title: Targeting thymic epithelia AR enhances T-cell reconstitution and bone marrow transplant grafting efficacy.
abstract: Although thymic involution has been linked to the increased testosterone in males after puberty, its detailed mechanism and clinical application related to T-cell reconstitution in bone marrow transplantation (BMT) remain unclear. By performing studies with reciprocal BMT and cell-specific androgen receptor (AR) knockout mice, we found that AR in thymic epithelial cells, but not thymocytes or fibroblasts, played a more critical role to determine thymic cellularity. Further dissecting the mechanism using cell-specific thymic epithelial cell-AR knockout mice bearing T-cell receptor transgene revealed that elevating thymocyte survival was due to the enhancement of positive selection resulting in increased positively selected T-cells in both male and female mice. Targeting AR, instead of androgens, either via genetic knockout of thymic epithelial AR or using an AR-degradation enhancer (ASC-J9®), led to increased BMT grafting efficacy, which may provide a new therapeutic approach to boost T-cell reconstitution in the future.
authors.affiliation: George H Whipple Laboratory for Cancer Research, University of Rochester Medical Center, Rochester, New York 14642, USA.
authors.forename: Kuo-Pao
authors.initials: KP
authors.lastname: Lai
authors.forename: Jiann-Jyh
authors.initials: JJ
authors.lastname: Lai
authors.forename: Philip
authors.initials: P
authors.lastname: Chang
authors.forename: Saleh
authors.initials: S
authors.lastname: Altuwaijri
authors.forename: Jong-Wei
authors.initials: JW
authors.lastname: Hsu
authors.forename: Kuang-Hsiang
authors.initials: KH
authors.lastname: Chuang
authors.forename: Chih-Rong
authors.initials: CR
authors.lastname: Shyr
authors.forename: Shuyuan
authors.initials: S
authors.lastname: Yeh
authors.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D016026:Bone Marrow Transplantation / Q000379:methods*; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D003474:Curcumin / Q000031:analogs & derivatives / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009929:Organ Size; D059748:Proteolysis / Q000187:drug effects; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism / Q000502:physiology*; D060168:Thymocytes / Q000378:metabolism / Q000502:physiology; D013950:Thymus Gland / Q000033:anatomy & histology / Q000166:cytology*
chemical_list: D003474:Curcumin; D011944:Receptors, Androgen; D011948:Receptors, Antigen, T-Cell; C471106:ASC-J9 compound