title: A peptide tetramer Tk-tPN induces tolerance of cardiac allografting by conversion of type 1 to type 2 immune responses via the Toll-like receptor 2 signal-promoted activation of the MCP1 gene.
abstract: The plant protein trichosanthin (Tk) and its derived peptide tetramer Tk-tPN have been shown to stimulate the type 2 immune responses for treating autoimmune disease. This work explores the possibility of using Tk-tPN as a non-toxic immunosuppressant to induce transplantation tolerance using the mechanisms by which T-cell-mediated immune responses are transferred from type 1 to type 2 through innate immunity-related pathways. Immunocytes and cytokine secretions involved in the mouse cardiac allografting model with Tk-tPN treatment were characterized. Identification of critical genes and analysis of their functions through Toll-like receptor (TLR) -initiated signalling and the possible epigenetic changes were performed. Mean survival times of the cardiac allografts were delayed from 7.7 ± 0.3 days (control) to 22.7 ± 3.9 days (P < 0.01) or 79.1 ± 19.2 days (P < 0.0001) when Tk-tPN was introduced into the recipients alone or together with rapamycin, respectively. The grafting tolerance was donor-specific. The secretion pattern of the type 1 cytokine/transcription factor (IL-2(+) IFN-γ(+) T-bet(+)), which is responsible for the acute graft rejection, was shifted to the type 2 factor (IL-4(+) IL-10(+) Gata3+), together with a selective expansion of the IL-4/IL-10-producing CD8+ CD28- regulatory T-cell subset. A TLR2-initiated high expression of chemokine gene MCP1 was detectable simultaneously. Epigenetically Tk/Tk-tPN could also acetylate the histone H3K9 of MCP1 promoter to skew the immunity towards T helper type 2 responses. Tk/Tk-tPN is therefore capable of down-regulating the type 1 response-dominant rejection of cardiac allografts by evoking type 2 immunity through the activation of a TLR2-initiated signalling pathway and MCP1 gene to expand the IL-4/IL-10-secreting CD8+ CD28- regulatory T cells. Tk-tPN could be a promising novel immunosuppressant to induce tolerance in allotransplantation.
authors.affiliation: Shanghai Institute of Immunology, Shanghai, China.
authors.forename: Zuoqing
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Immunology, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Neng
authors.initials: N
authors.lastname: Yang
authors.affiliation: Shanghai Institute of Immunology, Shanghai, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Immunology, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Gu
authors.affiliation: Transplantation Unit, Shanghai Ruijin Hospital, Shanghai, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Shanghai Institute of Immunology, Shanghai, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Transplantation Unit, Shanghai Ruijin Hospital, Shanghai, China.
authors.forename: Peijun
authors.initials: P
authors.lastname: Zhou
authors.affiliation: Shanghai Institute of Immunology, Shanghai, China.
authors.forename: Liming
authors.initials: L
authors.lastname: Lu
authors.affiliation: Department of Immunology, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Kuang-Yen
authors.initials: KY
authors.lastname: Chou
mesh_terms: D064591:Allografts; D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000276:immunology; D014181:Transplantation Immunology / Q000276:immunology*; D023001:Transplantation Tolerance / Q000276:immunology*; D015978:Trichosanthin / Q000494:pharmacology*
chemical_list: D018932:Chemokine CCL2; D007166:Immunosuppressive Agents; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D015978:Trichosanthin
keywords: CD8+ CD28− regulatory T cells; Toll-like receptor 2 signalling; cardiac allografting; monocyte chemoattractant protein-1; trichosanthin-derived peptide