title: The immunosuppressant Protosappanin A diminished recipient T cell migration into allograft via inhibition of IP-10 in rat heart transplant.
abstract: The immunosuppressant Protosappanin A (PrA), isolated from the medicinal herb, promotes cardiac allograft survival, diminishes inflammatory cell infiltration, and inhibits interferon γ-induced protein 10 kDa (IP-10) mRNA expression in rats cardiac grafts. Binding of the chemokine IP-10 to its cognate receptor, CXCR3, plays crucial roles in allograft immunity, especially by mediating the recruitment of effector T cells to allografted tissues. In this study, we attempted to determine whether PrA-mediated inhibition of IP-10 contributes to the effect of reduced T cell infiltration into cardiac allograft within a rat model. Administration of PrA (25 mg/kg daily) via oral gavage following heart transplantation significantly reduced the increase of IP-10 mRNA level in allograft and prevented IP-10 secretion by peripheral blood mononuclear cells (PBMC) isolated from recipient rats seven days posttransplantation. Furthermore, in vitro experiments demonstrated that PrA addition to control PBMC prevented IP-10 secretion. Chemotactic migration assays were utilized to evaluate recipient T cell migration towards PBMC supernatant. PrA administration impaired PBMC supernatant-induced T cell migration. Additional in vitro experiments revealed that PrA slightly reduced naïve T cell migration towards chemokines. The presence of IP-10 in PBMC supernatant prevented PrA from reducing T cell migration in PrA-treated recipients. Neither CXCR3 chemokine ligand Mig nor non-CXCR3 chemokine ligand SDF-1 had any effect on T cell migration in PrA-treated recipients. The addition of anti-CXCR3 antibody restored PrA-mediated inhibition of T cell migration. Immunofluorescence microscopy showed that IP-10 was expressed mainly in CD68 positive infiltrating monocytes. Furthermore, PrA consistently reduced CXCR3+T cell infiltration into cardiac allografts. The reduced intensity of CXCR3 staining in PrA-treated allografts contributed to the previously depressed naïve T cell migrating activity induced by PrA. Collectively, these data indicate that PrA inhibition of IP-10 activity reduced recipient T cell migration and infiltration of cardiac allografts, thus partially explaining the immunosuppressive effect of PrA.
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.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: Jieqiong
authors.initials: J
authors.lastname: He
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: Jingbo
authors.initials: J
authors.lastname: Hou
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: Jian
authors.initials: J
authors.lastname: Wu
authors.affiliation: The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, Heilongjiang Province, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Sun
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: Jinjin
authors.initials: J
authors.lastname: Cui
authors.affiliation: The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, Heilongjiang Province, China.
authors.forename: Jiangtian
authors.initials: J
authors.lastname: Tian
authors.affiliation: Department of Cardiology, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Miaomiao
authors.initials: M
authors.lastname: Jiang
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: Bo
authors.initials: B
authors.lastname: Yu
mesh_terms: D064591:Allografts; D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects* / Q000276:immunology; D054357:Chemokine CXCL10 / Q000276:immunology*; D016027:Heart Transplantation; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D010636:Phenols / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D054367:Receptors, CXCR3 / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D054357:Chemokine CXCL10; D007166:Immunosuppressive Agents; D010636:Phenols; D054367:Receptors, CXCR3; C539355:CD68 protein, rat; D000097382:CD68 Molecule; C091326:Cxcl10 protein, rat; C515189:Cxcr3 protein, rat; C090723:protosappanin A