Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Graft-Versus-Tumor Effects

Cutaneous lymphocyte antigen-positive T cells may predict the development of acute GVHD: alterations and differences of CLA+ T- and NK-cell fractions

Abstract

Acute GVHD (aGVHD) is a serious complication after allogeneic SCT (allo-SCT). However, an adequate immunological index is not yet available for assessing its severity. We analyzed the fraction of cutaneous lymphocyte antigen (CLA)+ cells in peripheral blood T and natural killer (NK) cells in 33 patients and evaluated its association with aGVHD. The CLA+ T-cell fraction often increased 3–7 days before the onset of aGVHD, and the maximum percentage of CLA+ T cells in grades II–IV aGVHD cases was significantly higher than that in grade 0 or I aGVHD (P<0.01). When the cutoff value of the maximum CLA+ T-cell percentage was set at 20%, any higher percentage was a significant risk for the development of severe aGVHD (P<0.0001). The maximum CLA+ T-cell percentage was significantly correlated with a high body temperature, low percutaneous oxygen saturation, and fibrinogen/fibrin degradation product D-dimer level. The post-allo-SCT CLA+ T cells exhibited a high ability to produce IL-2 and IFN-γ, and may be the effectors and immunological markers for aGVHD. The CLA+ NK-cell-fraction steadily increased 2–4 weeks after allo-SCT but was not influenced by aGVHD. The CLA+ T-cell percentage may predict the development of severe aGVHD in clinical settings.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Sullivan KM . Graft-vs-Host Disease. In: Blume KG, Fornman SJ, Applebaum FR (eds). Thomas' Hematopoietic Cell Transplantation, 3rd edn. Blackwell: Oxford, 2004, pp 635–664.

    Google Scholar 

  2. Ferrara JLM, Deeg HJ . Graft versus host disease. N Engl J Med 1991; 324: 667–674.

    Article  CAS  Google Scholar 

  3. Goker H, Haznedaroglu IC, Chao NJ . Acute graft-vs-host disease: pathobiology and management. Exp Hematol 2001; 29: 259–277.

    Article  CAS  Google Scholar 

  4. Ferrara JL . Pathogenesis of acute graft-versus-host disease: cytokines and cellular effectors. J Hematother Stem Cell Res 2000; 9: 299–306.

    Article  CAS  Google Scholar 

  5. Hill GR, Crawford GM, Cooke KR, Brinson YS, Pan L, Ferrara JL . Total body irradiation and acute graft-versus-host disease: the role of gastrointestinal damage and inflammatory cytokines. Blood 1997; 90: 3204–3213.

    CAS  PubMed  Google Scholar 

  6. Ferrara JL, Cooke KR, Teshima T . The pathophysiology of acute graft-versus-host disease. Int J Hematol 2003; 78: 181–187.

    Article  CAS  Google Scholar 

  7. Nestel F, Kichian K, You-Ten K, Desbarats J, Price K, Lapp W et al. The role of endotoxin in the pathogenesis of acute graft-versus-host disease. In: Ferrara JL, Deeg HJ, Burakoff SJ (eds). Graft-vs-Host Disease, 2nd edn. Marcel Dekker Inc.: New York, 1996, pp 513–516.

  8. Butcher EC, Williams M, Youngman K, Rott L, Briskin M . Lymphocyte trafficking and regional immunity. Adv Immunol 1999; 72: 209–253.

    Article  CAS  Google Scholar 

  9. Campbell DJ, Butcher EC . Rapid acquisition of tissue specific homing phenotypes by CD4(+) T cell activated in cutaneous or mucosal lymphoid tissue. J Exp Med 2002; 195: 135–141.

    Article  CAS  Google Scholar 

  10. Picker LJ, Treer JR, Ferguson-Darnell B, Collins PA, Bergstresser PR, Terstappen LW . Control of lymphocyte recirculation in man. II. Differential regulation of the cutaneous lymphocyte-associated antigen, a tissue-selective homing receptor for skin-homing T cells. J Immunol 1993; 150: 1122–1136.

    CAS  PubMed  Google Scholar 

  11. Fuhlbrigge RC, Kieffer JD, Armerding D, Kupper TS . Cutaneous lymphocyte antigen is a specialized form of PSGL-1 expressed on skin-homing T cells. Nature 1997; 389: 978–981.

    Article  CAS  Google Scholar 

  12. Berg EL, Yoshino T, Rott LS, Robinson MK, Warnock RA, Kishimoto TK et al. The cutaneous lymphocyte antigen is a skin lymphocyte homing receptor for the vascular lectin endothelial cell-leukocyte adhesion molecule 1. J Exp Med 1991; 174: 1461–1466.

    Article  CAS  Google Scholar 

  13. Leung DY, Gately M, Trumble A, Ferguson-Darnell B, Schlievert PM, Picker LJ . Bacterial superantigens induce T cell expression of the skin selective homing receptor, the cutaneous lymphocyte-associated antigen, via stimulation of interleukin 12 production. J Exp Med 1995; 181: 747–753.

    Article  CAS  Google Scholar 

  14. Tsuchiyama J, Yoshino T, Toba K, Harada N, Nishiuchi R, Akagi T et al. Induction and characterization of cutaneous lymphocyte antigen (CLA) on natural killer cells. Br J Hematol 2002; 118: 654–662.

    Article  CAS  Google Scholar 

  15. Faaij CM, Lankester AC, Spierings E, Hoogeboom M, Bowman EP, Bierings M et al. A possible role for CCL27/CTACK-CCR10 interaction in recruiting CD4+ T cells in human graft-versus-host disease. Br J Hematol 2006; 133: 538–549.

    Article  Google Scholar 

  16. Scharf SJ, Smith AG, Hansen JA, McFarland C, Erlich HA . Quantitative determination of bone marrow transplant engraftment using fluorescent polymerase chain reaction primers for human identity markers. Blood 1995; 85: 1954–1963.

    CAS  PubMed  Google Scholar 

  17. Andrew DP, Ruffing N, Kim CH, Miao W, Heath H, Li Y et al. C-C chemokine receptor 4 expression defines a major subset of circulating nonintestinal memory T cells of both Th1 and Th2 potential. J Immunol 2001; 166: 103–111.

    Article  CAS  Google Scholar 

  18. Farrell AM, Antrobus P, Simpson D, Powell S, Chapel HM, Ferry BL . A rapid flow cytometric assay to detect CD4+ and CD8+ T-helper (Th) 0, Th1 and Th2 cells in whole blood and its application to study cytokine levels in atopic dermatitis before and after cyclosporin therapy. Br J Dermatol 2001; 144: 24–33.

    Article  CAS  Google Scholar 

  19. Ohara T, Koyama K, Kusunoki Y, Hayashi T, Tsuyama N, Kubo Y et al. Memory functions and death proneness in three CD4+CD45RO+ human T cell subsets. J Immunol 2002; 169: 39–48.

    Article  CAS  Google Scholar 

  20. Beilhack A, Schultz S, Baker J, Beilhack FG, Nihsimura 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  Google Scholar 

  21. Anasetti C, Velardi A . Hematopoietic cell transplantation from HLA partially matched related donors. In: Blume KG, Fornman SJ, Applebaum FR (eds). Thomas' Hematopoietic cell transplantation, 3rd edn. Blackwell: Oxford, 2004, pp 1116–1131.

    Google Scholar 

  22. Hsieh CS, Macatonia SE, Tripp CS, Wolf SF, O'Garra A, Murphy KM . Development of Th-1 CD4+ cells through IL-12 produced by Listeria-induced macrophages. Science 1993; 260: 547–549.

    Article  CAS  Google Scholar 

  23. Scott P . IL-12: initiation cytokine for cell mediated immunity. Science 1993; 260: 496–497.

    Article  CAS  Google Scholar 

  24. Rosenstein M, Ettinghasusen SE, Rosenberg SA . Extravasation of intravascular fluid mediated by the systemic administration of recombinant interleukin 2. J Immunol 1986; 137: 1735–1742.

    CAS  PubMed  Google Scholar 

  25. Thompson JA, Cox WW, Lindgren CG, Collins C, Neraas KA, Bonnem EM et al. Subcutaneous gamma interferon in cancer patients: toxicity, pharmacokinetics, and immunomodulatory effects. Cancer Immunol Immunother 1987; 25: 47–53.

    Article  CAS  Google Scholar 

  26. Mahmoud HH, Pui CH, Kennedy W, Jaffe HS, Crist WM, Murphy SB . Phase 1 study of recombinant human interferon gamma in children with relapsed acute leukemia. Leukemia 1992; 6: 1181–1191.

    CAS  PubMed  Google Scholar 

  27. Petrovic A, Alpdogan O, Willis LM, Eng JM, Greenberg AS, Kappel BJ et al. LPAM (α4β7 integrin) is an important homing integrin on alloreactive T cells in the development of intestinal graft-versus-host disease. Blood 2004; 103: 1542–1547.

    Article  CAS  Google Scholar 

  28. Stacey N, Cox J, Loblay R, Crosbie J . Neuraminidase pretreatment of donor lymphocytes and graft-versus-host disease. Exp Hematol 1989; 17: 273–277.

    CAS  PubMed  Google Scholar 

  29. Haddad W, Cooper C J, Zhang Z, Brown JB, Zhu Y, Issekutz A et al. P-selectin and P-selectin glycoprotein ligand 1 are major determinants for Th1 cell recruitment to Nonlymphoid effector sites in the intestinal lamina propria. J Exp Med 2003; 198: 369–377.

    Article  CAS  Google Scholar 

  30. Schuyser E, Struyf S, Damme JV . The CC chemokine CCL20 and its receptor CCR6. Cytokine Growth Factor Rev 2003; 14: 409–426.

    Article  Google Scholar 

  31. Sugita S, Kohno T, Yamamoto K, Imaizumi Y, Nakajima H, Ishimaru T et al. Induction of macrophage-inflammatory protein 3 gene expression by TNF-α dependent NF-κB activation. J Immunol 2002; 168: 5621–5628.

    Article  CAS  Google Scholar 

  32. Lukacs NW, Prosser DM, Wiekowski M, Lira SA, Cook DN . Requirement for the chemokine receptor CCR6 in allergic pulmonary inflammation. J Exp Med 2001; 194: 551–555.

    Article  CAS  Google Scholar 

  33. Saeki H, Tamaki K . Thymus and activation regulated chemokine (TARC)/CCL17 and skin diseases. J Dermatol Sci 2006; 43: 75–84.

    Article  CAS  Google Scholar 

  34. Horikawa T, Nakayama T, Hikita I, Yamada H, Fujisawa R, Bito T et al. IFN-gamma-inducible expression of thymus and activation-regulated chemokine/CCL17 and macrophage-derived chemokine/CCL22 in epidermal keratinocytes and their roles in atopic dermatitis. Int Immunol 2002; 14: 767–773.

    Article  CAS  Google Scholar 

  35. Berin MC, Eckmann L, Broide DH, Kagnoff MF . Regulated production of the T helper 2-type T-cell chemoattractant TARC by human bronchial epithelial cells in vitro and in human lung xenografts. Am J Respir Cell Mol Biol 2001; 24: 382–389.

    Article  CAS  Google Scholar 

  36. Yamashita U, Kuroda E . Regulation of macrophage-derived chemokine (MDC, CCL22) production. Crit Rev Immunol 2002; 22: 105–114.

    Article  CAS  Google Scholar 

  37. Lloyd CM, Rankin SM . Chemokines in allergic airway disease. Curr Opin Pharmacol 2003; 3: 443–447.

    Article  CAS  Google Scholar 

  38. Terada N, Nomura T, Kim WJ, Otsuka Y, Takahashi R, Yamashita T et al. Expression of C-C chemokine TARC in human nasal mucosa and its regulation by cytokines. Clin Exp Allergy 2001; 12: 1923–1931.

    Article  Google Scholar 

  39. Nasu K, Sun B, Nishida M, Fukuda J, Narahara H, Miyakawa I . Cultured human endometrial epithelial cells produce thymus and activation-regulated chemokine with stimulation of interleukin-4 and interleukin-13. Fertil Steril 2004; 82: 1014–1018.

    Article  CAS  Google Scholar 

  40. Fukuda K, Fujitsu Y, Seki K, Kumagai N, Nishida T . Differential expression of thymus- and activation-regulated chemokine (CCL17) and macrophage-derived chemokine (CCL22) by human fibroblasts from cornea, skin, and lung. J Allergy Clin Immunol 2003; 111: 520–526.

    Article  CAS  Google Scholar 

  41. Mutis T, Gillespie G, Schrama E, Falkenburg JH, Moss P, Goulmy E . Tetrameric HLA class 1-minor histocompatibility antigen peptide complexes demonstrate minor histocompatibility anitgen-specific cytotoxic T lymphoctes in patients with graft-versus-host disease. Nat Med 1999; 5: 839–842.

    Article  CAS  Google Scholar 

  42. Dickinson AM, Wang XN, Sviland L, Vyth-Dreese FA, Jackson GH, Schumacher TN et al. In situ dissection of the graft-versus-host activities of cytotoxic T-cells specific for minor histocompatibility antigens. Nat Med 2002; 8: 410–414.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the medical and nursing staff of Niigata University Medical and Dental Hospital for their help in patient care; the laboratory staff for examining the clinical samples; Ms M Sakaue and Ms H Itoh for their technical assistance; Dr R Nishiuchi (Department of Pediatrics, Okayama University Graduate School of Medical and Dental Sciences), Dr T Teshima, Dr M Harada (Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences), for their valuable advice.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to J Tsuchiyama.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tsuchiyama, J., Yoshino, T., Saito, T. et al. Cutaneous lymphocyte antigen-positive T cells may predict the development of acute GVHD: alterations and differences of CLA+ T- and NK-cell fractions. Bone Marrow Transplant 43, 863–873 (2009). https://doi.org/10.1038/bmt.2008.392

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2008.392

Keywords

This article is cited by

Search

Quick links