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Ferrara (Abstract)

Cellular Therapy and Transplantation (CTT), Vol. 3, No. 9
doi: 10.3205/ctt-2010-No9-abstract71
© The Authors. This abstract is provided under the following license: Creative Commons Attribution 3.0 Unported

Abstract accepted for "4th Raisa Gorbacheva Memorial Meeting on Hematopoietic Stem Cell Transplantation",
Saint Petersburg, Russia, September 18–20, 2010

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Biomarkers of acute GVHD

James L.M. Ferrara, M.D., D.Sc

University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA

Correspondence: James L.M. Ferrara, M.D., D.Sc., Combined Blood & Marrow Transplant Program, University of Michigan Comprehensive Cancer Center 6303 1500 E Medical Center Dr SPC 5942 Ann Arbor, MI USA 48109-5942, E-mail: ferrara@spam is badmed.umich.edu

Abstract

No validated biomarkers exist for acute graft-versus-host disease (GVHD). We have used three approaches to address this issue. The first two approaches involve plasma proteomics analyses. Using a microarray technique, we screened plasma with antibody microarrays for 120 proteins in a discovery set of 42 patients who underwent transplantation, which revealed 8 potential biomarkers for diagnostic of GVHD. We then measured by enzyme-linked immunosorbent assay (ELISA) the levels of these biomarkers in samples from 424 patients who underwent transplantation randomly divided into training (n=282) and validation (n=142) sets. Logistic regression analysis of these 8 proteins determined a composite biomarker panel of 4 proteins (interleukin-2-receptor-alpha, tumor-necrosis-factor-receptor-1, interleukin-8, and hepatocyte growth factor) that optimally discriminated patients with and without GVHD. The area under the receiver operating characteristic curve distinguishing these 2 groups in the training set was 0.91 (95% confidence interval, 0.87–0.94) and 0.86 (95% confidence interval, 0.79–0.92) in the validation set. In patients with GVHD, Cox regression analysis revealed that the biomarker panel predicted survival independently of GVHD severity. This panel of 4 biomarkers can confirm the diagnosis of GVHD in patients at onset of clinical symptoms of GVHD and provided prognostic information independent of GVHD severity.

In a second proteomics approach, we used a large-scale quantitative proteomic discovery procedure to identify biomarker candidates of skin GVHD and validated the lead candidate, elafin, with enzyme-linked immunosorbent assay in samples from 492 patients. Elafin was overexpressed in GVHD skin biopsies. Plasma concentrations of elafin were significantly higher at the onset of skin GVHD, correlated with the eventual maximum grade of GVHD, and were associated with a greater risk of death relative to other known risk factors (hazard ratio, 1.78). Using these two proteomics approaches we have identified five potential plasma biomarkers for GVHD.

The third approach involved the analysis of cellular biomarkers. Several groups have reported associations between regulatory T Cells (Tregs) and GVHD in animal models. We therefore conducted a prospective analysis of peripheral blood Tregs as determined by the frequency of CD4(+)CD25(hi)FOXP3(+) lymphocytes in 215 BMT patients. Autologous BMT patients (N=90) and allogeneic BMT patients without GVHD (N=65) had similar Treg frequencies after BMT, whereas allogeneic patients with GVHD (N=60) had Treg frequencies that were 40% less than those without GVHD. Treg frequencies decreased linearly with increasing grades of GVHD at onset and correlated with eventual maximum grade of GVHD (p<0.001). In addition, frequency of Tregs at onset of GVHD predicted the response to GVHD treatment (p=0.003). Patients with Treg frequencies less than the median had higher non-relapse mortality than patients with Tregs greater than the median, but experienced equivalent relapse mortality, resulting in an inferior survival at two years (38% vs. 63%, p=0.03). Treg frequency may therefore also serve as a biomarker of acute GVHD and has prognostic value in this group of patients.

Keywords: acute graft-versus-host disease, biomarkers

 

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