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Haematopoietic stem cell transplantation: can our genes predict clinical outcome?

  • Anne M. Dickinson (a1), Jane L. Harrold (a1) and Hannah Cullup (a1)
Abstract
Abstract

Haematopoietic stem cell transplantation (HSCT) is currently the only curative treatment for many patients with malignant and non-malignant haematological diseases. The success of HSCT is greatly reduced by the development of complications, which include graft-versus-host disease (GVHD), relapse and infection. Human leukocyte antigen (HLA) matching of patients and donors is essential, but does not completely prevent these complications; non-HLA genes may also have an impact upon transplant outcome. Polymorphisms within genes that are associated with an individual's capability to mount an immune response to alloantigen and infectious pathogens and/or response to drugs (pharmacogenomics) are all currently being studied for their association with HSCT outcome. This review summarises the potential role of non-HLA polymorphisms in predicting HSCT outcome, from studies on retrospective transplant cohorts of HLA-identical siblings and matched unrelated donors. The clinical relevance and interpretation of non-HLA genetics, and how these could be used alongside clinical risk factors in HSCT, are also discussed.

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Corresponding author
*Corresponding author: Anne Dickinson, Institute of Cellular Medicine, School of Clinical and Laboratory Sciences, Newcastle upon Tyne, NE2 4HH, UK. Tel/Fax: +44 (0)191 222 6794; E-mail: a.m.dickinson@ncl.ac.uk
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1 E. Petersdorf (2001) Genomics of unrelated-donor hematopoietic cell transplantation. Curr Opin Immunol 13, 582-589

2 J.L. Bidwell (1999) Human cytokine gene nucleotide sequence alignments: supplement 1. Eur J Immunogenet 26, 135-223

3 J.L. Bidwell (1998) Human cytokine gene nucleotide sequence alignments, 1998. Eur J Immunogenet 25, 83-265

4 D. Turner (1997) Cytokine gene polymorphism and heart transplant rejection. Transplantation 64, 776-779

5 H. Glucksberg (1974) Clinical manifestations of graft-versus-host disease in human recipients of marrow from HLA-matched sibling donors. Transplantation 18, 295-304

8 W. Krenger , G.R. Hill and J.L. Ferrara (1997) Cytokine cascades in acute graft-versus-host disease [Review]. Transplantation 64, 553-558

9 L. Eckmann (2006) Sensor molecules in intestinal innate immunity against bacterial infections. Curr Opin Gastroenterol 22, 95-101

10 G. Harris , R. KuoLee and W. Chen (2006) Role of Toll-like receptors in health and diseases of gastrointestinal tract. World J Gastroenterol 12, 2149-2160

11 F.P. Nestel (1992) Macrophage priming and lipopolysaccharide-triggered release of tumor necrosis factor alpha during graft-versus-host disease. J Exp Med 175, 405-413

12 W.D. Shlomchik (1999) Prevention of graft versus host disease by inactivation of host antigen-presenting cells. Science 285, 412-415

13 C.C. Matte (2004) Donor APCs are required for maximal GVHD but not for GVL. Nature Med 10, 987-992

14 M.P. Collin (2006) The fate of human Langerhans cells in hematopoietic stem cell transplantation. J Exp Med 203, 27-33

15 Y. Maeda (2005) Both perforin and Fas ligand are required for the regulation of alloreactive CD8+ T cells during acute graft-versus-host disease. Blood 105, 2023-2027

16 T.A. Graubert (1997) Perforin/granzyme-dependent and independent mechanisms are both important for the development of graft-versus-host disease after murine bone marrow transplantation. J Clin Invest 100, 904-911

17 H.M. Shulman (1980) Chronic graft-versus-host syndrome in man. A long-term clinicopathologic study of 20 Seattle patients. Am J Med 69, 204-217

18 G. Akpek (2003) Performance of a new clinical grading system for chronic graft-versus-host disease: a multicenter study. Blood 102, 802-809

19 H.T. Greinix (2007) A single-center pilot validation study of a new chronic GVHD skin scoring system. Biol Blood Marrow Transplant 13, 715-723

20 H.N. Claman (1985) Chronic graft-versus-host disease as a model for scleroderma. II. Mast cell depletion with deposition of immunoglobulins in the skin and fibrosis. Cell Immunol 94, 73-84

21 C.G. Mullighan and P.G. Bardy (2004) Advances in the genomics of allogeneic haemopoietic stem cell transplantation. Drug Development Research 62, 273-292

23 H. Takahashi (2000) Contribution of TNF-alpha and IL-10 gene polymorphisms to graft-versus-host disease following allo-hematopoietic stem cell transplantation. Bone Marrow Transplant 26, 1317-1323

26 G. Socié (2001) Both genetic and clinical factors predict the development of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Transplantation 72, 699-706

27 A. Nordlander (2002) The TNFd4 allele is correlated to moderate-to-severe acute graft-versus-host disease after allogeneic stem cell transplantation. Br J Haematol 119, 1133-1336

28 V. Rocha (2002) Host defence and inflammatory gene polymorphisms are associated with outcomes after HLA-identical sibling bone marrow transplant. Blood 100, 3908-3918

29 M.T. Lin (2003) Relation of an interleukin-10 promoter polymorphism to graft-versus-host disease and survival after hematopoietic-cell transplantation. N Engl J Med 349, 2201-2210

30 C. Mullighan (2004) Non-HLA immunogenetic polymorphisms and the risk of complications after allogeneic hemopoietic stem-cell transplantation. Transplantation 77, 587-596

31 K. Bogunia-Kubik , M. Polak and A. Lange (2003) TNF polymorphisms are associated with toxic but not with aGVHD complications in the recipients of allogeneic sibling haematopoietic stem cell transplantation. Bone Marrow Transplant 32, 617-622

33 I. Holzinger (1995) Cloning and genomic characterization of LST1: a new gene in the human TNF region. Immunogenetics 42, 315-322

34 I.A. Udalova (1993) Highly informative typing of the human TNF locus using six adjacent polymorphic markers. Genomics 16, 180-186

35 F. Pociot (1991) A tumour necrosis factor beta gene polymorphism in relation to monokine secretion and insulin-dependent diabetes mellitus. Scand J Immunol 33, 37-49

36 D.M. Turner (1995) A genetic marker of high TNF-alpha production in heart transplant recipients. Transplantation 60, 1113-1117

38 B.E. Shaw (2004) Polymorphisms in the TNFA gene promoter region show evidence of strong linkage disequilibrium with HLA and are associated with delayed neutrophil engraftment in unrelated donor hematopoietic stem cell transplantation. Tissue antigens 63, 401-411

39 L. Zheng (1995) Induction of apoptosis in mature T cells by tumour necrosis factor. Nature 377, 348-351

40 G.L. Stark (2003) Tumour necrosis factor receptor type II 196M/R genotype correlates with circulating soluble receptor levels in normal subjects and with graft-versus-host disease after sibling allogeneic bone marrow transplantation. Transplantation 76, 1742-1749

41 C. Morita (2001) Association of tumor necrosis factor receptor type II polymorphism 196R with Systemic lupus erythematosus in the Japanese: molecular and functional analysis. Arthritis Rheum 44, 2819-2827

42 C.J. Edwards-Smith (1999) Interleukin-10 promoter polymorphism predicts initial response of chronic hepatitis C to interferon alfa. Hepatology 30, 526-530

43 D.H. Kim (2005) IL-10 promoter gene polymorphism associated with the occurrence of chronic GVHD and its clinical course during systemic immunosuppressive treatment for chronic GVHD after allogeneic peripheral blood stem cell transplantation. Transplantation 79, 1615-1622

44 K.W. Seo (2005) Protective role of interleukin-10 promoter gene polymorphism in the pathogenesis of invasive pulmonary aspergillosis after allogeneic stem cell transplantation. Bone Marrow Transplant 36, 1089-1095

46 J. Cavet (2001) Interferon-gamma and interleukin-6 gene polymorphisms associate with graft-versus-host disease in HLA-matched sibling bone marrow transplantation. Blood 98, 1594-1600

48 A. Mlynarczewska (2004) 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

50 K. Bogunia-Kubik (2006) The presence of IFNG 3/3 genotype in the recipient associates with increased risk for Epstein-Barr virus reactivation after allogeneic haematopoietic stem cell transplantation. Br J Haematol 132, 326-332

51 H. Cullup and G. Stark (2005) Interleukin-1 polymorphisms and graft versus host disease. Leuk Lymphoma 46, 517-523

52 H. Cullup (2001) Donor interleukin-1 receptor antagonist genotype associated with acute graft-versus-host disease in human leukocyte antigen-matched sibling allogeneic transplants. Br J Haematol 113, 807-813

53 H. Cullup (2003) Polymorphisms of IL-1alpha constitute independent risk factors for chronic graft versus host disease following allogeneic bone marrow transplantation. Br J Haematol 122, 778-787

54 C.F. Terry , V. Loukaci and F.R. Green (2000) Cooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulation. J Biol Chem 275, 18138-18144

55 S.L. Ferrari (2003) Two promoter polymorphisms regulating interleukin-6 gene expression are associated with circulating levels of C-reactive protein and markers of bone resorption in postmenopausal women. J Clin Endocrinol Metab 88, 255-259

56 D. Fishman (1998) 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 102, 1369-1376

57 L. Karabon (2005) IL-6 and IL-10 promoter gene polymorphisms of patients and donors of allogeneic sibling hematopoietic stem cell transplants associate with the risk of acute graft-versus-host disease. Hum Immunol 66, 700-710

58 T. Banovic (2005) TGF-beta in allogeneic stem cell transplantation: friend or foe? Blood 106, 2206-2214

59 D.J. Grainger (1999) Genetic control of the circulating concentration of transforming growth factor type beta 1. Hum Mol Genet 8, 93-97

60 M.S. Leffell (2001) Association between TGF-beta expression and severe GVHD in allogeneic bone marrow transplantation. Transplant proceedings 33, 485-486

61 H. Hattori (2002) Polymorphisms of transforming growth factor-beta1 and transforming growth factor-beta1 type II receptor genes are associated with acute graft-versus-host disease in children with HLA-matched sibling bone marrow transplantation. Bone Marrow Transplant 30, 665-671

62 B. Yigit (2006) Analysis of CC chemokine receptor 5 and 2 polymorphisms and renal transplant survival. Cell Biochem Funct 25, 423-426

64 L.A. Welniak (2004) An absence of CCR5 on donor cells results in acceleration of acute graft-vs-host disease. Exp Hematol 32, 318-324

65 C.A. Wysocki (2004) Differential roles for CCR5 expression on donor T cells during graft-versus-host disease based on pretransplant conditioning. J Immunol 173, 845-854

66 T.H. Terwey (2005) CCR2 is required for CD8-induced graft-versus-host disease. Blood 106, 3322-3330

67 C.M. Faaij (2006) A possible role for CCL27/CTACK-CCR10 interaction in recruiting CD4 T cells to skin in human graft-versus-host disease. Br J Haematol 133, 538-549

68 M. Jaksch , M. Remberger and J. Mattsson (2005) Increased gene expression of chemokine receptors is correlated with acute graft-versus-host disease after allogeneic stem cell transplantation. Biology of blood marrow transplantion 11, 280-287

69 U. Duffner (2003) Role of CXCR3-induced donor T-cell migration in acute GVHD. Exp Hematol 31, 897-902

70 R. Varona (2005) CCR6 regulates CD4+ T-cell-mediated acute graft-versus-host disease responses. Blood 106, 18-26

71 J. Loeffler (2006) Polymorphisms in the genes encoding chemokine receptor 5, interleukin-10, and monocyte chemoattractant protein 1 contribute to cytomegalovirus reactivation and disease after allogeneic stem cell transplantation. J Clin Microbiol 44, 1847-1850

73 T. Kaisho and S. Akira (2003) Regulation of dendritic cell function through toll-like receptors. Curr Mol Med 3, 759-771

74 T. Kaisho and S. Akira (2004) Pleiotropic function of Toll-like receptors. Microbes Infect 6, 1388-1394

75 E. Lorenz (2001) Association of TLR4 mutations and the risk for acute GVHD after HLA-matched-sibling hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 7, 384-387

76 S. Kesh (2005) TLR1 and TLR6 polymorphisms are associated with susceptibility to invasive aspergillosis after allogeneic stem cell transplantation. Ann NY Acad Sci 1062, 95-103

77 E. Holler (2004) Both donor and recipient NOD2/CARD15 mutations associate with transplant-related mortality and GvHD following allogeneic stem cell transplantation. Blood 104, 889-894

78 E. Holler (2006) 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 107, 4189-4193

80 C.G. Mullighan (2002) Mannose-binding lectin gene polymorphisms are associated with major infection following allogeneic hemopoietic stem cell transplantation. Blood 99, 3524-3529

81 H.M. van der Straaten (2005) The FcgammaRIIa-polymorphic site as a potential target for acute graft-versus-host disease in allogeneic stem cell transplantation. Biol Blood Marrow Transplant 11, 206-212

82 G. Cavanagh (2005) Donor CD31 genotype impacts on transplant complications after human leukocyte antigen-matched sibling allogeneic bone marrow transplantation. Transplantation 79, 602-605

83 E. Behar (1996) Polymorphism of adhesion molecule CD31 and its role in acute graft-versus-host disease. N Engl J Med 334, 286-291

85 F.C. Grumet (2001) CD31 mismatching affects marrow transplantation outcome. Biol Blood Marrow Transplant 7, 503-512

86 P.G. Middleton (2003) Oestrogen receptor alpha gene polymorphism associates with occurrence of graft-versus-host disease and reduced survival in HLA-matched sib-allo BMT. Bone Marrow Transplant 32, 41-47

87 P.G. Middleton (2002) Vitamin D receptor gene polymorphism associates with graft-versus-host disease and survival in HLA-matched sibling allogeneic bone marrow transplantation. Bone Marrow Transplant 30, 223-228

88 K. Bogunia-Kubik and A. Lange (2005) HSP70-hom gene polymorphism in allogeneic hematopoietic stem-cell transplant recipients correlates with the development of acute graft-versus-host disease. Transplantation 79, 815-820

89 L.J. Keen (2004) Interleukin-10 and tumor necrosis factor alpha region haplotypes predict transplant-related mortality after unrelated donor stem cell transplantation. Blood 103, 3599-3602

90 F. Bettens (2006) Association of TNFd and IL-10 polymorphisms with mortality in unrelated hematopoietic stem cell transplantation. Transplantation 81, 1261-1267

91 M. Remberger (2003) Serum levels of cytokines correlate to donor chimerism and acute graft-vs.-host disease after haematopoietic stem cell transplantation. Eur J Haematol 70, 384-391

92 Y. Ishikawa (2002) Polymorphisms in TNFA and TNFR2 affect outcome of unrelated bone marrow transplantation. Bone Marrow Transplant 29, 569-575

93 M.L. MacMillan (2003) Interleukin-1 genotype and outcome of unrelated donor bone marrow transplantation. Br J Haematol 121, 597-604

95 M.L. MacMillan (2003) High-producer interleukin-2 genotype increases risk for acute graft-versus-host disease after unrelated donor bone marrow transplantation. Transplantation 76, 1758-1762

96 Z. Shamim (2006) Genetic polymorphisms in the genes encoding human interleukin-7 receptor-alpha: prognostic significance in allogeneic stem cell transplantation. Bone Marrow Transplant 37, 485-491

97 B.H. Joshi (2006) Role of interleukin-13 in cancer, pulmonary fibrosis, and other T(H)2-type diseases. Vitam Horm 74, 479-504

98 W.J. Jordan (2004) IL-13 production by donor T cells is prognostic of acute graft-versus-host disease following unrelated donor stem cell transplantation. Blood 103, 717-724

99 J. Ohashi (2003) A single-nucleotide substitution from C to T at position -1055 in the IL-13 promoter is associated with protection from severe malaria in Thailand. Genes Immun 4, 528-531

100 A.K. Steck (2005) Association of non-HLA genes with type 1 diabetes autoimmunity. Diabetes 54, 2482-2486

101 J. Yang , H.L. Qiao and Z.M. Dong (2005) Polymorphisms of IL-13 and IL-4-IL-13-SNPs in patients with penicillin allergies. Eur J Clin Pharmacol 61, 803-809

102 S.M. Cardoso (2004) Patient interleukin-18 GCG haplotype associates with improved survival and decreased transplant-related mortality after unrelated-donor bone marrow transplantation. Br J Haematol 126, 704-710

103 P. Reddy (2003) Pretreatment of donors with interleukin-18 attenuates acute graft-versus-host disease via STAT6 and preserves graft-versus-leukemia effects. Blood 101, 2877-2885

104 C.M. Ulrich (2001) Pharmacogenetics of methotrexate: toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism. Blood 98, 231-234

106 K. Robien (2004) Methylenetetrahydrofolate reductase genotype affects risk of relapse after hematopoietic cell transplantation for chronic myelogenous leukemia. Clin Cancer Res 10, 7592-7598

107 S. Kalayoglu-Besisik (2003) Methylenetetrahydrofolate reductase C677T polymorphism and toxicity in allogeneic hematopoietic cell transplantation. Transplantation 76, 1775-1777

108 N. Murphy (2006) Donor methylenetetrahydrofolate reductase genotype is associated with graft-versus-host disease in hematopoietic stem cell transplant patients treated with methotrexate. Bone Marrow Transplant 37, 773-779

110 D. Anglicheau (2004) CYP3A5 and MDR1 genetic polymorphisms and cyclosporine pharmacokinetics after renal transplantation. Clin Pharmacol Ther 75, 422-433

111 A.R. Kallianpur (2005) Genomic screening and complications of hematopoietic stem cell transplantation: has the time come? Bone Marrow Transplant 35, 1-16

112 A. Gratwohl (2002) Graft-versus-host disease and outcome in HLA-identical sibling transplantations for chronic myeloid leukemia. Blood 100, 3877-3886

113 A. Gratwohl (1998) Risk assessment for patients with chronic myeloid leukaemia before allogeneic blood or marrow transplantation. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Lancet 352, 1087-1092

114 D. Weisdorf (1991) Risk factors for acute graft-versus-host disease in histocompatible donor bone marrow transplantation. Transplantation 51, 1197-1203

116 E. Clave (2005) Prognostic value of pretransplantation host thymic function in HLA-identical sibling hematopoietic stem cell transplantation. Blood 105, 2608-2613

117 K. Talvensaari (2002) A broad T-cell repertoire diversity and an efficient thymic function indicate a favorable long-term immune reconstitution after cord blood stem cell transplantation. Blood 99, 1458-1464

118 H. Oh (2005) Comparison of graft-versus-host-disease and survival after HLA-identical sibling bone marrow transplantation in ethnic populations. Blood 105, 1408-1416

119 Z. Kubistova (2006) Distribution of 22 cytokine gene polymorphisms in the healthy Czech population. Int J Immunogenet 33, 261-267

120 J.E. Laguila Visentainer (2005) Relationship between cytokine gene polymorphisms and graft-versus-host disease after allogeneic stem cell transplantation in a Brazilian population. Cytokine 32, 171-177

121 W.M. Leisenring (2006) An acute graft-versus-host disease activity index to predict survival after hematopoietic cell transplantation with myeloablative conditioning regimens. Blood 108, 749-755

122 W.E. Ollier (2004) Cytokine genes and disease susceptibility. Cytokine 28, 174-178

123 H.M. Colhoun , P.M. McKeigue and G. Davey Smith (2003) Problems of reporting genetic associations with complex outcomes. Lancet 361, 865-872

124 A.H. Filipovich (2005) National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 11, 945-956

125 A.M. Dickinson (2006) Biobanks and registries for HSCT research: potential for future individualized medicine. Int J Immunogenet 33, 153-154

W.D. Schlomchik (2007) Graft-versus-host disease. Nat Rev Immunol 7, 340-352

M. Rossi (2005) Human dendritic cells: potent antigen-presenting cells at the crossroads of innate and adaptive immunity. J Immunol 175, 1373-1381

C.A. Wysocki (2005) Leukocyte migration and graft-versus-host disease. Blood 105, 4191-4199

L. Ruggeri (2006) Allogeneic hematopoietic transplantation and natural killer cell recognition of missing self. Immunol Rev 214, 202-218

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