Abstract
Chronic GVHD (cGVHD) after allogeneic hematopoietic SCT (HSCT) is characterized by an infiltration of T cells into target organs including the oral mucosa and salivary glands. This study was designed to clarify the molecular mechanism of the local accumulation of pathogenic T cells in cGVHD. The expression of cytokines, chemokines and chemokine receptors in the buccal mucosa (BM), labial salivary glands (LSG) and PBMC from 16 patients with cGVHD after allogeneic HSCT was examined. The mRNA expression of T helper 1 (Th1) and Th2 cytokines, and several chemokines and chemokine receptors was significantly increased in the BM and LSG from cGVHD patients, in comparison with both those in the BM and LSG from controls, respectively, and also with those in the PBMC from cGVHD patients. Furthermore, the mRNA expression of Th2 cytokines, macrophage-derived chemokine and CC chemokine receptor 4 was closely associated with a strong T-cell infiltration in the BM and LSG from cGVHD patients. These results suggest that cGVHD might be initiated and/or maintained by Th1/Th0 cells and thereafter progresses in association with Th2 cell accumulation via the interaction of particular chemokine and chemokine receptors.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Greenspan JS, Daniels TE, Talal N, Sylvester RA . The histopathology of Sjogren's syndrome in labial salivary gland biopsies. Oral Surg Oral Med Oral Pathol 1974; 37: 217–229.
Snider D, Liang H . Early intestinal Th1 inflammation and mucosal T cell recruitment during acute graft-versus-host reaction. J Immunol 2001; 166: 5991–5999.
Atkinson K . Chronic graft-versus-host disease. Bone Marrow Transplant 1990; 5: 69–82.
Lawley TJ, Peck GL, Moutsopoulos HM, Gratwohl AA, Deisseroth AB . Scleroderma, Sjogren-like syndrome, and chronic graft-versus-host disease. Ann Intern Med 1977; 87: 707–709.
Janin-Mercier A, Devergie A, Arrago JP, Brocheriou C, Lemarchand-Venencie F, Rain JD et al. Systemic evaluation of Sjogren-like syndrome after bone marrow transplantation in man. Transplantation 1987; 43: 677–679.
Gratwohl AA, Moutsopoulos HM, Chused TM, Akizuki M, Wolf RO, Sweet JB et al. Sjogren-type syndrome after allogeneic bone-marrow transplantation. Ann Intern Med 1977; 87: 703–706.
Hiroki A, Nakamura S, Shinohara M, Oka M . Significance of oral examination in chronic graft-versus-host disease. J Oral Pathol Med 1994; 23: 209–215.
Nakamura S, Hiroki A, Shinohara M, Gondo H, Ohyama Y, Mouri T et al. Oral involvement in chronic graft-versus-host disease after allogeneic bone marrow transplantation. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996; 82: 556–563.
Hiroki A, Nakamura S, Shinohara M, Gondo H, Ohyama Y, Hayashi S et al. A comparison of glandular involvement between chronic graft-versus-host disease and Sjogren's syndrome. Int J Oral Maxillofac Surg 1996; 25: 298–307.
Axell T, Rundquist L . Oral lichen planus--a demographic study. Community Dent Oral Epidemiol 1987; 15: 52–56.
Ohyama Y, Nakamura S, Matsuzaki G, Shinohara M, Hiroki A, Oka M et al. T-cell receptor V alpha and V beta gene use by infiltrating T cells in labial glands of patients with Sjogren's syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1995; 79: 730–737.
Mouri T, Nakamura S, Ohyama Y, Matsuzaki G, Shinohara M, Kishihara K et al. T cell receptor V alpha and V beta gene usage by tumour-infiltrating lymphocytes in oral squamous cell carcinoma. Cancer Immunol Immunother 1996; 43: 10–18.
Sasaki M, Nakamura S, Ohyama Y, Shinohara M, Ezaki I, Hara H et al. Accumulation of common T cell clonotypes in the salivary glands of patients with human T lymphotropic virus type I-associated and idiopathic Sjogren's syndrome. J Immunol 2000; 164: 2823–2831.
Kawamura E, Nakamura S, Sasaki M, Ohyama Y, Kadena T, Kumamaru W et al. Accumulation of oligoclonal T cells in the infiltrating lymphocytes in oral lichen planus. J Oral Pathol Med 2003; 32: 282–289.
Kumamaru W, Nakamura S, Kadena T, Yamada A, Kawamura E, Sasaki M et al. T-cell receptor Vbeta gene usage by T cells reactive with the tumor-rejection antigen SART-1 in oral squamous cell carcinoma. Int J Cancer 2004; 108: 686–695.
Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL . Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 1986; 136: 2348–2357.
Infante-Duarte C, Horton HF, Byrne MC, Kamradt T . Microbial lipopeptides induce the production of IL-17 in Th cells. J Immunol 2000; 165: 6107–6115.
Puliaev R, Nguyen P, Finkelman FD, Via CS . Differential requirement for IFN-gamma in CTL maturation in acute murine graft-versus-host disease. J Immunol 2004; 173: 910–919.
Weaver CT, Harrington LE, Mangan PR, Gavrieli M, Murphy KM . Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 2006; 24: 677–688.
Teshima T, Maeda Y, Ozaki K . Regulatory T cells and IL-17-producing cells in graft-versus-host disease. Immunotherapy 2011; 3: 833–852.
Fox RI, Kang HI, Ando D, Abrams J, Pisa E . Cytokine mRNA expression in salivary gland biopsies of Sjogren's syndrome. J Immunol 1994; 152: 5532–5539.
Konttinen YT, Kemppinen P, Koski H, Li TF, Jumppanen M, Hietanen J et al. T(H)1 cytokines are produced in labial salivary glands in Sjogren's syndrome, but also in healthy individuals. Scand J Rheumatol 1999; 28: 106–112.
Ohyama Y, Nakamura S, Matsuzaki G, Shinohara M, Hiroki A, Fujimura T et al. Cytokine messenger RNA expression in the labial salivary glands of patients with Sjogren's syndrome. Arthritis Rheum 1996; 39: 1376–1384.
Nakamura S, Ikebe-Hiroki A, Shinohara M, Ohyama Y, Mouri T, Sasaki M et al. An association between salivary gland disease and serological abnormalities in Sjogren's syndrome. J Oral Pathol Med 1997; 26: 426–430.
Wysocki CA, Panoskaltsis-Mortari A, Blazar BR, Serody JS . Leukocyte migration and graft-versus-host disease. Blood 2005; 105: 4191–4199.
Burns WR, Wang Y, Tang PC, Ranjbaran H, Iakimov A, Kim J et al. Recruitment of CXCR3+ and CCR5+ T cells and production of interferon-gamma-inducible chemokines in rejecting human arteries. Am J Transplant 2005; 5: 1226–1236.
Qin S, Rottman JB, Myers P, Kassam N, Weinblatt M, Loetscher M et al. The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions. J Clin Invest 1998; 101: 746–754.
Mancardi S, Vecile E, Dusetti N, Calvo E, Stanta G, Burrone OR et al. Evidence of CXC, CC and C chemokine production by lymphatic endothelial cells. Immunology 2003; 108: 523–530.
Welniak LA, Wang Z, Sun K, Kuziel W, Anver MR, Blazar BR et al. An absence of CCR5 on donor cells results in acceleration of acute graft-vs-host disease. Exp Hematol 2004; 32: 318–324.
Duffner U, Lu B, Hildebrandt GC, Teshima T, Williams DL, Reddy P et al. Role of CXCR3-induced donor T-cell migration in acute GVHD. Exp Hematol 2003; 31: 897–902.
Serody JS, Burkett SE, Panoskaltsis-Mortari A, Ng-Cashin J, McMahon E, Matsushima GK et al. T-lymphocyte production of macrophage inflammatory protein-1alpha is critical to the recruitment of CD8(+) T cells to the liver, lung, and spleen during graft-versus-host disease. Blood 2000; 96: 2973–2980.
Wysocki CA, Burkett SB, Panoskaltsis-Mortari A, Kirby SL, Luster AD, McKinnon K et al. Differential roles for CCR5 expression on donor T cells during graft-versus-host disease based on pretransplant conditioning. J Immunol 2004; 173: 845–854.
Piper KP, Horlock C, Curnow SJ, Arrazi J, Nicholls S, Mahendra P et al. CXCL10-CXCR3 interactions play an important role in the pathogenesis of acute graft-versus-host disease in the skin following allogeneic stem-cell transplantation. Blood 2007; 110: 3827–3832.
Ichiba T, Teshima T, Kuick R, Misek DE, Liu C, Takada Y et al. Early changes in gene expression profiles of hepatic GVHD uncovered by oligonucleotide microarrays. Blood 2003; 102: 763–771.
Imai T, Baba M, Nishimura M, Kakizaki M, Takagi S, Yoshie O . The T cell-directed CC chemokine TARC is a highly specific biological ligand for CC chemokine receptor 4. J Biol Chem 1997; 272: 15036–15042.
Imai T, Nagira M, Takagi S, Kakizaki M, Nishimura M, Wang J et al. Selective recruitment of CCR4-bearing Th2 cells toward antigen-presenting cells by the CC chemokines thymus and activation-regulated chemokine and macrophage-derived chemokine. Int Immunol 1999; 11: 81–88.
Bonecchi R, Bianchi G, Bordignon PP, D'Ambrosio D, Lang R, Borsatti A et al. Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s. J Exp Med 1998; 187: 129–134.
Sallusto F, Lenig D, Mackay CR, Lanzavecchia A . Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes. J Exp Med 1998; 187: 875–883.
Tsunawaki S, Nakamura S, Ohyama Y, Sasaki M, Ikebe-Hiroki A, Hiraki A et al. Possible function of salivary gland epithelial cells as nonprofessional antigen-presenting cells in the development of Sjogren's syndrome. J Rheumatol 2002; 29: 1884–1896.
Pober JS, Gimbrone MA, Lapierre LA, Mendrick DL, Fiers W, Rothlein R et al. Overlapping patterns of activation of human endothelial cells by interleukin 1, tumor necrosis factor, and immune interferon. J Immunol 1986; 137: 1893–1896.
Dustin ML, Springer TA . Lymphocyte function-associated antigen-1 (LFA-1) interaction with intercellular adhesion molecule-1 (ICAM-1) is one of at least three mechanisms for lymphocyte adhesion to cultured endothelial cells. J Cell Biol 1988; 107: 321–331.
Cotran R, Pober J . Endothelial activation: its role in inflammatory and immune reactions. In: Simionescu N, Simionescu M eds. Endothelial Cell Biology. Plenum Press: New York, 1988 pp 335–347.
Acknowledgements
We express our gratitude to Dr BT Quinn for his critical review of the article. This study was supported in part by grants from the Ministry of Education, Science and Culture of Japan.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Hayashida, JN., Nakamura, S., Toyoshima, T. et al. Possible involvement of cytokines, chemokines and chemokine receptors in the initiation and progression of chronic GVHD. Bone Marrow Transplant 48, 115–123 (2013). https://doi.org/10.1038/bmt.2012.100
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/bmt.2012.100
Keywords
This article is cited by
-
Durable responses to ibrutinib in patients with relapsed CLL after allogeneic stem cell transplantation
Bone Marrow Transplantation (2016)
-
Treatment of refractory sclerodermatous chronic graft-versus-host disease with intravenous lidocaine infusions
Bone Marrow Transplantation (2014)