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Mod Pathol. 2019 Apr;32(4):560-567. doi: 10.1038/s41379-018-0170-z. Epub 2018 Nov 13.

Amphiregulin in intestinal acute graft-versus-host disease: a possible diagnostic and prognostic aid.

Author information

1
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
2
Mayo Clinic, Rochester, MN, USA.
3
Department of Internal Medicine, University of Minnesota, Minneapolis, MN, USA.
4
Department of Internal Medicine, Division of Gastroenterology, University of Minnesota, Minneapolis, MN, USA.
5
Biostatistics and Informatics, University of Minnesota, Minneapolis, MN, USA.
6
Hematology, Oncology and Transplant, University of Minnesota, Minneapolis, MN, USA.
7
Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.
8
College of Biological Sciences, University of Minnesota, Minneapolis, MN, USA.
9
Hematology, Oncology and Transplant, University of Minnesota, Minneapolis, MN, USA. sgholtan@umn.edu.

Abstract

Amphiregulin, a weak epidermal growth factor receptor agonist, is elevated, while epidermal growth factor, a strong epidermal growth factor receptor agonist, is low in the blood of patients with severe acute graft-versus-host disease. However, the tissue expression and function of these epidermal growth factor receptor ligands in acute graft-versus-host disease target organs is unknown. We compared by immunohistochemistry expression of amphiregulin and epidermal growth factor in archived, formalin-fixed, paraffin-embedded intestinal tissues of 48 patients with biopsy-proven gastrointestinal acute graft-versus-host disease to 3 groups: (1) 10 non-hematopoietic cell transplant normal controls, (2) 11 patients with newly diagnosed ulcerative colitis (ulcerative colitis), (3) 8 patients with a clinical diagnosis of acute graft-versus-host disease despite pathologically non-diagnostic biopsies, (4) and 10 cases of cytomegalovirus colitis. We used a semi-quantitative score of 0 (absent) through 3 (strong) to describe the intensity of immunohistochemical staining. We correlated serum and tissue amphiregulin and epidermal growth factor in patients with acute graft-versus-host disease. Gastrointestinal amphiregulin was significantly lower in acute graft-versus-host disease biopsies (median score 1), ulcerative colitis (median score 1.5), and cytomegalovirus colitis (median score 1) than in normal colon (median score 2, p = 0.004, p = 0.03, p = 0.009 respectively). Amphiregulin expression in was low in 74% of acute graft-versus-host disease cases with or without significant apoptosis. Patients with acute graft-versus-host disease exhibiting the pattern of high gastrointestinal amphiregulin but low serum amphiregulin (n = 14) had the best 1-year survival at 71%, but patients with high serum amphiregulin had poorer survival (<30%) regardless of gastrointestinal amphiregulin expression. Overall, our results lead to the hypothesis that amphiregulin is released into the circulation from damaged intestinal epithelium and stroma, although contributions from other cellular sources are likely. Low gastrointestinal amphiregulin expression by immunohistochemistry may be further studied for its utility in the pathologic acute graft-versus-host disease diagnosis without classic apoptotic changes.

PMID:
30425334
DOI:
10.1038/s41379-018-0170-z

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