Serum cytokeratin-18 fragments as quantitative markers of epithelial apoptosis in liver and intestinal graft-versus-host disease

Abstract

Graft-versus-host disease (GVHD) is the main complication of allogeneic stem cell transplantation. However, diagnosis of GVHD and evaluation of response to immunosuppressive treatment is sometimes difficult. Since apoptosis is the histopathologic hallmark in GVHD, we investigated whether active GVHD-induced target organ destruction is mirrored by serum levels of the caspasecleaved neo-epitope of cytokeratin-18 fragments (CK18Fs). Serum CK18F kinetics was monitored by M30 antibodybased enzyme-linked immunosorbent assay (ELISA) in 50 patients who fulfilled histopathologic and/or clinical criteria diagnostic for GVHD. Both intestinal and hepatic GVHD were consistently associated with significant elevations of CK18F levels over baseline. Responses of GVHD to immunosuppressive therapy were paralleled by CK18F decreases, whereas resistant GVHD was characterized by persistent CK18F rises. Clinical conditions that might represent relevant differential diagnoses, such as toxic mucositis, noncomplicated, infection-related diarrhea, and veno-occlusive disease were not associated with CK18F elevations. In conclusion, CK18F monitoring provides a serum marker for quantitative assessment of GVHD-associated apoptotic activity in intestinal and hepatic GVHD. Although apoptosis is not GVHD-specific, CK18Fs may help to distinguish active GVHD from GVHD-unrelated conditions with similar symptoms, and to monitor response to immunosuppressive treatment. Prospective studies are warranted to evaluate how CK18Fs may assist in the diagnosis, grading, and treatment guidance of GVHD.

Monitoring of TNFR1, IL-2Rα, HGF, CCL8, IL-8 and IL-12p70 following HSCT and their role as GVHD biomarkers in paediatric patients

“…18 Moreover, the HGF serum concentration was found to be correlated to gastrointestinal GVHD together with regenerating islet-derived 3-alpha (REG3a 19 ) and cytokeratin-18. 20 The IL-7 serum concentration was also monitored in a study of 31 patients who underwent reduced intensity MFD-HSCT. Acute GVHD was significantly associated with a higher IL-7 concentration on days þ 7 and þ 14 together with the CD34 þ cell dose, with high sensitivity and specificity.…”

Biomarkers for acute GVHD: can we predict the unpredictable?

“…21 Cytokeratin 18 is an intermediate filament present in epithelial and parenchymal cells, which is cleaved by caspases when apoptosis is induced, resulting in the release of cytokeratin 18 fragments. Luft et al 22 showed that serum cytokeratin 18 fragment levels correlated with the severity of hepatic and intestinal acute GVHD and decreased in response to successful treatment. Syndecan-1 is a transmembrane heparin sulfate proteoglycan present on the surface of most epithelial cells, including skin, liver and intestine, and serum levels were shown to be significantly elevated in acute GVHD with a correlation with the severity of disease.…”

“…Recently, investigators from the University of Michigan spearheaded an effort to evaluate the prognostic value of a panel of biomarkers comprised of TNFR1, IL-2Ra, IL-8, HGF, elafin and reg3a. Samples T-cell growth factor, stimulates production of TNF-a and IFN-g Activated NK cells, induces IFN-g production Nakamura et al 16 Fujimori et al 17 Shaiegan et al 18 Mohty et al Visentainer et al 12 Visentainer et al 12 Liem et al 13 Other circulating molecules Uguccioni et al 20 Okamoto et al 21 Luft et al 22 Seidel et al 23 Kircher et al 24 Hubel et al 26 Chen et al 25 Lymphocytetrafficking molecules a4b7 integrin…”

Pentostatin for treatment of steroid-refractory acute GVHD: a retrospective single-center analysis

“…8 Destruction of target tissues is mediated through recruitment of effector leukocytes expressing cell surface and soluble immune effector molecules (for example, Fas ligand, TNF-a, TNF-related apoptosis-inducing ligand (TRAIL), perforin, granzymes and IFN-g), resulting in apoptosis of the epithelial target cells. 9,10 However, steroid exposure induces a rapid decline of T-lymphocyte turnover, both systemically and locally, in the affected tissues. Therefore, steroid-resistant GVHD cannot be explained by tissue-infiltrating, alloreactive T lymphocytes alone.…”