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Open Access Research article

A diagnostic window for the treatment of acute graft-versus-host disease prior to visible clinical symptoms in a murine model

Carina A Bäuerlein123, Simone S Riedel123, Jeanette Baker1234, Christian Brede123, Ana-Laura Jordán Garrote123, Martin Chopra12, Miriam Ritz12, Georg F Beilhack5, Stephan Schulz6, Robert Zeiser7, Paul G Schlegel38, Hermann Einsele13, Robert S Negrin4 and Andreas Beilhack123*

Author Affiliations

1 Department of Medicine II, Würzburg University Clinics, Zinklesweg 10, Würzburg, D-97078, Germany

2 Interdisciplinary Center for Clinical Research (IZKF), Würzburg, Germany

3 Graduate School of Life Sciences, Würzburg, Germany

4 Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University, Stanford, CA, USA

5 Department of Medicine III, Vienna Medical University, Vienna, Austria

6 Institute of Pathology Charité, Berlin, Germany

7 Department of Hematology and Oncology, Freiburg University Medical Center, Freiburg, Germany

8 Department of Pediatrics, Würzburg University Hospital, Würzburg, Germany

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BMC Medicine 2013, 11:134  doi:10.1186/1741-7015-11-134

Published: 21 May 2013

Abstract

Background

Acute graft-versus-host disease (aGVHD) poses a major limitation for broader therapeutic application of allogeneic hematopoietic cell transplantation (allo-HCT). Early diagnosis of aGVHD remains difficult and is based on clinical symptoms and histopathological evaluation of tissue biopsies. Thus, current aGVHD diagnosis is limited to patients with established disease manifestation. Therefore, for improved disease prevention it is important to develop predictive assays to identify patients at risk of developing aGVHD. Here we address whether insights into the timing of the aGVHD initiation and effector phases could allow for the detection of migrating alloreactive T cells before clinical aGVHD onset to permit for efficient therapeutic intervention.

Methods

Murine major histocompatibility complex (MHC) mismatched and minor histocompatibility antigen (miHAg) mismatched allo-HCT models were employed to assess the spatiotemporal distribution of donor T cells with flow cytometry and in vivo bioluminescence imaging (BLI). Daily flow cytometry analysis of peripheral blood mononuclear cells allowed us to identify migrating alloreactive T cells based on homing receptor expression profiles.

Results

We identified a time period of 2 weeks of massive alloreactive donor T cell migration in the blood after miHAg mismatch allo-HCT before clinical aGVHD symptoms appeared. Alloreactive T cells upregulated α4β7 integrin and P-selectin ligand during this migration phase. Consequently, targeted preemptive treatment with rapamycin, starting at the earliest detection time of alloreactive donor T cells in the peripheral blood, prevented lethal aGVHD.

Conclusions

Based on this data we propose a critical time frame prior to the onset of aGVHD symptoms to identify alloreactive T cells in the peripheral blood for timely and effective therapeutic intervention.

Keywords:
Allogeneic stem cell transplantation; Graft-versus-host disease; Minor histocompatibility antigen mismatch transplantation