title: Short-term MyD88 inhibition ameliorates cardiac graft rejection and promotes donor-specific hyporesponsiveness of skin grafts in mice.
abstract: Recognition of evolutionarily conserved ligands by Toll-like receptors (TLRs) triggers signaling cascades in innate immune cells to amplify adaptive immune responses. Nearly all TLRs require MyD88 to transduce downstream signaling. MyD88 deficiency has been shown to promote the allograft acceptance in mice. However, direct evidence for therapeutic potential of MyD88 inhibitors remains lacking. Herein, we used a MyD88 inhibitor, namely ST2825, to explore its therapeutic potential and mechanisms in fully allogeneic skin and heart transplant models. Phenotypic maturation of dendritic cells stimulated by TLR ligands was alleviated by ST2825 in parallel with reduced T-cell proliferation in vitro. A short-course treatment with ST2825 significantly prolonged cardiac graft survival (mean survival time = 18.5 ± 0.92 days vs. 7.25 ± 0.46 days). ST2825-treated group had significantly reduced proinflammatory cytokines in allografts compared with control group. ST2825 combined with anti-CD154 induced long-term skin allograft acceptance in about one-third of recipients (>100 days). 'Skin-tolerant' recipients showed attenuated donor-specific IFN-γ responses, intact IL-4 responses, and compromised alloantibody responses. We conclude that MyD88 inhibitor ST2825 attenuates acute cardiac rejection and promotes donor-specific hyporesponsiveness in stringent skin transplant models. The direct evidence suggests that pharmacological inhibition of MyD88 hold promising potential for transplant rejection.
authors.affiliation: Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education and Key Laboratory of Organ Transplantation, Ministry of Health, Wuhan, China.|Department of Endocrinology and Metabolism, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Wen-Tao
authors.initials: WT
authors.lastname: He
authors.affiliation: Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education and Key Laboratory of Organ Transplantation, Ministry of Health, Wuhan, China.
authors.forename: Li-Min
authors.initials: LM
authors.lastname: Zhang
authors.affiliation: Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education and Key Laboratory of Organ Transplantation, Ministry of Health, Wuhan, China.|Department of General Surgery, Tianjin Union Medical Center, Tianjin, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Li
authors.affiliation: Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education and Key Laboratory of Organ Transplantation, Ministry of Health, Wuhan, China.|Department of General Surgery, Tianjin Union Medical Center, Tianjin, China.
authors.forename: Shu-Yuan
authors.initials: SY
authors.lastname: Li
authors.affiliation: Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education and Key Laboratory of Organ Transplantation, Ministry of Health, Wuhan, China.
authors.forename: Zuo-Chuan
authors.initials: ZC
authors.lastname: Ding
authors.affiliation: Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education and Key Laboratory of Organ Transplantation, Ministry of Health, Wuhan, China.
authors.forename: Ze-Min
authors.initials: ZM
authors.lastname: Fang
authors.affiliation: Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education and Key Laboratory of Organ Transplantation, Ministry of Health, Wuhan, China.
authors.forename: Fan-Ying
authors.initials: FY
authors.lastname: Meng
authors.affiliation: Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education and Key Laboratory of Organ Transplantation, Ministry of Health, Wuhan, China.
authors.forename: Zhonghua Klaus
authors.initials: ZK
authors.lastname: Chen
authors.affiliation: Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education and Key Laboratory of Organ Transplantation, Ministry of Health, Wuhan, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhou
mesh_terms: D000818:Animals; D023201:CD40 Ligand / Q000378:metabolism; D018899:CpG Islands; D003713:Dendritic Cells / Q000166:cytology; D005260:Female; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000379:methods*; D006574:Heterocyclic Compounds, 2-Ring / Q000494:pharmacology*; D007249:Inflammation; D007518:Isoantibodies / Q000276:immunology; D008214:Lymphocytes / Q000166:cytology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000037:antagonists & inhibitors*; D012867:Skin / Q000473:pathology; D016038:Skin Transplantation; D013141:Spiro Compounds / Q000494:pharmacology*; D014019:Tissue Donors; D023001:Transplantation Tolerance; D014184:Transplantation, Homologous
chemical_list: D006574:Heterocyclic Compounds, 2-Ring; D007518:Isoantibodies; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C525002:ST2825; D013141:Spiro Compounds; D023201:CD40 Ligand
keywords: MyD88; cardiac transplantation; dendritic cells; donor-specific hyporesponsiveness; skin transplantation