title: Peptide nucleic acid antisense prolongs skin allograft survival by means of blockade of CXCR3 expression directing T cells into graft.
abstract: CXCR3, predominantly expressed on memory/activated T cells, is a receptor for both IFN-gamma-inducible protein 10/CXC chemokine ligand (CXCL)10 and monokine induced by IFN-gamma/CXCL9. It was reported that CXC chemokines IFN-gamma-inducible protein 10/CXCL10 and monokine induced by IFN-gamma/CXCL9 play a critical role in the allograft rejection. We report that CXCR3 is a dominant factor directing T cells into mouse skin allograft, and that peptide nucleic acid (PNA) CXCR3 antisense significantly prolongs skin allograft survival by means of blockade of CXCR3 expression directing T cells into allografts in mice. We found that CXCR3 is highly up-regulated in spleen T cells and allografts from BALB/c recipients by day 7 of receiving transplantation, whereas CCR5 expression is moderately increased. We designed PNA CCR5 and PNA CXCR3 antisenses, and i.v. treated mice that received skin allograft transplantations. The PNA CXCR3 at a dosage of 10 mg/kg/day significantly prolonged mouse skin allograft survival (17.1 +/- 2.4 days) compared with physiological saline treatment (7.5 +/- 0.7 days), whereas PNA CCR5 (10 mg/kg/day) marginally prolonged skin allograft survival (10.7 +/- 1.1 days). The mechanism of prolongation of skin allograft survival is that PNA CXCR3 directly blocks the CXCR3 expression in T cells, which is responsible for directing T cells into skin allograft to induce acute rejection, without interfering with other functions of the T cells. These results were obtained at mRNA and protein levels by flow cytometry and real-time quantitative RT-PCR technique, and confirmed by chemotaxis, Northern and Western blot assays, and histological evaluation of skin grafts. The present study indicates the therapeutic potential of PNA CXCR3 to prevent acute transplantation rejection.
authors.affiliation: Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Ming
authors.initials: M
authors.lastname: Jiankuo
authors.forename: Wang
authors.initials: W
authors.lastname: Xingbing
authors.forename: Huang
authors.initials: H
authors.lastname: Baojun
authors.forename: Wu
authors.initials: W
authors.lastname: Xiongwin
authors.forename: Li
authors.initials: L
authors.lastname: Zhuoya
authors.forename: Xiong
authors.initials: X
authors.lastname: Ping
authors.forename: Xu
authors.initials: X
authors.lastname: Yong
authors.forename: Liu
authors.initials: L
authors.lastname: Anting
authors.forename: Hu
authors.initials: H
authors.lastname: Chunsong
authors.forename: Gong
authors.initials: G
authors.lastname: Feili
authors.forename: Tan
authors.initials: T
authors.lastname: Jinquan
mesh_terms: D000208:Acute Disease; D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000276:immunology*; D018450:Disease Progression; D006085:Graft Survival / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016376:Oligonucleotides, Antisense / Q000494:pharmacology* / Q000627:therapeutic use; D020135:Peptide Nucleic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D016038:Skin Transplantation / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: C515188:Cxcr3 protein, mouse; D016376:Oligonucleotides, Antisense; D020135:Peptide Nucleic Acids; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine