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CTLA-4 +49A>G polymorphism of recipients of HLA-matched sibling allogeneic stem cell transplantation is associated with survival and relapse incidence

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Abstract

Conflicting observations have been reported about the role of CTLA-4 gene polymorphisms in the clinical outcome of allogeneic hematopoietic stem cell transplantation (HSCT). We have investigated three polymorphisms of the CTLA-4 gene (−318C>T, +49A>G, CT60G>A) in 133 donor/recipient pairs who underwent HLA-matched sibling donor HSCT for hematological malignancies. We found no association of the clinical outcome of the HSCT with either recipient or donor −318C>T and CT60G>A polymorphisms. At variance, we found a significant association of donor +49A>G G/G genotype with longer overall survival (OS; log-rank test, P = 0.04), and the number of +49A>G G-alleles in the recipient with longer OS (P = 0.027), longer disease-free survival (P = 0.036) and reduced relapse rate (P = 0.042). However, only recipient +49A>G polymorphism was retained as independent prognostic factor in a multivariate analysis, suggesting that the expression of CTLA-4 on the cells of recipient may be relevant for the clinical outcome of HSCT.

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References

  1. Walunas TL, Lenschow DJ, Bakker CY, Linsley PS, Freeman GJ, Green JM, Thompson CB, Bluestone JA (1994) CTLA-4 can function as a negative regulator of T cell activation. Immunity 1:405–413

    Article  CAS  PubMed  Google Scholar 

  2. Lee KM, Chuang E, Griffin M, Khattri R, Hong DK, Zhang W, Straus D, Samelson LE, Thompson CB, Bluestone JA (1998) Molecular basis of T cell inactivation by CTLA-4. Science 282:2263–2266

    Article  CAS  PubMed  Google Scholar 

  3. Sho M, Yamada A, Najafian N, Salama AD, Harada H, Sandner SE, Sanchez-Fueyo A, Zheng XX, Strom TB, Sayegh MH (2002) Physiological mechanisms of regulating alloimmunity: cytokines, CTLA-4, CD25+ cells, and the alloreactive T cell clone size. J Immunol 169:3744–3751

    CAS  PubMed  Google Scholar 

  4. Ito T, Ueno T, Clarkson MR, Yuan X, Jurewicz MM, Yagita H, Azuma M, Sharpe AH, Auchincloss H Jr, Sayegh MH, Najafian N (2005) Analysis of the role of negative T cell costimulatory pathways in CD4 and CD8 T cell-mediated alloimmune responses in vivo. J Immunol 174:6648–6656

    CAS  PubMed  Google Scholar 

  5. Fevery S, Billiau AD, Sprangers B, Rutgeerts O, Lenaerts C, Goebels J, Landuyt W, Kasran A, Boon L, Sagaert X, De Wolf-Peeters C, Waer M, Vandenberghe P (2007) CTLA-4 blockade in murine bone marrow chimeras induces a host-derived antileukemic effect without graft-versus-host disease. Leukemia 21:1451–1459

    Article  CAS  PubMed  Google Scholar 

  6. Kouki T, Sawai Y, Gardine CA, Fisfalen ME, Alegre ML, DeGroot LJ (2000) CTLA-4 gene polymorphism at position 49 in exon 1 reduces the inhibitory function of CTLA-4 and contributes to the pathogenesis of Graves' disease. J Immunol 165:6606–6611

    CAS  PubMed  Google Scholar 

  7. Mäurer M, Loserth S, Kolb-Mäurer A, Ponath A, Wiese S, Kruse N, Rieckmann P (2002) A polymorphism in the human cytotoxic T-lymphocyte antigen 4 (CTLA4) gene (exon 1 +49) alters T-cell activation. Immunogenetics 54:1–8

    Article  PubMed  CAS  Google Scholar 

  8. Ueda H, Howson JM, Esposito L, Heward J, Snook H, Chamberlain G, Rainbow DB, Hunter KM, Smith AN, Di Genova G, Herr MH, Dahlman I et al (2003) Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423:506–511

    Article  CAS  PubMed  Google Scholar 

  9. Gough SC, Walker LS, Sansom DM (2005) CTLA4 gene polymorphism and autoimmunity. Immunol Rev 204:102–115

    Article  CAS  PubMed  Google Scholar 

  10. Pérez-García A, De la Cámara R, Román-Gómez J, Jiménez-Velasco A, Encuentra M, Nieto JB, de la Rubia J, Urbano-Ispizúa A, Brunet S, Iriondo A, González M, Serrano D, Espigado I, Solano C, Ribera JM, Pujal JM, Hoyos M, Gallardo D (2007) GVHD/Immunotherapy Committee of the Spanish Group of Hematopoietic Stem Cell TransplantationCTLA-4 polymorphisms and clinical outcome after allogeneic stem cell transplantation from HLA-identical sibling donors. Blood 110:461–467

    Article  PubMed  CAS  Google Scholar 

  11. Vannucchi AM, Guidi S, Guglielmelli P, Glinz S, Lombardini L, Busca A, Locatelli F, Dall'Omo AM, Bosi A (2007) Significance of CTLA-4 and CD14 genetic polymorphisms in clinical outcome after allogeneic stem cell transplantation. Bone Marrow Transplant 40:1001–1002

    Article  CAS  PubMed  Google Scholar 

  12. Azarian M, Busson M, Lepage V, Charron D, Toubert A, Loiseau P, de Latour RP, Rocha V, Socié G (2007) Donor CTLA-4 +49 A/G*G/G genotype is associated with chronic GvHD after HLA-identical haematopoietic stem-cell transplantations. Blood 110:4623–4624

    Article  CAS  PubMed  Google Scholar 

  13. Balbi G, Ferrera F, Rizzi M, Piccioli P, Morabito A, Cardamone L, Ghio M, Palmisano GL, Carrara P, Pedemonte S, Sessarego M, De Angioletti M, Notaro R, Indiveri F, Pistillo MP (2007) Association of -318 C/T and +49 A/G CTLA-4 gene polymorphisms with a clinical subset of Italian patients with systemic sclerosis. Clin Exp Immunol 149:40–47

    Article  CAS  PubMed  Google Scholar 

  14. Piccioli P, Serra M, Pedemonte S, Balbi G, Loiacono F, Lastraioli S, Gargiulo L, Morabito A, Zuccaro D, Del Mastro L, Pistillo MP, Venturini M, De Angioletti M, Notaro R (2008) Hexa-primer amplification refractory mutation system PCR for the single tube simultaneous genotyping of two close polymorphisms. Clin Chem 54:227–229

    Article  CAS  PubMed  Google Scholar 

  15. Svahn J, Capasso M, Lanciotti M, Marrone A, Haupt R, Bacigalupo A, Pongiglione C, Boschetto L, Longoni D, Pillon M, Pistorio A, Di Michele P et al (2005) The polymorphisms -318C > T in the promoter and 49A > G in exon 1 of CTLA4 and the risk of aplastic anemia in a Caucasian population. Bone Marrow Transplant 35(Suppl 1):S89–S92

    Article  CAS  PubMed  Google Scholar 

  16. Petrone A, Giorgi G, Galgani A, Alemanno I, Corsello SM, Signore A, Di Mario U, Nisticò L, Cascino I, Buzzetti R (2005) CT60 single nucleotide polymorphisms of the cytotoxic T-lymphocyte-associated antigen-4 gene region is associated with Graves' disease in an Italian population. Thyroid 15:232–238

    Article  CAS  PubMed  Google Scholar 

  17. Pistillo MP, Tazzari PL, Palmisano GL, Pierri I, Bolognesi A, Ferlito F, Capanni P, Polito L, Ratta M, Pileri S, Piccioli M, Basso G, Rissotto L, Conte R, Gobbi M, Stirpe F, Ferrara GB (2003) CTLA-4 is not restricted to the lymphoid cell lineage and can function as a target molecule for apoptosis induction of leukemic cells. Blood 101:202–209

    Article  CAS  PubMed  Google Scholar 

  18. Laurent S, Palmisano GL, Martelli AM, Kato T, Tazzari PL, Pierri I, Clavio M, Dozin B, Balbi G, Megna M, Morabito A, Lamparelli T, Bacigalupo A, Gobbi M, Pistillo MP (2007) CTLA-4 expressed by chemoresistant, as well as untreated, myeloid leukaemia cells can be targeted with ligands to induce apoptosis. Br J Haematol 136:597–608

    Article  CAS  PubMed  Google Scholar 

  19. Wang XB, Giscombe R, Yan Z, Heiden T, Xu D, Lefvert AK (2002) Expression of CTLA-4 by human monocytes. Scand J Immunol 55:53–60

    Article  CAS  PubMed  Google Scholar 

  20. Madrigal A, Shaw BE (2008) Immunogenetic factors in donors and patients that affect the outcome of hematopoietic stem cell transplantation. Blood Cells Mol Dis 40:40–43

    Article  CAS  PubMed  Google Scholar 

  21. Anjos S, Nguyen A, Ounissi-Benkalha H, Tessier MC, Polychronakos C (2002) A common autoimmunity predisposing signal peptide variant of the cytotoxic T-lymphocyte antigen 4 results in inefficient glycosylation of the susceptibility allele. J Biol Chem 277:46478–46486

    Article  CAS  PubMed  Google Scholar 

  22. Greenwald RJ, Freeman GJ, Sharpe AH (2005) The B7 family revisited. Annu Rev Immunol 23:515–548

    Article  PubMed  CAS  Google Scholar 

  23. Bashey A, Medina B, Corringham S, Pasek M, Carrier E, Vrooman L, Lowy I, Solomon SR, Morris LE, Holland HK, Mason JR, Alyea EP, Soiffer RJ, Ball ED (2009) CTLA4 blockade with ipilimumab to treat relapse of malignancy after allogeneic hematopoietic cell transplantation. Blood 113:1581–1588

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported in part by grants from Ministero dell'Istruzione, dell’Università e della Ricerca (MIUR-PRIN 2007, project WEYB3A) and from Regione Liguria.

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Authors and Affiliations

  1. Medical Oncology C, National Cancer Research Institute, Genoa, Italy

    Patrizia Piccioli & Martina Serra

  2. Department of Oncology, Biology and Genetics, University of Genoa, Genoa, Italy

    Giuseppe Balbi

  3. Breast Cancer Laboratory of Tumour Genetics Unit, National Cancer Research Institute, L.go R. Benzi 10, 16132, Genoa, Italy

    Anna Morabito, Stefania Laurent & Maria Pia Pistillo

  4. Division of Hematology, San Martino Hospital, Genoa, Italy

    Teresa Lamparelli & Andrea Bacigalupo

  5. Department of Hematology and Oncology, University of Genoa, Genoa, Italy

    Marco Gobbi

  6. Clinical Epidemiology Unit, National Cancer Research Institute, Genoa, Italy

    Beatrice Dozin & Paolo Bruzzi

  7. University of Genoa and National Cancer Research Institute, Genoa, Italy

    Anna Maria Ferraris

  8. Laboratory of Genetics and Gene Transfer, Core Research Laboratory, Istituto Toscano Tumori (CRL-ITT), Florence, Italy

    Rosario Notaro

Authors
  1. Patrizia Piccioli
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  2. Giuseppe Balbi
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  3. Martina Serra
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  4. Anna Morabito
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  5. Teresa Lamparelli
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  6. Marco Gobbi
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  7. Stefania Laurent
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  8. Beatrice Dozin
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  9. Paolo Bruzzi
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  10. Anna Maria Ferraris
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  11. Andrea Bacigalupo
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  12. Rosario Notaro
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  13. Maria Pia Pistillo
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Corresponding author

Correspondence to Maria Pia Pistillo.

Additional information

Rosario Notaro and Maria Pia Pistillo equally contributed to this work.

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Piccioli, P., Balbi, G., Serra, M. et al. CTLA-4 +49A>G polymorphism of recipients of HLA-matched sibling allogeneic stem cell transplantation is associated with survival and relapse incidence. Ann Hematol 89, 613–618 (2010). https://doi.org/10.1007/s00277-009-0885-5

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  • DOI: https://doi.org/10.1007/s00277-009-0885-5

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