title: The Immunosuppressant Protosappanin A Promotes Dendritic Cell-Mediated Expansion of Alloantigen-Specific Tregs and Prolongs Allograft Survival in Rats.
abstract: Protosappanin A (PrA), an immunosuppressive ingredient of the medicinal herb Caesalpinia sappan L, prolongs heart allograft survival in rats, possibly by impairing the function of antigen-presenting cells (APCs). We examined the effects of PrA on the maturation and function of dendritic cells (DCs), a potent class of APCs, and the downstream cell-cell and intracellular signaling pathways mediating the immunosuppressive activity of PrA. PrA inhibited LPS-stimulated maturation of Wistar rat DCs in vitro as reflected by reduced expression of costimulatory molecules (CD80 and CD86) and reduced expression of TLR4 and NF-κB, two critical signaling components for antigen recognition. PrA also enhanced the release of IL-10 and decreased the release of IL-12 from DCs, but had no effect on the production of TGF-ß. In mixed cultures, Wistar DCs pretreated with PrA impaired the proliferation of Sprague Dawley (SD) rat T cells while promoting the expansion of SD rat CD4(+)CD25(+) regulatory T cells (Tregs). Both oral PrA treatment and infusion of PrA-pretreated Wistar DCs prolonged cardiac allograft survival (Wistar donor, SD recipient) and expanded recipient CD4(+)CD25(+)Foxp3(+) Tregs. Donor spleen cells, but not spleen cells from a third rat strain (DA), supported the expansion of recipient CD4(+)CD25(+)Foxp3(+) Tregs and suppressed recipient T cell proliferation. We conclude that PrA triggers a tolerogenic state in DCs that allows for the induction of alloantigen-specific Tregs and the suppression of allograft rejection in vivo.
authors.affiliation: The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, Heilongjiang Province, China ; Department of Cardiology, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Maomao
authors.initials: M
authors.lastname: Zhang
authors.forename: Shuo
authors.initials: S
authors.lastname: Zhang
authors.forename: Jian
authors.initials: J
authors.lastname: Wu
authors.forename: Yong
authors.initials: Y
authors.lastname: Sun
authors.forename: Lili
authors.initials: L
authors.lastname: Li
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Du
authors.forename: Jingjin
authors.initials: J
authors.lastname: Liu
authors.forename: Jingbo
authors.initials: J
authors.lastname: Hou
authors.forename: Bo
authors.initials: B
authors.lastname: Yu
mesh_terms: D000818:Animals; D029911:Caesalpinia; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology*; D006085:Graft Survival / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D016753:Interleukin-10 / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D008070:Lipopolysaccharides / Q000378:metabolism; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D010636:Phenols / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013047:Specific Pathogen-Free Organisms; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D010636:Phenols; C090723:protosappanin A; D016753:Interleukin-10; D018664:Interleukin-12