TY  - JOUR
A1  - Bäuerlein, Carina A.
A1  - Riedel, Simone S.
A1  - Baker, Jeanette
A1  - Brede, Christian
A1  - Jordán Garrote, Ana-Laura
A1  - Chopra, Martin
A1  - Ritz, Miriam
A1  - Beilhack, Georg F.
A1  - Schulz, Stephan
A1  - Zeiser, Robert
A1  - Schlegel, Paul G.
A1  - Einsele, Hermann
A1  - Negrin, Robert S.
A1  - Beilhack, Andreas
T1  - A diagnostic window for the treatment of acute graft-versus-host disease prior to visible clinical symptoms in a murine model
JF  - BMC Medicine
N2  - 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.
KW  - Allogeneic stem cell transplantation
KW  - Graft-versus-host disease
KW  - Minor histocompatibility antigen mismatch transplantation
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-96797
UR  - http://www.biomedcentral.com/1741-7015/11/134
ER  -