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.

  • Letter to the Editor
  • Published:

Evaluation of EPI-X4 as a urinary peptide biomarker for diagnosis and prognosis of late acute GvHD

Bone Marrow Transplantation volume 51, pages 1137–1139 (2016)Cite this article

Subjects

Today, malignant and nonmalignant hematologic diseases can be treated with allogeneic hematopoietic cell transplantation (HCT). Following transplantation, many patients acquire life-threatening complications such as severe acute GvHD and require additional immunosuppressive therapy. Diagnosis and prognosis of acute GvHD relies on clinical parameters such as diarrhea, elevated liver tests and skin rash, and is confirmed by organ biopsies to distinguish GvHD from other complications that show similar symptoms. Currently, no method is available to predict the risk of acquiring GvHD or to diagnose GvHD without invasive procedures, although accumulating evidence suggests that plasma-derived biomarkers will be incorporated in the future.1, 2, 3, 4 Acute GvHD can be the ‘classic’ form occurring <100 days after HCT, or ‘late acute GvHD’ characterized by persistent, recurrent or new-onset acute GvHD present after day 100.5

A noninvasive method to identify specific biomarkers would allow impending GvHD to be recognized before the onset of clinical symptoms and might improve patients’ outcomes by allowing pre-emptive treatment with immunosuppressive medications before GvHD is established. An ideal biomarker would also provide information about severity and likely treatment responsiveness. To identify a prognostic marker for GvHD, Kaiser et al. determined polypeptide patterns in urine from patients that developed GvHD using a liquid chromatography–mass spectrometry-based technique.6 Among the 16 identified GvHD-specific peptides was a human serum albumin (hSA)-derived peptide encompassing amino-acid residues 408–423 (LVRYTKKVPQVSTPTL). This albumin fragment was also the most prominently excreted peptide and could be detected in urine up to 15 days before GvHD development.6 Interestingly, the very same peptide was recently identified as natural antagonist of the CXC chemokine receptor 4 (CXCR4).7 CXCR4 signaling has a key role in immune responses, organogenesis and inflammation, and its deregulation is associated with various diseases. The hSA (408–423) peptide binds to the extracellular region of CXCR4 and inhibits chemokine-induced receptor signaling, prompting the name EPI-X4 (endogenous peptide inhibitor of CXCR4). EPI-X4 mobilizes hematopoietic stem cells and has anti-inflammatory properties in vivo.7 Moreover, the peptide reaches concentrations in the μg/mL range in the urine of patients with renal inflammation, suggesting its use as diagnostic marker for chronic kidney diseases.7 Given the accepted role of inflammation in the development of GvHD8 and the occurrence of EPI-X4 in the urine of classic acute GvHD samples,6 we tested whether EPI-X4 might serve as novel biomarker for diagnosis of late acute GvHD.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

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

References

  1. 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  Google Scholar 

  2. Paczesny S, Braun TM, Levine JE, Hogan J, Crawford J, Coffing B et al. Elafin is a biomarker of graft-versus-host disease of the skin. Sci Transl Med 2010; 2: 13ra12.

    Article  Google Scholar 

  3. Ponce DM, Hilden P, Mumaw C, Devlin SM, Lubin M, Giralt S et al. High day 28 ST2 levels predict for acute graft-versus-host disease and transplant-related mortality after cord blood transplantation. Blood 2015; 125: 199–205.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant 2015; 21: 389–401.e1.

    Article  Google Scholar 

  6. Kaiser T, Kamal H, Rank A, Kolb HJ, Holler E, Ganser A et al. Proteomics applied to the clinical follow up of patients after allogeneic hematopoietic stem cell transplantation. Blood 2004; 104: 340–349.

    Article  CAS  Google Scholar 

  7. Zirafi O, Kim KA, Ständker L, Mohr KB, Sauter D, Heigele A et al. Discovery and characterization of an endogenous CXCR4 antagonist. Cell Rep 2015; 11: 737–747.

    Article  CAS  Google Scholar 

  8. Magenau J, Reddy P . Next generation treatment of acute graft-versus-host disease. Leukemia 2014; 28: 2283–2291.

    Article  CAS  Google Scholar 

  9. Arora M, Cutler CS, Jagasia MH, Pidala J, Chai X, Martin PJ et al. Late acute and chronic graft-versus-host disease after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2016; 22: 449–455.

    Article  Google Scholar 

  10. Mohr KB, Zirafi O, Hennies M, Wiese S, Kirchhoff F, Münch J . Sandwich enzyme-linked immunosorbent assay for the quantification of human serum albumin fragment 408-423 in bodily fluids. Anal Biochem 2015; 476: 29–35.

    Article  CAS  Google Scholar 

  11. Chen YB, Cutler CS . Biomarkers for acute GVHD: can we predict the unpredictable? Bone Marrow Transplant 2013; 48: 755–760.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The Chronic GvHD Consortium (U54 CA163438) is part of the National Center for Advancing Translational Sciences (NCATS) Rare Diseases Clinical Research Network (RDCRN). RDCRN is an initiative of the Office of Rare Disease Research (ORDR), NCATS, funded through a collaboration between NCATS and the National Cancer Institute. Janis A Müller is funded by a fellowship from the International Graduate School in Molecular Medicine Ulm. This study was supported by a grant from the German Research Foundation to JM.

Author information

Author notes

  1. J A Müller and O Zirafi: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Molecular Virology, Ulm University Medical Centre, Ulm, Germany

    J A Müller, O Zirafi & J Münch

  2. Department of Urology, University of California, San Francisco, CA, USA

    N R Roan

  3. Gladstone Institute of Virology and Immunology, The J. David Gladstone Institutes, San Francisco, CA, USA

    N R Roan

  4. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    S J Lee

  5. Ulm Peptide Pharmaceuticals, University of Ulm, Ulm, Germany

    J Münch

Authors
  1. J A Müller
    View author publications

    Search author on:PubMed Google Scholar

  2. O Zirafi
    View author publications

    Search author on:PubMed Google Scholar

  3. N R Roan
    View author publications

    Search author on:PubMed Google Scholar

  4. S J Lee
    View author publications

    Search author on:PubMed Google Scholar

  5. J Münch
    View author publications

    Search author on:PubMed Google Scholar

Corresponding authors

Correspondence to S J Lee or J Münch.

Ethics declarations

Competing interests

OZ and JM declare that they filed an application for a patent to utilize the ELISA for the diagnosis and prognosis of diseases of the kidneys and GvHD. The remaining authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Müller, J., Zirafi, O., Roan, N. et al. Evaluation of EPI-X4 as a urinary peptide biomarker for diagnosis and prognosis of late acute GvHD. Bone Marrow Transplant 51, 1137–1139 (2016). https://doi.org/10.1038/bmt.2016.65

Download citation

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/bmt.2016.65

This article is cited by

Search

Advanced search

Quick links