Steroid treatment alters adhesion molecule and chemokine expression in experimental acute graft-vs.-host disease of the intestinal tract.
OBJECTIVE
Acute graft-vs.-host disease (aGVHD) is a major complication after allogeneic bone marrow transplantation (allo-BMT) that is characterized by high morbidity and mortality. Systemic treatment with steroids has been the mainstay of first-line therapy of aGVHD, although controlled experimental data in this context are limited.


METHODS
Using a haploidentical murine BMT model, steroid effects on hepatic and intestinal inflammation during aGVHD have been investigated. Lethally irradiated B6D2F1 mice received bone marrow cells and splenocytes from either syngeneic (B6D2F1) or allogeneic (C57BL/6) donors.


RESULTS
Intraperitoneal administration of prednisolone (2 mg/kg body weight every day) early after onset of GVHD from day +10 until day +42 resulted in reduced clinical GVHD severity and improved survival of allogeneic recipients. Although the liver was barely affected by prednisolone treatment, aGVHD-related histopathologic injury of the gastrointestinal tract was strongly reduced in association with diminished expression of interferon-γ, tumor necrosis factor, CXCL 9-11, CCL2-3, mucosal addressin cell adhesion molecule-1, and intercellular adhesion molecule-1. Prednisolone-induced reduction of adhesion molecule expression in the gut manifested earlier than seen for cytokines or chemokines. Interestingly, when starting steroid treatment on day +28, the course of GVHD was unchanged and no major differences in cyto- or chemokine expression in gastrointestinal tract or liver on day +42 were seen.


CONCLUSIONS
When started early after GVHD onset, prednisolone-related beneficial effects can affect aGVHD target organs differently, involving divergent regulation of inflammation and leukocyte migration. Specifically, a change in adhesion properties between leukocytes and endothelial cells in the gastrointestinal tract may be one of the initial steps in a cascade of steroid-related aGVHD-attenuating events.
Department of Hematology and Oncology, University of Regensburg Medical School, Regensburg, Germany.
Abdellatif
A
Bouazzaoui
Elena
E
Spacenko
Gunnar
G
Mueller
Elisabeth
E
Huber
Thomas
T
Schubert
Ernst
E
Holler
Reinhard
R
Andreesen
Gerhard C
GC
Hildebrandt
D000818:Animals; D016026:Bone Marrow Transplantation; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D018925:Chemokines / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D041981:Gastrointestinal Tract / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006086:Graft vs Host Disease / Q000188:drug therapy*; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D007410:Intestinal Diseases / Q000188:drug therapy; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011241:Prednisone / Q000494:pharmacology / Q000627:therapeutic use; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology
D015815:Cell Adhesion Molecules; D018925:Chemokines; D016207:Cytokines; D007166:Immunosuppressive Agents; D011241:Prednisone