Involvement of OX40-OX40L interactions in the intestinal manifestations of the murine acute graft-versus-host disease.
OBJECTIVE
The intestinal histology of murine semiallogeneic graft-versus-host (GVH) disease is characterized by lymphocytic infiltrates, crypt hyperplasia, and villous atrophy. Mechanisms of T cell-mediated changes of the mucosal architecture were investigated.


METHODS
The rate of cellular apoptosis and proliferation, changes in the composition of extracellular matrix (ECM), and the role of OX40-OX40L interactions in the pathogenesis of villous atrophy and crypt hyperplasia were examined.


RESULTS
The rate of apoptosis and the number of proliferating cells were significantly increased in GVH animals compared with control animals. In addition, expression of tenascin, an ECM component, was down-regulated in GVH animals. Inhibition of OX40-OX40L interactions in GVH animals by administration of an OX40-Ig fusion protein completely prevented the development of crypt hyperplasia and villous atrophy in GVH animals. Tenascin expression was up-regulated in OX40-Ig-treated mice compared with GVH animals, suggesting an important function of this ECM component in mucosal repair.


CONCLUSIONS
The OX40-OX40L interaction is crucial in the pathogenesis of GVH, a T cell-mediated intestinal disease. The data suggest that the ECM component tenascin is probably relevant for the regeneration and maintenance of intestinal tissue architecture.
Stüber
E
E
Department of Internal Medicine, I. Medizinische Universitätsklinik, Christian-Albechts-Universität, Kiel, Germany.
Von Freier
A
A
Marinescu
D
D
Fölsch
U R
UR
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D004847:Epithelial Cells / Q000502:physiology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006086:Graft vs Host Disease / Q000473:pathology / Q000503:physiopathology*; D007136:Immunoglobulins / Q000502:physiology; D007421:Intestine, Small / Q000473:pathology; D007422:Intestines / Q000473:pathology / Q000503:physiopathology*; D007583:Jejunum / Q000473:pathology / Q000503:physiopathology; D007700:Kinetics; D008562:Membrane Glycoproteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D053278:OX40 Ligand; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D012038:Regeneration / Q000502:physiology; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000276:immunology / Q000502:physiology; D048069:Tumor Necrosis Factors
D016326:Extracellular Matrix Proteins; D007136:Immunoglobulins; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; C505717:Tnfrsf4 protein, mouse; C504586:Tnfsf4 protein, mouse; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D048069:Tumor Necrosis Factors