title: Epithelial cytoprotection sustains ectopic expression of tissue-restricted antigens in the thymus during murine acute GVHD.
abstract: Development of acute graft-versus-host disease (aGVHD) predisposes to chronic GVHD with autoimmune manifestations. A characteristic of experimental aGVHD is the de novo generation of autoreactive T cells. Central tolerance is dependent on the intrathymic expression of tissue-restricted peripheral self-antigens (TRA), which is in mature medullary thymic epithelial cells (mTEC(high)) partly controlled by the autoimmune regulator (Aire). Because TECs are targets of donor T-cell alloimmunity, we tested whether murine aGVHD interfered with the capacity of recipient Aire(+)mTEC(high) to sustain TRA diversity. We report that aGVHD weakens the platform for central tolerance induction because individual TRAs are purged from the total repertoire secondary to a decline in the Aire(+)mTEC(high) cell pool. Peritransplant administration of an epithelial cytoprotective agent, fibroblast growth factor-7, maintained a stable pool of Aire(+)mTEC(high), with an improved TRA transcriptome despite aGVHD. Taken together, our data provide a mechanism for how autoimmunity may develop in the context of antecedent alloimmunity.
authors.affiliation: Department of Biomedicine, University of Basel and Basel University Children's Hospital, Mattenstrasse 28, Basel, Switzerland.
authors.forename: Simone
authors.initials: S
authors.lastname: Dertschnig
authors.forename: Gretel
authors.initials: G
authors.lastname: Nusspaumer
authors.forename: Robert
authors.initials: R
authors.lastname: Ivanek
authors.forename: Mathias M
authors.initials: MM
authors.lastname: Hauri-Hohl
authors.forename: Georg A
authors.initials: GA
authors.lastname: Holländer
authors.forename: Werner
authors.initials: W
authors.lastname: Krenger
mesh_terms: D000208:Acute Disease; D000818:Animals; D000941:Antigens / Q000235:genetics* / Q000378:metabolism; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000276:immunology*; D005260:Female; D015870:Gene Expression / Q000502:physiology; D006086:Graft vs Host Disease / Q000235:genetics* / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D013950:Thymus Gland / Q000378:metabolism* / Q000473:pathology
chemical_list: D000941:Antigens; D001324:Autoantigens