (2010)Cite this article

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Abstract

T helper (Th) 17 cells have emerged as important mediators in infectious and inflammatory diseases and, recently, in transplant rejection. We analyzed the associations between five common genetic variants in the IL-23/Th17 signaling pathway, namely in IL17A, IL17F and IL23R genes, and clinical outcome in T cell-depleted allogeneic SCT (allo-SCT). In the multivariate analysis, variants in IL23R and IL17A genes were the most important prognostic factors. Thus, patient GA genotype at rs11209026 in IL23R was associated with improved overall survival (hazard ratio (HR)=0.48; P=0.028) and, in donor, with decreased risk of fungal infections (P=0.05). In contrast, patient TC and CC genotypes at rs8193036 in IL17A gene were associated with increased risk of CMV infection (HR=3.68; P=0.011) and patient acute GVHD (HR=7.08; P=0.008), respectively. These results suggest that genetic variants in the IL-23/Th17 inflammatory pathway are important prognostic factors for the clinical outcome of allo-SCT. Although validation studies are ultimately required, our results would suggest the potential usefulness of IL-23/Th17 genotyping in donor selection and patient evaluation.

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References

  1. Bochud PY, Chien JW, Marr KA, Leisenring WM, Upton A, Janer M et al. Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation. N Engl J Med 2008; 359: 1766–1777.

    Article  CAS  Google Scholar 

  2. Carvalho A, Cunha C, Carotti A, Aloisi T, Guarrera O, Di Ianni M et al. Polymorphisms in Toll-like receptor genes and susceptibility to infections in allogeneic stem cell transplantation. Exp Hematol 2009; 37: 1022–1029.

    Article  CAS  Google Scholar 

  3. Granell M, Urbano-Ispizua A, Pons A, Arostegui JI, Gel B, Navarro A et al. Common variants in NLRP2 and NLRP3 genes are strong prognostic factors for the outcome of HLA-identical sibling allogeneic stem cell transplantation. Blood 2008; 112: 4337–4342.

    Article  CAS  Google Scholar 

  4. 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  Google Scholar 

  5. Dickinson AM . Non-HLA genetics and predicting outcome in HSCT. Int J Immunogenet 2008; 35: 375–380.

    Article  CAS  Google Scholar 

  6. Skert C, Damiani D, Michelutti A, Patriarca F, Arpinati M, Fili C et al. Kinetics of Th1/Th2 cytokines and lymphocyte subsets to predict chronic GVHD after Allo-SCT: results of a prospective study. Bone Marrow Transplant 2009; 44: 729–737.

    Article  CAS  Google Scholar 

  7. Weaver CT, Hatton RD, Mangan PR, Harrington LE . IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol 2007; 25: 821–852.

    Article  CAS  Google Scholar 

  8. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006; 441: 235–238.

    Article  CAS  Google Scholar 

  9. Kastelein RA, Hunter CA, Cua DJ . Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation. Annu Rev Immunol 2007; 25: 221–242.

    Article  CAS  Google Scholar 

  10. Liang SC, Tan XY, Luxenberg DP, Karim R, Dunussi-Joannopoulos K, Collins M et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med 2006; 203: 2271–2279.

    Article  CAS  Google Scholar 

  11. Khader SA, Bell GK, Pearl JE, Fountain JJ, Rangel-Moreno J, Cilley GE et al. IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge. Nat Immunol 2007; 8: 369–377.

    Article  CAS  Google Scholar 

  12. Zelante T, De Luca A, D’Angelo C, Moretti S, Romani L . IL-17/Th17 in anti-fungal immunity: what's new? Eur J Immunol 2009; 39: 645–648.

    Article  CAS  Google Scholar 

  13. Korn T, Oukka M, Kuchroo V, Bettelli E . Th17 cells: effector T cells with inflammatory properties. Semin Immunol 2007; 19: 362–371.

    Article  CAS  Google Scholar 

  14. Doreau A, Belot A, Bastid J, Riche B, Trescol-Biemont MC, Ranchin B et al. Interleukin 17 acts in synergy with B cell-activating factor to influence B cell biology and the pathophysiology of systemic lupus erythematosus. Nat Immunol 2009; 10: 778–785.

    Article  CAS  Google Scholar 

  15. Mitchell P, Afzali B, Lombardi G, Lechler RI . The T helper 17-regulatory T cell axis in transplant rejection and tolerance. Curr Opin Organ Transplant 2009; 14: 326–331.

    Article  Google Scholar 

  16. Yi T, Zhao D, Lin CL, Zhang C, Chen Y, Todorov I et al. Absence of donor Th17 leads to augmented Th1 differentiation and exacerbated acute graft-versus-host disease. Blood 2008; 112: 2101–2110.

    Article  CAS  Google Scholar 

  17. Carlson MJ, West ML, Coghill JM, Panoskaltsis-Mortari A, Blazar BR, Serody JS . In vitro-differentiated TH17 cells mediate lethal acute graft-versus-host disease with severe cutaneous and pulmonary pathologic manifestations. Blood 2009; 113: 1365–1374.

    Article  CAS  Google Scholar 

  18. Kappel LW, Goldberg GL, King CG, Suh DY, Smith OM, Ligh C et al. IL-17 contributes to CD4-mediated graft-versus-host disease. Blood 2009; 113: 945–952.

    Article  CAS  Google Scholar 

  19. Fabrega E, Lopez-Hoyos M, San Segundo D, Casafont F, Pons-Romero F . Changes in the serum levels of interleukin-17/interleukin-23 during acute rejection in liver transplantation. Liver Transpl 2009; 15: 629–633.

    Article  Google Scholar 

  20. Atalar K, Afzali B, Lord G, Lombardi G . Relative roles of Th1 and Th17 effector cells in allograft rejection. Curr Opin Organ Transplant 2009; 14: 23–29.

    Article  Google Scholar 

  21. Min SI, Ha J, Park CG, Won JK, Park YJ, Min SK et al. Sequential Evolution of IL-17 Responses in the early period of allograft rejection. Exp Mol Med 2009; 41: 707–716.

    Article  CAS  Google Scholar 

  22. Huang W, Na L, Fidel PL, Schwarzenberger P . Requirement of interleukin-17A for systemic anti-Candida albicans host defense in mice. J Infect Dis 2004; 190: 624–631.

    Article  CAS  Google Scholar 

  23. Tilg H, Moschen AR, Kaser A . Suppression of interleukin-17 by type I interferons: a contributing factor in virus-induced immunosuppression? Eur Cytokine Netw 2009; 20: 1–6.

    CAS  PubMed  Google Scholar 

  24. Hou W, Kang HS, Kim BS . Th17 cells enhance viral persistence and inhibit T cell cytotoxicity in a model of chronic virus infection. J Exp Med 2009; 206: 313–328.

    Article  CAS  Google Scholar 

  25. Zelante T, De Luca A, Bonifazi P, Montagnoli C, Bozza S, Moretti S et al. IL-23 and the Th17 pathway promote inflammation and impair antifungal immune resistance. Eur J Immunol 2007; 37: 2695–2706.

    Article  CAS  Google Scholar 

  26. Aversa F, Tabilio A, Velardi A, Cunningham I, Terenzi A, Falzetti F et al. Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype. N Engl J Med 1998; 339: 1186–1193.

    CAS  PubMed  Google Scholar 

  27. Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 2002; 295: 2097–2100.

    Article  CAS  Google Scholar 

  28. 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.

    Article  CAS  Google Scholar 

  29. Kawaguchi M, Takahashi D, Hizawa N, Suzuki S, Matsukura S, Kokubu F et al. IL-17F sequence variant (His161Arg) is associated with protection against asthma and antagonizes wild-type IL-17F activity. J Allergy Clin Immunol 2006; 117: 795–801.

    Article  CAS  Google Scholar 

  30. Wang JY, Shyur SD, Wang WH, Liou YH, Lin CG, Wu YJ et al. The polymorphisms of interleukin 17A (IL17A) gene and its association with pediatric asthma in Taiwanese population. Allergy 2009; 64: 1056–1060.

    Article  CAS  Google Scholar 

  31. Carvalho A, Marques A, Maciel P, Rodrigues F . Study of disease-relevant polymorphisms in the TLR4 and TLR9 genes: a novel method applied to the analysis of the Portuguese population. Mol Cell Probes 2007; 21: 316–320.

    Article  CAS  Google Scholar 

  32. Liu Q, Thorland EC, Heit JA, Sommer SS . Overlapping PCR for bidirectional PCR amplification of specific alleles: a rapid one-tube method for simultaneously differentiating homozygotes and heterozygotes. Genome Res 1997; 7: 389–398.

    Article  CAS  Google Scholar 

  33. De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 2008; 46: 1813–1821.

    Article  Google Scholar 

  34. Aversa F, Terenzi A, Tabilio A, Falzetti F, Carotti A, Ballanti S et al. Full haplotype-mismatched hematopoietic stem-cell transplantation: a phase II study in patients with acute leukemia at high risk of relapse. J Clin Oncol 2005; 23: 3447–3454.

    Article  Google Scholar 

  35. Gray RJ . A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 1988; 16: 1141–1154.

    Article  Google Scholar 

  36. Scrucca L, Santucci A, Aversa F . Competing risk analysis using R: an easy guide for clinicians. Bone Marrow Transplant 2007; 40: 381–387.

    Article  CAS  Google Scholar 

  37. Fine JP, Gray RJ . A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 1999; 94: 496–509.

    Article  Google Scholar 

  38. Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 2006; 314: 1461–1463.

    Article  CAS  Google Scholar 

  39. Kohyama S, Ohno S, Isoda A, Moriya O, Belladonna ML, Hayashi H et al. IL-23 enhances host defense against vaccinia virus infection via a mechanism partly involving IL-17. J Immunol 2007; 179: 3917–3925.

    Article  CAS  Google Scholar 

  40. Kryczek I, Wei S, Szeliga W, Vatan L, Zou W . Endogenous IL-17 contributes to reduced tumor growth and metastasis. Blood 2009; 114: 357–359.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank CM Benedetti for editorial assistance. This study was supported by the Specific Targeted Research Project ‘MANASP’ (LSHE-CT-2006), contract number 037899 (FP6) and the Italian Projects PRIN 2007KLCKP8_004 (to LM) and PRIN 2007KLCKP8_005 (to FB). AC and CC were financially supported by fellowships from Fundação para a Ciência e Tecnologia, Portugal (contracts SFRH/BPD/46292/2008 and SFRH/BD/65962/2009).

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  1. A Carvalho and C Cunha: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of,

    A Carvalho, C Cunha, L Pitzurra, F Bistoni & L Romani

  2. Department of Experimental Medicine and Biochemical Sciences, Microbiology, University of Perugia, Perugia, Italy

    A Carvalho, C Cunha, L Pitzurra, F Bistoni & L Romani

  3. Division of Hematology and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy

    M Di Ianni, T Aloisi, F Falzetti, A Carotti & F Aversa

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  1. A Carvalho
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Carvalho, A., Cunha, C., Di Ianni, M. et al. Prognostic significance of genetic variants in the IL-23/Th17 pathway for the outcome of T cell-depleted allogeneic stem cell transplantation. Bone Marrow Transplant 45, 1645–1652 (2010). https://doi.org/10.1038/bmt.2010.28

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