title: CD4+ Foxp3+ regulatory T cells induced by TGF-β, IL-2 and all-trans retinoic acid attenuate obliterative bronchiolitis in rat trachea transplantation.
abstract: Obliterative bronchiolitis (OB) is the major obstacle for long-term allograft survival in lung transplantation, and the underlying mechanism is still not well understood. Regulatory T cells (Tregs) have been shown to be essential in the maintenance of immune tolerance. In this study we investigated the role of Tregs in protecting OB in rat. We show that the combination of TGF-β, Interleukin (IL)-2, and all-trans retinoic acid (atRA) could induce naïve rat CD4(+)CD25(-) T cells to differentiate into CD4(+)CD25(+)Foxp3(+) T cells in vitro, and they acquired suppressive function. In a rat orthotopic tracheal transplantation OB model, the adoptive transfer of the induced Tregs reduced symptoms of airway obliteration and fibrication of grafts when compared with adoptive transfer of control cells without suppressive property. Moreover, recipients treated with the induced Tregs secreted high level of immunosuppressive cytokine TGF-β and IL-10, and low level of pro-inflammatory cytokines IL-17, IFN-γ, IL-6, and MCP-1, and had fewer effector T cells including Th17 cells and Th1 cells in the graft. Taken together, these findings suggest that in vitro induced Tregs by the combination of TGF-β, IL-2, and atRA are effective in protecting rat trachea allograft rejection through the inhibition of effector T cells and their function. These datas implicate new therapies to prevent OB and allograft rejection in human lung transplantation.
authors.affiliation: Shanghai East Hospital, Tongji University School of Medicine, Department of Cardiovascular and Thoracic Surgery, Shanghai, 200120, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Shi
authors.forename: Hao
authors.initials: H
authors.lastname: Cao
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Zhou
authors.forename: Qin
authors.initials: Q
authors.lastname: Lan
authors.forename: Songguo
authors.initials: S
authors.lastname: Zheng
authors.forename: Zhongmin
authors.initials: Z
authors.lastname: Liu
authors.forename: Qinchuan
authors.initials: Q
authors.lastname: Li
authors.forename: Huimin
authors.initials: H
authors.lastname: Fan
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001989:Bronchiolitis Obliterans / Q000276:immunology / Q000517:prevention & control*; D015704:CD4 Antigens / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D007376:Interleukin-2 / Q000494:pharmacology*; D008297:Male; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000637:transplantation; D014132:Trachea / Q000276:immunology / Q000637:transplantation*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D023001:Transplantation Tolerance / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D015704:CD4 Antigens; D016207:Cytokines; D051858:Forkhead Transcription Factors; C500522:Foxp3 protein, rat; D007376:Interleukin-2; D016212:Transforming Growth Factor beta; D014212:Tretinoin