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

Please always quote using this URN: urn:nbn:de:bvb:20-opus-96797
  • 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 weBackground 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.show moreshow less

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Metadaten
Author: Carina A. Bäuerlein, Simone S. Riedel, Jeanette Baker, Christian Brede, Ana-Laura Jordán Garrote, Martin Chopra, Miriam Ritz, Georg F. Beilhack, Stephan Schulz, Robert Zeiser, Paul G. Schlegel, Hermann Einsele, Robert S. Negrin, Andreas Beilhack
URN:urn:nbn:de:bvb:20-opus-96797
Document Type:Journal article
Faculties:Graduate Schools / Graduate School of Life Sciences
Medizinische Fakultät / Kinderklinik und Poliklinik
Medizinische Fakultät / Medizinische Klinik und Poliklinik II
Language:English
Parent Title (English):BMC Medicine
Year of Completion:2013
Source:In: BMC Medicine (2013) 11: 134, doi:10.1186/1741-7015-11-134
URL:http://www.biomedcentral.com/1741-7015/11/134
DOI:https://doi.org/10.1186/1741-7015-11-134
Sonstige beteiligte Institutionen:Interdisciplinary Center for Clinical Research (IZKF), Würzburg, Germany
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:Allogeneic stem cell transplantation; Graft-versus-host disease; Minor histocompatibility antigen mismatch transplantation
Release Date:2014/04/30
Collections:Open-Access-Publikationsfonds / Förderzeitraum 2013
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung