2. Academic Validation
  3. Histone/protein deacetylase 11 targeting promotes Foxp3+ Treg function

Histone/protein deacetylase 11 targeting promotes Foxp3+ Treg function

  • Sci Rep. 2017 Aug 17;7(1):8626. doi: 10.1038/s41598-017-09211-3.
Jianbing Huang 1,  Liqing Wang 2,  Satinder Dahiya 2,  Ulf H Beier 3,  Rongxiang Han 2,  Arabinda Samanta 2,  Joel Bergman 4,  Eduardo M Sotomayor 5,  Edward Seto 5,  Alan P Kozikowski 4,  Wayne W Hancock 6
Affiliations

Affiliations

  • 1 Department of Cardiothoracic Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
  • 2 Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, and Biesecker Center for Pediatric Liver Diseases, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • 3 Division of Nephrology, Department of Pediatrics, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • 4 Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, IL, 60612, USA.
  • 5 George Washington University Cancer Center, Washington, DC, 20037, USA.
  • 6 Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, and Biesecker Center for Pediatric Liver Diseases, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. whancock@mail.med.upenn.edu.
PMID: 28819166 DOI: 10.1038/s41598-017-09211-3
Abstract

Current interest in Foxp3+ T-regulatory (Treg) cells as therapeutic targets in transplantation is largely focused on their harvesting pre-transplant, expansion and infusion post-transplantation. An alternate strategy of pharmacologic modulation of Treg function using histone/protein deacetylase inhibitors (HDACi) may allow more titratable and longer-term dosing. However, the effects of broadly acting HDACi vary, such that HDAC isoform-selective targeting is likely required. We report data from mice with constitutive or conditional deletion of HDAC11 within Foxp3+ Treg cells, and their use, along with small molecule HDAC11 inhibitors, in allograft models. Global HDAC11 deletion had no effect on health or development, and compared to WT controls, Foxp3+ Tregs lacking HDAC11 showed increased suppressive function, and increased expression of Foxp3 and TGF-β. Likewise, compared to WT recipients, conditional deletion of HDAC11 within Tregs led to long-term survival of fully MHC-mismatched cardiac allografts, and prevented development of transplant arteriosclerosis in an MHC class II-mismatched allograft model. The translational significance of HDAC11 targeting was shown by the ability of an HDAC11i to promote long-term allograft allografts in fully MHC-disparate strains. These data are powerful stimuli for the further development and testing of HDAC11-selective pharmacologic inhibitors, and may ultimately provide new therapies for transplantation and autoimmune diseases.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-145757
    HDAC11 Inhibitor