While the AIRE expression in β cells did induce TRA expression, w

While the AIRE expression in β cells did induce TRA expression, when compared with thymic medullary epithelial cells, the authors found minor overlap in the

gene expression patterns. This suggests a cell specific aspect to the expressed AIRE and that AIRE has the general ability to promote the TRA expression regardless of where it may be expressed 34. Prompted by our in vitro observations, ALK inhibitor we generated a panel of chimeric mice to test whether the ectopic expression of AIRE through transfer of transduced BM can influence the development of EAE. As previously published, we confirmed that the ectopic expression of MOG following transplantation of BM transduced by retrovirus encoding Mog prevented EAE development 29. While transplantation of Aire-transduced BM did not completely protect mice from EAE development, there was significant retardation in the induction of EAE compared with control groups. In our earlier studies with ectopic expression of MOG, we observed evidence of thymic deletion of MOG35–55-specific T cells 29. We predict that a similar mechanism may also be active here but this needs to be confirmed. While the ectopic gene expression in our system

is not restricted to any particular cell lineage due to the ubiquitous nature of the retroviral promoter, dendritic cells would be considered the main BM-derived instigator Midostaurin cell line of tolerance 41, 42 through uptake and presentation of antigen 43, 44. However, it has been shown that if dendritic cells can directly express antigen, then tolerance to that antigen can also ensue 45. Given

this, we suggest that MOG expressed within dendritic cells derived from transduced BM could drive tolerance within the thymus through deletion and/or much possibility through the generation of T regulatory cells 46. Our model will also promote the ectopic AIRE expression in the range of peripherally destined cells such as dendritic cells, macrophages and B cells, and thus cannot be overlooked at this stage as another potential avenue for mechanisms capable of promoting tolerance. Finally, we cannot rule out the possibility that the ectopic expression of Aire may be exerting its effect on EAE independently of TRA expression. AIRE is also known to transcriptionally activate or repress non-TRA, such as cytokine and cytokine receptors 47 and thus could influence immune responses. Whether a similar effect is occurring in our model of ectopically expressed Aire is not known at this point. Autoimmune diseases remain a major clinical challenge and current treatments are non-curative and often involve non-specific immunosuppressive regimes. The prospect of developing strategies aimed at delivering antigen-specific tolerance would be a major advance in this field.

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