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-Host Disease

Endothelial damage is aggravated in acute GvHD and could predict its development

Bone Marrow Transplantation volume 52, pages 1317–1325 (2017)Cite this article

Subjects

Abstract

The aim of the present study was to explore whether there is enhanced endothelial dysfunction in patients developing acute GvHD (aGvHD) after allogeneic hematopoietic cell transplantation (allo-HCT) and to identify biomarkers with predictive and/or diagnostic value. In in vitro experiments, endothelial cells (ECs) were exposed to serum from patients with (aGvHD, n=31) and without (NoGvHD, n=13) aGvHD, to evaluate changes in surface adhesion receptors, the reactivity of the extracellular matrix by measuring the presence of Von Willebrand factor (VWF) and platelet adhesion, and the activation of intracellular signaling proteins. Plasma levels of VWF, ADAMTS-13, TNF receptor 1 (TNFR1), soluble vascular cell adhesion molecule 1 and soluble intercellular adhesion molecule 1 were also measured. In vitro results showed a more marked proinflammatory and prothrombotic phenotype in ECs in association with aGvHD. Regarding circulating biomarkers, levels of VWF and TNFR1 above an optimal cutoff score, taken independently or combined, at day 7 after allo-HCT, would be able to positively predict that around 90% of patients will develop aGvHD. Our results demonstrate that endothelial damage is aggravated in those allo-HCT recipients developing aGvHD, and that VWF and TNFR1 are promising predictive aGvHD biomarkers. These findings could contribute to improve the understanding of the pathophysiology of aGvHD.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Holtan SG, Pasquini M, Weisdorf DJ . Acute graft-versus-host disease : a bench-to-bedside update. Blood 2014; 124: 363–374.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Cutler C, Antin JH . Manifestations and treatment of acute graft-versus-host disease. Thomas Hematop Cell Transplant 2016; 5: 1012–1025.

    Article  Google Scholar 

  3. Carreras E . Veno-occlusive disease of the liver after hemopoietic cell transplantation. Eur J Haematol 2000; 64: 281–291.

    Article  CAS  PubMed  Google Scholar 

  4. George JN, Li X, McMinn JR, Terrell DR, Vesely SK, Selby GB . Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome following allogeneic HPC transplantation: a diagnostic dilemma. Transfusion 2004; 44: 294–304.

    PubMed  Google Scholar 

  5. Carreras E, Fernández-Avilés F, Silva L, Guerrero M, Fernández de Larrea C, Martínez C et al. Engraftment syndrome after auto-SCT: analysis of diagnostic criteria and risk factors in a large series from a single center. Bone Marrow Transplant 2010; 45: 1417–1422.

    Article  CAS  PubMed  Google Scholar 

  6. Nürnberger W, Willers R, Burdach S, Göbel U . Risk factors for capillary leakage syndrome after bone marrow transplantation. Ann Hematol 1997; 74: 221–224.

    Article  PubMed  Google Scholar 

  7. Carreras E, Diaz-Ricart M . The role of the endothelium in the short-term complications of hematopoietic SCT. Bone Marrow Transplant 2011; 46: 1495–1502.

    Article  CAS  PubMed  Google Scholar 

  8. Tichelli A, Gratwohl A . Vascular endothelium as ‘novel’ target of graft-versus-host disease. Best Pract Res Clin Haematol 2008; 21: 139–148.

    Article  CAS  PubMed  Google Scholar 

  9. Biedermann BC . Vascular endothelium and graft-versus-host disease. Best Pract Res Clin Haematol 2008; 21: 129–138.

    Article  CAS  PubMed  Google Scholar 

  10. Nagy ZA . Alloreactivity: an old puzzle revisited. Scand J Immunol 2012; 75: 463–470.

    Article  CAS  PubMed  Google Scholar 

  11. Blazar BR, Murphy WJ, Abedi M . Advances in graft-versus-host disease biology and therapy. Nat Rev Immunol 2012; 12: 443–458.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Petersdorf EW . Genetics of graft-versus-host disease: the major histocompatibility complex. Blood Rev 2013; 27: 1–12.

    Article  CAS  PubMed  Google Scholar 

  13. Sung AD, Chao NJ . Concise Review: acute graft-versus-host disease: Immunobiology, prevention, and treatment. Stem Cells Transl Med 2013; 2: 25–32.

    Article  CAS  PubMed  Google Scholar 

  14. Simonsen M . Graft-versus-host-reactions: the history that never was, and the way things happened to happen. Immunol Rev 1985; 88: 5–23.

    Article  CAS  PubMed  Google Scholar 

  15. Chakraverty R, Sykes M . The role of antigen-presenting cells in triggering graft-versus-host disease and graft-versus-leukemia. Blood 2007; 110: 9–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ferrara J, Levine J, Reddy P, Holler E . Graft-versus-host disease. Lancet 2009; 373: 1550–1561.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Markey KA, MacDonald KPA, Hill GR . The biology of graft-versus-host disease: experimental systems instructing clinical practice. Blood 2014; 124: 354–362.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhou H, Li Q, Zou P, You Y . Endothelial cells: a novel key player in immunoregulation in acute graft-versus-host disease? Med Hypotheses 2009; 72: 567–569.

    Article  CAS  PubMed  Google Scholar 

  19. Pober JS, Sessa WC . Evolving functions of endothelial cells in inflammation. Nat Rev Immunol 2007; 7: 803–815.

    Article  CAS  PubMed  Google Scholar 

  20. Deanfield JE, Halcox JP, Rabelink TJ . Endothelial function and dysfunction: testing and clinical relevance. Circulation 2007; 115: 1285–1295.

    Article  PubMed  Google Scholar 

  21. Penack O, Holler E, Van Den Brink MRM . Graft-versus-host disease: regulation by microbe-associated molecules and innate immune receptors. Blood 2010; 115: 1865–1872.

    Article  CAS  PubMed  Google Scholar 

  22. Davey MP, Martin TM, Planck SR, Lee J, Zamora D, Rosenbaum JT . Human endothelial cells express NOD2/CARD15 and increase IL-6 secretion in response to muramyl dipeptide. Microvasc Res 2006; 71: 103–107.

    Article  CAS  PubMed  Google Scholar 

  23. Oh H-M, Lee H-J, Seo G-S, Choi EY, Kweon SH, Chun CH et al. Induction and localization of NOD2 protein in human endothelial cells. Cell Immunol 2005; 237: 37–44.

    Article  CAS  PubMed  Google Scholar 

  24. Palomo M, Diaz-Ricart M, Carbo C, Rovira M, Fernandez-Aviles F, Martine C et al. Endothelial dysfunction after hematopoietic stem cell transplantation: role of the conditioning regimen and the type of transplantation. Biol Blood Marrow Transplant 2010; 16: 985–993.

    Article  CAS  PubMed  Google Scholar 

  25. Palomo M, Diaz-Ricart M, Carbo C, Rovira M, Fernandez-Aviles F, Escolar G et al. The release of soluble factors contributing to endothelial activation and damage after hematopoietic stem cell transplantation is not limited to the allogeneic setting and involves several pathogenic mechanisms. Biol Blood Marrow Transplant 2009; 15: 537–546.

    Article  CAS  PubMed  Google Scholar 

  26. Biedermann BC, Sahner S, Gregor M, Tsakiris DA, Jeanneret C, Pober JS et al. Endothelial injury mediated by cytotoxic T lymphocytes and loss of microvessels in chronic graft versus host disease. Lancet 2002; 359: 2078–2083.

    Article  PubMed  Google Scholar 

  27. Salat C, Holler E, Kolb HJ, Pihusch R, Reinhardt B, Hiller E . Endothelial cell markers in bone marrow transplant recipients with and without acute graft-versus-host disease. Bone Marrow Transplant 1997; 19: 909–914.

    Article  CAS  PubMed  Google Scholar 

  28. Luft T, Dietrich S, Falk C, Conzelmann M, Hess M, Benner A et al. Steroid-refractory GVHD: T-cell attack within a vulnerable endothelial system. Blood 2011; 118: 1685–1692.

    Article  CAS  PubMed  Google Scholar 

  29. Rachakonda SP, Penack O, Dietrich S, Blau O, Blau IW, Radujkovic A et al. Single-nucleotide polymorphisms within the thrombomodulin gene (THBD) predict mortality in patients with graft-versus-host disease. J Clin Oncol 2014; 32: 3421–3428.

    Article  PubMed  Google Scholar 

  30. Ades EW, Candal FJ, Swerlick RA, George VG, Summers S, Bosse DC et al. HMEC-1: establishment of an immortalized human microvascular endothelial cell line. J Invest Dermatol 1992; 99: 683–690.

    Article  CAS  PubMed  Google Scholar 

  31. Carmona A, Díaz-Ricart M, Palomo M, Molina P, Pino M, Rovira M et al. Distinct deleterious effects of cyclosporine and tacrolimus and combined tacrolimus-sirolimus on endothelial cells: protective effect of defibrotide. Biol Blood Marrow Transplant 2013; 19: 1439–1445.

    Article  CAS  PubMed  Google Scholar 

  32. Caballo C, Palomo M, Cases A, Galán AM, Molina P, Vera M et al. NFκB in the development of endothelial activation and damage in uremia: an in vitro approach. PLoS ONE 2012; 7: e43374.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Cid J, Caballo C, Pino M, Galan AM, Martínez N, Escolar G et al. Quantitative and qualitative analysis of coagulation factors in cryoprecipitate prepared from fresh-frozen plasma inactivated with amotosalen and ultraviolet A light. Transfusion 2013; 53: 600–605.

    Article  CAS  PubMed  Google Scholar 

  34. Hajian-Tilaki K . Receiver operating characteristic (ROC) curve analysis for medical diagnostic test evaluation. Caspian J Intern Med 2013; 4: 627–635.

    PubMed  PubMed Central  Google Scholar 

  35. Jones CM, Athanasiou T . Diagnostic accuracy meta-analysis: review of an important tool in radiological research and decision making. Br J Radiol 2009; 82: 441–446.

    Article  CAS  PubMed  Google Scholar 

  36. Almici C, Skert C, Verardi R, Di Palma A, Bianchetti A, Neva A et al. Changes in circulating endothelial cells count could become a valuable tool in the diagnostic definition of acute graft-versus-host disease. Transplantation 2014; 98: 706–712.

    Article  CAS  PubMed  Google Scholar 

  37. Denton MD, Geehan CS, Alexander SI, Sayegh MH, Briscoe DM . Endothelial cells modify the costimulatory capacity of transmigrating leukocytes and promote CD28-mediated CD4(+) T cell alloactivation. J Exp Med 1999; 190: 555–566.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ala A, Dhillon AP, Hodgson HJ . Role of cell adhesion molecules in leukocyte recruitment in the liver and gut. Int J Exp Pathol 2003; 84: 1–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Castor MGM, Pinho V, Teixeira MM . The role of chemokines in mediating graft versus host disease: opportunities for novel therapeutics. Front Pharmacol 2012; 3: 1–13.

    Article  Google Scholar 

  40. Roux PP, Blenis J . ERK and p38 MAPK-activated protein kinases : a family of protein kinases with diverse biological functions. Microbiol Mol Biol Rev 2004; 68: 320–344.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Davies C, Tournier C . Exploring the function of the JNK (c-Jun N-terminal kinase) signalling pathway in physiological and pathological processes to design novel therapeutic strategies. Biochem Soc Trans 2012; 40: 85–89.

    Article  CAS  PubMed  Google Scholar 

  42. Mannucci PM . von Willebrand factor. Arterioscler Thromb Vasc Biol 1998; 18: 1359–1362.

    Article  CAS  PubMed  Google Scholar 

  43. Paczesny S, Krijanovski OI, Braun TM, Choi SW, Clouthier SG, Kuick R et al. A biomarker panel for acute graft-versus-host disease. Blood 2009; 113: 273–278.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Paczesny S, Levine JE, Braun TM, Ferrara JL . Plasma biomarkers in graft-versus-host disease: a new era? Biol Blood Marrow Transplant 2009; 15: 33–38.

    Article  PubMed  Google Scholar 

  45. Carman CV, Martinelli R . T Lymphocyte–endothelial interactions: emerging understanding of trafficking and antigen-specific immunity. Front Immunol 2015; 6: 603.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Choi J, Enis DR, Koh KP, Shiao SL, Pober JST . lymphocyte–endothelial cell interactions. Annu Rev Immunol 2004; 22: 683–709.

    Article  CAS  PubMed  Google Scholar 

  47. Zarubin T, Han J . Activation and signaling of the p38 MAP kinase pathway. Cell Res 2005; 15: 11–18.

    Article  CAS  PubMed  Google Scholar 

  48. Tatekawa S, Kohno A, Ozeki K, Watamoto K, Ueda N, Yamaguchi Y et al. A novel diagnostic and prognostic biomarker panel for endothelial cell damage-related complications in allogeneic transplantation. Biol Blood Marrow Transplant 2016; 22: 1573–1581.

    Article  CAS  PubMed  Google Scholar 

  49. Choi SW, Kitko CL, Braun T, Paczesny S, Yanik G, Mineishi S et al. Change in plasma tumor necrosis factor receptor 1 levels in the first week after myeloablative allogeneic transplantation correlates with severity and incidence of GVHD and survival. Blood 2008; 112: 1539–1542.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Levine JE, Braun TM, Harris AC, Holler E, Taylor A, Miller H et al. A prognostic score for acute graft-versus-host disease based on biomarkers: a multicenter study. Lancet Haematol 2015; 2: e21–e29.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank the primary hemostasis laboratory group at Hospital Clinic de Barcelona for the contribution to the performing of some experiments and technical support. This research has been partially supported by Jazz Pharmaceuticals plc/Gentium, Inc. This study has been partially supported by two grants from the German Jose Carreras Leukaemia Foundation (R 07/41v and 11 R/2016), CERCA Programme/Generalitat de Catalunya.

Author information

Author notes

  1. E Mir, M Palomo, E Carreras and M Diaz-Ricart: Barcelona Endothelium Team.

Authors and Affiliations

  1. Josep Carreras Research Institute, Hospital Clinic Campus, University of Barcelona, Barcelona, Spain

    E Mir, M Palomo & E Carreras

  2. Hemotherapy and Hemostasis Department, CDB, IDIBAPS, Hospital Clinic, University of Barcelona, Barcelona, Spain

    E Mir, M Palomo, A Pereira, G Escolar & M Diaz-Ricart

  3. Stem Cell Transplantation Unit, IDIBAPS, Hospital Clinic, University of Barcelona, Barcelona, Spain

    M Rovira

  4. Department of Hematology, Oncology and Tumorimmunology, Charité Campus Virchow, Berlin, Germany

    O Penack

  5. Department of Hematology and Oncology, University Clinic Regensburg, Regensburg, Germany

    E Holler

Authors
  1. E Mir
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Palomo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Rovira
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Pereira
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G Escolar
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. O Penack
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. E Holler
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. E Carreras
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M Diaz-Ricart
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M Diaz-Ricart.

Ethics declarations

Competing interests

EC and OP declare conflict of interest with Jazz Pharmaceuticals plc/Gentium, Inc. as members of expert panel and speakers Bureau. All other authors declare no other conflict of interest.

Additional information

Supplementary Information accompanies this paper on Bone Marrow Transplantation website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mir, E., Palomo, M., Rovira, M. et al. Endothelial damage is aggravated in acute GvHD and could predict its development. Bone Marrow Transplant 52, 1317–1325 (2017). https://doi.org/10.1038/bmt.2017.121

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2017.121

This article is cited by

Search

Advanced search

Quick links