Aim: There are huge scientific, economic and practical advantages in developing pharmacologic approaches to enhance Foxp3+ Treg function in allograft recipients versus simply injecting enormous numbers of Tregs that survive only a few days post-transfer. Such pharmacologic modulation of Treg function has the advantages of being titratable and able to be given sort- or long-term, as needed. Our ongoing studies of the regulation of Foxp3 expression have shown that some but not other histone/protein deacetylase (Hdac) inhibitors promote Treg production and function, depending upon the isoform(s) targeted, leading us to validate in Hdac isoform-selective therapy.

Methods: Hdac11, the sole class IV HDAC enzyme, was identified in 2002 but has been little studied. We report data from (i) mice with constitutive Hdac11 deletion, (ii) mice with conditional deletion of Hdac11 just within Foxp3+ Treg cells, and (iii) use of new small molecule inhibitors (Hdac11i) in WT mice.

Results: Hdac11 deletion had no effect on overall health or development, including that of host immune cells. Hdac11 deletion promoted chromatin remodeling at the Foxp3 promoter, CNS1 and CNS3 sites, leading to increased Foxp3 gene expression. Compared to WT Tregs, Hdac11 deletion also led to increased Foxp3 acetylation and increased Foxp3 stability upon Treg activation. Compared to WT Tregs, Foxp3+ Tregs lacking Hdac11 showed increased suppressive function in vitro, and increased expression (p<0.01) of TGF-beta, CTLA4 and GITR but not IL-10. Likewise, compared to WT recipients, Hdac11-/- C57BL/6 recipients of fully MHC-mismatched BALB/c cardiac allografts showed prolonged allograft survival (p<0.01), and this effect was matched by long-term allograft survival in mice with conditional deletion of Hdac11 just within Treg cells (p<0.01). Lastly, Hdac11i use enhanced Treg function in vitro, and corresponding allograft studies are underway in vivo.

Conclusion: Hdac11 regulates Foxp3 gene expression and Foxp3 protein acetylation and stability, and Hdac11 targeting promotes Foxp3+ Treg suppressive functions in vivo and in vivo. These data point to the importance of developing and testing of selective Hdac11 small molecule inhibitors as a new approach in transplantation and autoimmunity.

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