Epithelial cytoprotection sustains ectopic expression of tissue-restricted antigens in the thymus during murine acute GVHD.

Journal article

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: Dertschnig, S; Nusspaumer, G; Ivanek, R; Hauri-Hohl, M; Holländer, G

• Publication status: Published
• Journal: Blood
• Volume: 122
• Issue: 5
• Pages: 837-841
• Publication date: 2013-08-01
• DOI: 10.1182/blood-2012-12-474759
• EISSN: 1528-0020
• ISSN: 0006-4971
• Language: English
• Keywords: Gene Expression; Graft vs Host Disease; Mice, Inbred C57BL; Antigens; Autoantigens; Thymus Gland; Female; Acute Disease; Mice; Epithelial Cells; Animals; Mice, Transgenic; Mice, Inbred BALB C; Mice, Inbred DBA