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Graft-versus-host Disease

Donor single nucleotide polymorphism in the CCR9 gene affects the incidence of skin GVHD

Bone Marrow Transplantation volume 45, pages 363–369 (2010)Cite this article

Abstract

The interactions between chemokines and their receptors may have an important role in initiating GVHD after allogeneic hematopoietic SCT (allo-HSCT). CCL25 and CCR9 are unique because they are exclusively expressed in epithelial cells and in Peyer's patches of the small intestine. We focused on rs12721497 (G926A), one of the non-synonymous single nucleotide polymorphisms (SNPs) in the CCR9 gene, and analyzed the SNP of donors in 167 consecutive patients who received allo-HSCT from an HLA-identical sibling donor. Genotypes were tested for associations with acute and chronic GVHD in each organ and transplant outcome. Multivariate analyses showed that the genotype 926AG was significantly associated with the incidence of acute stage ⩾2 skin GVHD (hazard ratio: 3.2; 95% confidence interval (95% CI): 1.1–9.1; P=0.032) and chronic skin GVHD (hazard ratio: 4.1; 95% CI: 1.1–15; P=0.036), but not with GVHD in other organs or with relapse, non-relapse mortality or OS. To clarify the functional differences between genotypes, each SNP in retroviral vectors was transfected into Jurkat cells. In chemotaxis assays, the 926G transfectant showed greater response to CCL25 than the 926A transfectant. In conclusion, more active homing of CCR9-926AG T cells to Peyer's patches may produce changes in Ag presentation and result in increased incidence of skin GVHD.

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References

  1. Perfetti P, Carlier P, Strada P, Gualandi F, Occhini D, Van Lint MT et al. Extracorporeal photopheresis for the treatment of steroid refractory acute GVHD. Bone Marrow Transplant 2008; 42: 609–617.

    Article  CAS  PubMed  Google Scholar 

  2. Kunkel EJ, Butcher EC . Chemokines and the tissue-specific migration of lymphocytes. Immunity 2002; 16: 1–4.

    Article  CAS  PubMed  Google Scholar 

  3. Campbell DJ, Kim CH, Butcher EC . Chemokines in the systemic organization of immunity. Immunol Rev 2003; 195: 58–71.

    Article  CAS  PubMed  Google Scholar 

  4. Campbell JJ, Butcher EC . Chemokines in tissue-specific and microenvironment-specific lymphocyte homing. Curr Opin Immunol 2000; 12: 336–341.

    Article  CAS  PubMed  Google Scholar 

  5. Moser B, Loetscher P . Lymphocyte traffic control by chemokines. Nat Immunol 2001; 2: 123–128.

    Article  CAS  PubMed  Google Scholar 

  6. Pan J, Kunkel EJ, Gosslar U, Lazarus N, Langdon P, Broadwell K et al. A novel chemokine ligand for CCR10 and CCR3 expressed by epithelial cells in mucosal tissues. J Immunol 2000; 165: 2943–2949.

    Article  CAS  PubMed  Google Scholar 

  7. Wang W, Soto H, Oldham ER, Buchanan ME, Homey B, Catron D et al. Identification of a novel chemokine (CCL28), which binds CCR10 (GPR2). J Biol Chem 2000; 275: 22313–22323.

    Article  CAS  PubMed  Google Scholar 

  8. Kunkel EJ, Campbell JJ, Haraldsen G, Pan J, Boisvert J, Roberts AI et al. Lymphocyte CC chemokine receptor 9 and epithelial thymus-expressed chemokine (TECK) expression distinguish the small intestinal immune compartment: epithelial expression of tissue-specific chemokines as an organizing principle in regional immunity. J Exp Med 2000; 192: 761–768.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Papadakis KA, Prehn J, Nelson V, Cheng L, Binder SW, Ponath PD et al. The role of thymus-expressed chemokine and its receptor CCR9 on lymphocytes in the regional specialization of the mucosal immune system. J Immunol 2000; 165: 5069–5076.

    Article  CAS  PubMed  Google Scholar 

  10. Stenstad H, Svensson M, Cucak H, Kotarsky K, Agace WW . Differential homing mechanisms regulate regionalized effector CD8alphabeta+ T cell accumulation within the small intestine. Proc Natl Acad Sci U S A 2007; 104: 10122–10127.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Onishi M, Kinoshita S, Morikawa Y, Shibuya A, Phillips J, Lanier LL et al. Applications of retrovirus-mediated expression cloning. Exp Hematol 1996; 24: 324–329.

    CAS  PubMed  Google Scholar 

  12. Yu CR, Peden KW, Zaitseva MB, Golding H, Farber JM . CCR9A and CCR9B: two receptors for the chemokine CCL25/TECK/Ck beta-15 that differ in their sensitivities to ligand. J Immunol 2000; 164: 1293–1305.

    Article  CAS  PubMed  Google Scholar 

  13. Przepiorka 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.

    CAS  PubMed  Google Scholar 

  14. Sullivan KM, Agura E, Anasetti C, Appelbaum F, Badger C, Bearman S et al. Chronic graft-versus-host disease and other late complications of bone marrow transplantation. Semin Hematol 1991; 28: 250–259.

    CAS  PubMed  Google Scholar 

  15. Inamoto Y, Suzuki R, Kuwatsuka Y, Yasuda T, Takahashi T, Tsujimura A et al. Long-term outcome after bone marrow transplantation for aplastic anemia using cyclophosphamide and total lymphoid irradiation as conditioning regimen. Biol Blood Marrow Transplant 2008; 14: 43–49.

    Article  CAS  PubMed  Google Scholar 

  16. Kallianpur AR . Genomic screening and complications of hematopoietic stem cell transplantation: has the time come? Bone Marrow Transplant 2005; 35: 1–16.

    Article  CAS  PubMed  Google Scholar 

  17. 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 

  18. Lin MT, Storer B, Martin PJ, Tseng LH, Gooley T, Chen PJ et al. Relation of an interleukin-10 promoter polymorphism to graft-versus-host disease and survival after hematopoietic-cell transplantation. N Engl J Med 2003; 349: 2201–2210.

    Article  CAS  PubMed  Google Scholar 

  19. Socie G, Loiseau P, Tamouza R, Janin A, Busson M, Gluckman E et al. Both genetic and clinical factors predict the development of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Transplantation 2001; 72: 699–706.

    Article  CAS  PubMed  Google Scholar 

  20. Cavet J, Dickinson AM, Norden J, Taylor PR, Jackson GH, Middleton PG . Interferon-gamma and interleukin-6 gene polymorphisms associate with graft-versus-host disease in HLA-matched sibling bone marrow transplantation. Blood 2001; 98: 1594–1600.

    Article  CAS  PubMed  Google Scholar 

  21. Mehta PA, Eapen M, Klein JP, Gandham S, Elliott J, Zamzow T et al. Interleukin-1 alpha genotype and outcome of unrelated donor haematopoietic stem cell transplantation for chronic myeloid leukaemia. Br J Haematol 2007; 137: 152–157.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zaballos A, Gutierrez J, Varona R, Ardavin C, Marquez G . Cutting edge: identification of the orphan chemokine receptor GPR-9-6 as CCR9, the receptor for the chemokine TECK. J Immunol 1999; 162: 5671–5675.

    CAS  PubMed  Google Scholar 

  23. Zabel BA, Agace WW, Campbell JJ, Heath HM, Parent D, Roberts AI et al. Human G protein-coupled receptor GPR-9-6/CC chemokine receptor 9 is selectively expressed on intestinal homing T lymphocytes, mucosal lymphocytes, and thymocytes and is required for thymus-expressed chemokine-mediated chemotaxis. J Exp Med 1999; 190: 1241–1256.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Mora JR, von Andrian UH . Role of retinoic acid in the imprinting of gut-homing IgA-secreting cells. Semin Immunol 2009; 21: 28–35.

    Article  CAS  PubMed  Google Scholar 

  25. Wurbel MA, Philippe JM, Nguyen C, Victorero G, Freeman T, Wooding P et al. The chemokine TECK is expressed by thymic and intestinal epithelial cells and attracts double- and single-positive thymocytes expressing the TECK receptor CCR9. Eur J Immunol 2000; 30: 262–271.

    Article  CAS  PubMed  Google Scholar 

  26. Norment AM, Bogatzki LY, Gantner BN, Bevan MJ . Murine CCR9, a chemokine receptor for thymus-expressed chemokine that is up-regulated following pre-TCR signaling. J Immunol 2000; 164: 639–648.

    Article  CAS  PubMed  Google Scholar 

  27. Heitger A, Neu N, Kern H, Panzer-Grumayer ER, Greinix H, Nachbaur D et al. Essential role of the thymus to reconstitute naive (CD45RA+) T-helper cells after human allogeneic bone marrow transplantation. Blood 1997; 90: 850–857.

    CAS  PubMed  Google Scholar 

  28. Beilhack A, Schulz S, Baker J, Beilhack GF, Nishimura R, Baker EM et al. Prevention of acute graft-versus-host disease by blocking T-cell entry to secondary lymphoid organs. Blood 2008; 111: 2919–2928.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Niess JH, Reinecker HC . Lamina propria dendritic cells in the physiology and pathology of the gastrointestinal tract. Curr Opin Gastroenterol 2005; 21: 687–691.

    Article  PubMed  Google Scholar 

  30. Hosoe N, Miura S, Watanabe C, Tsuzuki Y, Hokari R, Oyama T et al. Demonstration of functional role of TECK/CCL25 in T lymphocyte-endothelium interaction in inflamed and uninflamed intestinal mucosa. Am J Physiol Gastrointest Liver Physiol 2004; 286: G458–G466.

    Article  CAS  PubMed  Google Scholar 

  31. Wurbel MA, Malissen M, Guy-Grand D, Meffre E, Nussenzweig MC, Richelme M et al. Mice lacking the CCR9 CC-chemokine receptor show a mild impairment of early T- and B-cell development and a reduction in T-cell receptor gammadelta(+) gut intraepithelial lymphocytes. Blood 2001; 98: 2626–2632.

    Article  CAS  PubMed  Google Scholar 

  32. Wacholder S, Rothman N, Caporaso N . Counterpoint: bias from population stratification is not a major threat to the validity of conclusions from epidemiological studies of common polymorphisms and cancer. Cancer Epidemiol Biomarkers Prev 2002; 11: 513–520.

    PubMed  Google Scholar 

  33. Youn BS, Yu KY, Oh J, Lee J, Lee TH, Broxmeyer HE . Role of the CC chemokine receptor 9/TECK interaction in apoptosis. Apoptosis 2002; 7: 271–276.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Dr Toshio Kitamura for providing the pMX-IRES-Puro vector and PLAT-A packaging cells. This study was supported in part by a Health and Labor Science Research Grant (20251001) from the Ministry of Health, Labour and Welfare of Japan, a Grant-in-Aid for Scientific Research (20591149 and 19591105) from the Ministry of Education, Culture, Sports, Science and Technology, and Grants-in-Aid from the National Institute of Biomedical Innovation and the Sankyo Memorial Foundation, Japan.

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Authors and Affiliations

  1. Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Y Inamoto, M Murata, A Katsumi, Y Ishikawa, K Sugimoto, S Terakura, A Abe, T Matsushita & T Naoe

  2. Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan

    Y Inamoto, Y Kuwatsuka, A Tsujimura, M Onizuka, T Nishida, T Kanie, H Taji, H Iida, R Suzuki, K Miyamura & Y Kodera

  3. Department of Infectious Diseases, Nagoya University Graduate School of Medicine, Nagoya, Japan

    H Kiyoi

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Correspondence to A Katsumi.

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Inamoto, Y., Murata, M., Katsumi, A. et al. Donor single nucleotide polymorphism in the CCR9 gene affects the incidence of skin GVHD. Bone Marrow Transplant 45, 363–369 (2010). https://doi.org/10.1038/bmt.2009.131

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  • DOI: https://doi.org/10.1038/bmt.2009.131

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