Blood Journal
Leading the way in experimental and clinical research in hematology

Regenerating islet-derived 3-alpha is a biomarker of gastrointestinal graft-versus-host disease

  1. James L. M. Ferrara1,*,
  2. Andrew C. Harris1,*,
  3. Joel K. Greenson2,
  4. Thomas M. Braun3,
  5. Ernst Holler4,
  6. Takanori Teshima5,
  7. John E. Levine1,
  8. Sung W. J. Choi1,
  9. Elisabeth Huber6,
  10. Karin Landfried4,
  11. Koichi Akashi5,
  12. Mark Vander Lugt1,
  13. Pavan Reddy7,
  14. Alice Chin8,
  15. Qing Zhang8,
  16. Samir Hanash8, and
  17. Sophie Paczesny1
  1. Departments of 1Pediatrics,
  2. 2Pathology, and
  3. 3Biostatistics, University of Michigan, Ann Arbor, MI;
  4. 4Department of Hematology/Oncology, University Medical Center Regensburg, Regensburg, Germany;
  5. 5Center for Cellular and Molecular Medicine, Kyushu University Graduate School of Science, Fukuoka, Japan;
  6. 6Institute of Pathology, University Medical Center Regensburg, Regensburg, Germany;
  7. 7Department of Internal Medicine, University of Michigan, Ann Arbor, MI; and
  8. 8Molecular Diagnostics Program, Fred Hutchinson Cancer Research Center, Seattle, WA

Abstract

There are no plasma biomarkers specific for GVHD of the gastrointestinal (GI) tract, the GVHD target organ most associated with nonrelapse mortality (NRM) following hematopoietic cell transplantation (HCT). Using an unbiased, large-scale, quantitative proteomic discovery approach to identify candidate biomarkers that were increased in plasma from HCT patients with GI GVHD, 74 proteins were increased at least 2-fold; 5 were of GI origin. We validated the lead candidate, REG3α, by ELISA in samples from 1014 HCT patients from 3 transplantation centers. Plasma REG3α concentrations were 3-fold higher in patients at GI GVHD onset than in all other patients and correlated most closely with lower GI GVHD. REG3α concentrations at GVHD onset predicted response to therapy at 4 weeks, 1-year NRM, and 1-year survival (P ≤ .001). In a multivariate analysis, advanced clinical stage, severe histologic damage, and high REG3α concentrations at GVHD diagnosis independently predicted 1-year NRM, which progressively increased with higher numbers of onset risk factors present: 25% for patients with 0 risk factors to 86% with 3 risk factors present (P < .001). REG3α is a plasma biomarker of GI GVHD that can be combined with clinical stage and histologic grade to improve risk stratification of patients.

  • Submitted August 20, 2011.
  • Accepted September 27, 2011.
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