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:

Stem cell transplantation

Extracellular vesicles as potential biomarkers of acute graft-vs-host disease

Leukemia volume 32, pages 765–773 (2018)Cite this article

Subjects

Abstract

Acute graft-vs-host disease (GVHD) is a serious complication after allografting. We carried out an exploratory study to investigate a potential correlation of surface antigens on extracellular vesicles (EVs) and acute GVHD. EVs were extracted from serum samples from 41 multiple myeloma patients who underwent allografting. EVs were characterized by flow cytometry using a panel of 13 antibodies against specific membrane proteins that were reported to be predictive of acute GVHD. We observed a correlation between three potential biomarkers expressed on EV surface and acute GVHD onset by both logistic regression analysis and Cox proportional hazard model. In our study, CD146 (MCAM-1) was correlated with an increased risk—by almost 60%—of developing GVHD, whereas CD31 and CD140-α (PECAM-1 and PDGFR-α) with a decreased risk—by almost 40 and 60%, respectively. These biomarkers also showed a significant change in signal level from baseline to the onset of acute GVHD. Our novel study encourages future investigations into the potential correlation between EVs and acute GVHD. Larger prospective multicenter studies are currently in progress.

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

Similar content being viewed by others

References

  1. Reddy P, Ferrara JLM . Immunobiology of acute graft-versus-host disease. Blood Rev 2003; 17: 187–194.

    Article  PubMed  Google Scholar 

  2. Pidala J, Kim J, Anasetti C, Nishihori T, Betts B, Field T et al. The global severity of chronic graft-versus-host disease, determined by National Institutes of Health consensus criteria, is associated with overall survival and non-relapse mortality. Haematologica 2011; 96: 1678–1684.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Storb R, Gyurkocza B, Storer BE, Sorror ML, Blume K, Niederwieser D et al. Graft-versus-host disease and graft-versus-tumor effects after allogeneic hematopoietic cell transplantation. J Clin Oncol 2013; 31: 1530–1538.

    Article  CAS  PubMed  Google Scholar 

  4. Harris AC, Ferrara JLM, Levine JE . Advances in predicting acute GVHD. Br J Haematol 2013; 160: 288–302.

    Article  CAS  PubMed  Google Scholar 

  5. Hansen JA, Chien JW, Warren EH, Zhao LP, Martin PJ . Defining genetic risk for graft-versus-host disease and mortality following allogeneic hematopoietic stem cell transplantation. Curr Opin Hematol 2010; 17: 483–492.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Xiao B, Wang Y, Li W, Baker M, Guo J, Corbet K et al. Plasma microRNA signature as a noninvasive biomarker for acute graft-versus-host disease. Blood 2013; 122: 3365–3375.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ranganathan P, Heaphy CEA, Costinean S, Stauffer N, Na C, Hamadani M et al. Regulation of acute graft-versus-host disease by microRNA-155. Blood 2012; 119: 4786–4797.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Leonhardt F, Grundmann S, Behe M, Bluhm F, Dumont RA, Braun F et al. Inflammatory neovascularization during graft-versus-host disease is regulated by αv integrin and miR-100. Blood 2013; 121: 3307–3318.

    Article  CAS  PubMed  Google Scholar 

  9. Gimondi S, Dugo M, Vendramin A, Bermema A, Biancon G, Cavané A et al. Circulating miRNA panel for prediction of acute graft-versus-host disease in lymphoma patients undergoing matched unrelated hematopoietic stem cell transplantation. Exp Hematol 2016; 44: 624–634.

    Article  CAS  PubMed  Google Scholar 

  10. Toubai T, Tanaka J, Paczesny S, Shono Y, Reddy P, Imamura M . Role of cytokines in the pathophysiology of acute graft-versus-host disease (GVHD): are serum/plasma cytokines potential biomarkers for diagnosis of acute GVHD following allogeneic hematopoietic cell transplantation (Allo-HCT)? Curr Stem Cell Res Ther 2012; 7: 229–239.

    Article  CAS  PubMed  Google Scholar 

  11. Hori T, Naishiro Y, Sohma H, Suzuki N, Hatakeyama N, Yamamoto M et al. CCL8 is a potential molecular candidate for the diagnosis of graft-versus-host disease. Blood 2008; 111: 4403–4412.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ali AM, DiPersio JF, Schroeder MA . The role of biomarkers in the diagnosis and risk stratification of acute graft-versus-host disease: a systematic review. Biol Blood Marrow Transplant 2016; 22: 1552–1564.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Majka M, Janowska-Wieczorek A, Ratajczak J, Ehrenman K, Pietrzkowski Z, Kowalska MA et al. Numerous growth factors, cytokines, and chemokines are secreted by human CD34(+) cells, myeloblasts, erythroblasts, and megakaryoblasts and regulate normal hematopoiesis in an autocrine/paracrine manner. Blood 2001; 97: 3075–3085.

    Article  CAS  PubMed  Google Scholar 

  14. Ratajczak J, Wysoczynski M, Hayek F, Janowska-Wieczorek A, Ratajczak MZ . Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication. Leukemia 2006; 20: 1487–1495.

    Article  CAS  PubMed  Google Scholar 

  15. Ratajczak J, Miekus K, Kucia M, Zhang J, Reca R, Dvorak P et al. Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery. Leukemia 2006; 20: 847–856.

    Article  CAS  PubMed  Google Scholar 

  16. Yáñez-Mó M, PR-M Siljander, Andreu Z, Zavec AB, Borràs FE, Buzas EI et al. Biological properties of extracellular vesicles and their physiological functions. J Extracell Vesicles 2015; 4: 27066.

    Article  PubMed  Google Scholar 

  17. Chiam K, Wang T, Watson DI, Mayne GC, Irvine TS, Bright T et al. Circulating serum exosomal miRNAs as potential biomarkers for esophageal adenocarcinoma. J Gastrointest Surg 2015; 19: 1208–1215.

    Article  PubMed  Google Scholar 

  18. Hornick NI, Huan J, Doron B, Goloviznina NA, Lapidus J, Chang BH et al. Serum exosome microRNA as a minimally-invasive early biomarker of AML. Sci Rep 2015; 5: 11295.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Matsumura T, Sugimachi K, Iinuma H, Takahashi Y, Kurashige J, Sawada G et al. Exosomal microRNA in serum is a novel biomarker of recurrence in human colorectal cancer. Br J Cancer 2015; 113: 275–281.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Preston RA, Jy W, Jimenez JJ, Mauro LM, Horstman LL, Valle M et al. Effects of severe hypertension on endothelial and platelet microparticles. Hypertension 2003; 41: 211–217.

    Article  CAS  PubMed  Google Scholar 

  21. Paczesny S . Discovery and validation of graft-versus-host disease biomarkers. Blood 2013; 121: 585–594.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Pidala J, Sarwal M, Roedder S, Lee SJ . Biologic markers of chronic GVHD. Bone Marrow Transplant 2014; 49: 324–331.

    Article  CAS  PubMed  Google Scholar 

  23. August KJ, Chiang K-Y, Bostick RM, Flanders WD, Waller EK, Langston A et al. Biomarkers of immune activation to screen for severe, acute GVHD. Bone Marrow Transplant 2011; 46: 601–604.

    Article  CAS  PubMed  Google Scholar 

  24. Ahmed SS, Wang XN, Norden J, Pearce K, El-Gezawy E, Atarod S et al. Identification and validation of biomarkers associated with acute and chronic graft versus host disease. Bone Marrow Transplant 2015; 50: 1563–1571.

    Article  CAS  PubMed  Google Scholar 

  25. Levine JE, Paczesny S, Sarantopoulos S . Clinical applications for biomarkers of acute and chronic graft-versus-host disease. Biol Blood Marrow Transplant 2012; 18: S116–S124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Paczesny S, Raiker N, Brooks S, Mumaw C . Graft-versus-host disease biomarkers: omics and personalized medicine. Int J Hematol 2013; 98: 275–292.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bruno B, Rotta M, Patriarca F, Mordini N, Allione B, Carnevale-Schianca F et al. A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med 2007; 356: 1110–1120.

    Article  CAS  PubMed  Google Scholar 

  28. Bruno B, Sorasio R, Patriarca F, Montefusco V, Guidi S, Busca A et al. Unrelated donor haematopoietic cell transplantation after non-myeloablative conditioning for patients with high-risk multiple myeloma. Eur J Haematol 2007; 78: 330–337.

    Article  CAS  PubMed  Google Scholar 

  29. Georges GE, Maris MB, Maloney DG, Sandmaier BM, Sorror ML, Shizuru JA et al. Nonmyeloablative unrelated donor hematopoietic cell transplantation to treat patients with poor-risk, relapsed, or refractory multiple myeloma. Biol Blood Marrow Transplant 2007; 13: 423–432.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Bruno B, Rotta M, Patriarca F, Mattei D, Allione B, Carnevale-Schianca F et al. Nonmyeloablative allografting for newly diagnosed multiple myeloma: the experience of the Gruppo Italiano Trapianti di Midollo. Blood 2009; 113: 3375–3382.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Giaccone L, Storer B, Patriarca F, Rotta M, Sorasio R, Allione B et al. Long-term follow-up of a comparison of nonmyeloablative allografting with autografting for newly diagnosed myeloma. Blood 2011; 117: 6721–6727.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Passera R, Pollichieni S, Brunello L, Patriarca F, Bonifazi F, Montefusco V et al. Allogeneic hematopoietic cell transplantation from unrelated donors in multiple myeloma: study from the Italian Bone Marrow Donor Registry. Biol Blood Marrow Transplant 2013; 19: 940–948.

    Article  PubMed  Google Scholar 

  33. Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation 1974; 18: 295–304.

    Article  CAS  PubMed  Google Scholar 

  34. Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 2005; 11: 945–956.

    Article  PubMed  Google Scholar 

  35. Deregibus MC, Figliolini F, D’Antico S, Manzini PM, Pasquino C, De Lena M et al. Charge-based precipitation of extracellular vesicles. Int J Mol Med 2016; 38: 1359–1366.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Cantaluppi V, Biancone L, Figliolini F, Beltramo S, Medica D, Deregibus MC et al. Microvesicles derived from endothelial progenitor cells enhance neoangiogenesis of human pancreatic islets. Cell Transplant 2012; 21: 1305–1320.

    Article  PubMed  Google Scholar 

  37. Gooley TA, Leisenring W, Crowley J, Storer BE . Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med 1999; 18: 695–706.

    Article  CAS  PubMed  Google Scholar 

  38. White H . A heteroskedasticity-consistent covariance matrix and a direct test for heteroskedasticity. Econometrica 1980; 48: 817–838.

    Article  Google Scholar 

  39. Ferrara JLM, Levine JE, Reddy P, Holler E . Graft-versus-host disease. Lancet (London, England) 2009; 373: 1550–1561.

    Article  CAS  Google Scholar 

  40. Li W, Liu L, Gomez A, Zhang Q, Zhang J, Ramadan A et al. A novel Th17-prone CD146+CCR5+ T-cell population as an early marker of intestinal graft-versus-host disease. Blood 2014; 124: 3.

    Google Scholar 

  41. Li W, Liu L, Gomez A, Zhang J, Ramadan A, Zhang Q et al. Proteomics analysis reveals a Th17-prone cell population in presymptomatic graft-versus-host disease. JCI Insight 2016; 1: pii: e86660.

    Google Scholar 

  42. Selmi C . Autoimmunity in 2011. Clin Rev Allergy Immunol 2012; 43: 194–206.

    Article  CAS  PubMed  Google Scholar 

  43. Yang J, Sundrud MS, Skepner J, Yamagata T . Targeting Th17 cells in autoimmune diseases. Trends Pharmacol Sci 2014; 35: 493–500.

    Article  CAS  PubMed  Google Scholar 

  44. 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 

  45. Cao G, Savani RC, Fehrenbach M, Lyons C, Zhang L, Coukos G et al. Involvement of endothelial CD44 during in vivo angiogenesis. Am J Pathol 2006; 169: 325–336.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Garraud O, Cognasse F, Tissot J-D, Chavarin P, Laperche S, Morel P et al. Improving platelet transfusion safety: biomedical and technical considerations. Blood Transfus 2016; 14: 109–122.

    PubMed  PubMed Central  Google Scholar 

  47. Rank A, Nieuwland R, Crispin A, Grützner S, Iberer M, Toth B et al. Clearance of platelet microparticles in vivo. Platelets 2011; 22: 111–116.

    Article  CAS  PubMed  Google Scholar 

  48. Cheung K, Ma L, Wang G, Coe D, Ferro R, Falasca M et al. CD31 signals confer immune privilege to the vascular endothelium. Proc Natl Acad Sci USA 2015; 112: E5815–E5824.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ma L, Mauro C, Cornish GH, Chai J-G, Coe D, Fu H et al. Ig gene-like molecule CD31 plays a nonredundant role in the regulation of T-cell immunity and tolerance. Proc Natl Acad Sci USA 2010; 107: 19461–19466.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Clement M, Fornasa G, Guedj K, Ben Mkaddem S, Gaston A-T, Khallou-Laschet J et al. CD31 is a key coinhibitory receptor in the development of immunogenic dendritic cells. Proc Natl Acad Sci USA 2014; 111: E1101–E1110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Marelli-Berg FM, Clement M, Mauro C, Caligiuri G . An immunologist’s guide to CD31 function in T-cells. J Cell Sci 2013; 126: 2343–2352.

    Article  CAS  PubMed  Google Scholar 

  52. Cavanagh G, Chapman CE, Carter V, Dickinson AM, Middleton PG . Donor CD31 genotype impacts on transplant complications after human leukocyte antigen-matched sibling allogeneic bone marrow transplantation. Transplantation 2005; 79: 602–605.

    Article  CAS  PubMed  Google Scholar 

  53. Goodman RS, Ewing J, Evans PC, Craig J, Poulton K, Dyer PA et al. Donor CD31 genotype and its association with acute graft-versus-host disease in HLA identical sibling stem cell transplantation. Bone Marrow Transplant 2005; 36: 151–156.

    Article  CAS  PubMed  Google Scholar 

  54. Grumet FC, Hiraki DD, Brown BWM, Zehnder JL, Zacks ES, Draksharapu A et al. CD31 mismatching affects marrow transplantation outcome. Biol Blood Marrow Transplant 2001; 7: 503–512.

    Article  CAS  PubMed  Google Scholar 

  55. Tsirakis G, Pappa CA, Kanellou P, Stratinaki MA, Xekalou A, Psarakis FE et al. Role of platelet-derived growth factor-AB in tumour growth and angiogenesis in relation with other angiogenic cytokines in multiple myeloma. Hematol Oncol 2012; 30: 131–136.

    Article  CAS  PubMed  Google Scholar 

  56. Beer HD, Longaker MT, Werner S . Reduced expression of PDGF and PDGF receptors during impaired wound healing. J Invest Dermatol 1997; 109: 132–138.

    Article  CAS  PubMed  Google Scholar 

  57. Zhang N, Chan CWS, Sanchez-Guerrero E, Khachigian LM . Repression of PDGF-R-α after cellular injury involves TNF-α, formation of a c-Fos-YY1 complex, and negative regulation by HDAC. Am J Physiol Cell Physiol 2012; 302: C1590–C1598.

    Article  CAS  PubMed  Google Scholar 

  58. Levine JE . Implications of TNF-α in the pathogenesis and management of GVHD. Int J Hematol 2011; 93: 571–577.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Ritchie D, Seconi J, Wood C, Walton J, Watt V . Prospective monitoring of tumor necrosis factor alpha and interferon gamma to predict the onset of acute and chronic graft-versus-host disease after allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2005; 11: 706–712.

    Article  CAS  PubMed  Google Scholar 

  60. Wall IB, Moseley R, Baird DM, Kipling D, Giles P, Laffafian I et al. Fibroblast dysfunction is a key factor in the non-healing of chronic venous leg ulcers. J Invest Dermatol 2008; 128: 2526–2540.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was partly supported by Fondi di Ricerca Locale, Università degli Studi di Torino, Torino, Italy, and by Fondazione Neoplasie del sangue (FO.NE. SA), Torino, Italy.

Author contributions

BB and GC designed the study; GL, LB and BB wrote the report; BB supervised the conduction of the study and data analyses; SB, B and PO supervised the laboratory procedures; MF, EM, LG, MA and MB supervised data collection, analyzed data and reviewed and assisted in writing the manuscript; LL, LT, SB and AC undertook the experimental procedures; and GC and AE did statistical analysis.

Author information

Authors and Affiliations

  1. Dipartimento di Oncologia, A.O.U. Città della Salute e della Scienza di Torino, SSD Trapianto Allogenico di Cellule Staminali, Torino, Italy

    G Lia, L Brunello, P Omedè, M Festuccia, L Tosti, E Maffini, L Giaccone, M Boccadoro & B Bruno

  2. Dipartimento di Biotecnologie Molecolari e Scienze per la Salute, Università di Torino, School of Medicine, Torino, Italy

    G Lia, L Brunello, M Festuccia, L Tosti, E Maffini, L Giaccone, M Boccadoro & B Bruno

  3. Dipartimento di Scienze Mediche, Università degli Studi di Torino, Centro di Biotecnologie Molecolari, Torino, Italy

    S Bruno, A Carpanetto & G Camussi

  4. Dipartimento di Ematologia e Scienze Oncologiche ‘L. e A. Seràgnoli’, Università di Bologna, Bologna, Italy

    M Arpinati

  5. A.O.U. Città della Salute e della Scienza di Torino, Epidemiologia Clinica, Torino, Italy

    G Ciccone & A Evangelista

Authors
  1. G Lia
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L Brunello
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S Bruno
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Carpanetto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P Omedè
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M Festuccia
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. L Tosti
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. E Maffini
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. L Giaccone
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. M Arpinati
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. G Ciccone
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. M Boccadoro
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. A Evangelista
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. G Camussi
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. B Bruno
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to B Bruno.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lia, G., Brunello, L., Bruno, S. et al. Extracellular vesicles as potential biomarkers of acute graft-vs-host disease. Leukemia 32, 765–773 (2018). https://doi.org/10.1038/leu.2017.277

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2017.277

This article is cited by

Search

Advanced search

Quick links