Breakdown of thymic tolerance - an etiologic link between acute and chronic graft-versus-host disease

Abstract

Allogeneic haematopoietic stem cell transplantation (HSCT) is the standard therapy for many disorders of the haematological system. Its use is limited by the major complication acute graft-versus-host disease (GVHD). Development of acute GVHD predisposes to chronic GVHD whose autoimmune manifestations are integral components of disease. It remains uncertain, however, whether and how autoimmunity is linked to antecedent alloimmunity. A hallmark of murine acute GVHD is the de novo generation of autoreactive T cells that suggests breakdown of thymic tolerance induction. Central tolerance is dependent on the intrathymic expression of a full scope of tissue-restricted self-antigens (TRA), which is a distinct property of mature medullary thymic epithelial cells (mTEChigh). The ectopic expression of TRA in mTEChigh is partly controlled by the autoimmune regulator (Aire). Since the thymus epithelium is a target of donor T-cell alloimmunity, I hypothesised that thymic acute GVHD interfered with the mTEChigh capacity to sustain TRA diversity. I found that reductions in mTEChigh compartment sizes are universal manifestations of thymic acute GVHD in murine models of haploidentical, fully MHC-disparate and MHC-identical allogeneic HSCT. Moreover, acute GVHD weakens the platform for central tolerance induction because individual TRA are purged from the total repertoire secondary to a decline in the Aire+mTEChigh subset. The most substantially reduced TRA are enriched for genes specific for known target tissues of chronic GVHD. I provide direct evidence in a transgenic mouse system using ovalbumin (OVA) as a model neo-TRA that the de novo production of TRA-specific CD4+ T cells during acute GVHD is a consequence of impaired ectopic TRA expression. OVA-specific CD4+ T cells are present in the periphery in mice with acute GVHD. Peritransplant administration of an epithelial cytoprotective agent, fibroblast growth factor-7, maintains a stable pool of Aire+mTEChigh, which is due to enhanced proliferation of cells within the total mTEC compartment. In parallel, Fgf7 improves the TRA transcriptome despite acute GVHD. Taken together, these data indicate the presence of an etiologic link between acute GVHD and autoimmunity during subsequent chronic GVHD. The present results also suggest that approaches for epithelial cytoprotection may prove to prevent the emergence of thymus-dependent autoreactive T cells.