LR7激动剂imiquimod的研究进展.ppt

1、Imiquimod-a TLR7 agonist,Xiaochen Yu 2013 10 21,Introduction,Imiquimod was the first small molecule approved for topical use in humans that was shown to act through the Toll-like receptor (TLR) pathway. Imiquimod activates innate immune cells that express TLR7 including plasmacytoid dendritic cells

2、(pDC), B cells and likely some monocytes. Depending on the cell type, this activation results in secretion of cytokines including interferon- (IFN-) and others, upregulation of costimulatory molecule expression and maturation and/or proliferation.,It was first identified as a compound that has anti-

3、viral activity in pigs infected with herpes simplex virus, and has been successfully used for the treatment of genital warts caused by human papilloma virus in the clinical. Recent study revealed it also has direct proapoptotic activity against various tumor cell populations in vitro and in vivo.,th

4、e antiviral activity of imiquimod,Imiquimod and its analogues have no direct in vitro antiviral activity and are not virucidal, rather the antiviral is indirect through cytokine induction and immune activation.,resiquimod (S-28463), imiquimod (S-26308). Human peripheral blood mononuclear cells (PBMC

5、),Mo-DC, dendritic cells (DC) derived from monocytes, plasmacytoid dendritic cells (pDC),Imiquimods proapoptotic effect in vitro,Imiquimod inhibits cell proliferation in prostate cancer cell lines.（detected by MTT）,Imiquimod induces apoptosis by imiquimod dose-dependent and by pass of mitochondria-d

6、ependent in prostate cancer cells,A TLR7 inhibitor chloroquine does not restore the growth inhibition by imiquimod,Results: Imiquimod induced apoptosis was independently of TLR7 and MyD88,Imiquimod inhibits in vivo growth of prostate cancer in mice,the role of imiquimod in macrophage,Numerous macrop

7、hages are present in the shoulder regions of rupture-prone life threatening atherosclerotic plaques. Removal of macrophages from plaques by macrophage-specific induction of cell death could represent an attractive approach to stabilize the structure of the plaque. To initiate selective macrophage de

8、ath, we examined Toll-like receptor 7 (TLR7) as a potential target, since it is expressed in macrophages but not in SMCs.,TLR7 expressed in macrophages but not in SMCs,macrophages (M), bone marrow-derived macrophages (BMM) from WT,TLR7+ and TLR7- mice, and mouse aortic SMCs from WT mice.,imiquimod i

9、nduced cell apoptosis is dependent on TLR7,b, e Macrophages and SMCs were incubated for 24 h with imiquimod (0.130 lg/ml). Cell viability was examined by neutralred assays.,imiquimod induced macrophage autophagy by TLR7,Imiquimod-induced macrophage inflammation is TLR7 dependent,the role of imiquimo

10、d in atherosclerotic plaque,Local administration of imiquimod to rabbit atheroma-like lesions induced autophagy in macrophages without affecting SMCs, as demonstrated by TEM, and induced an increase in plaque area. In vivo treatment of atheroma-like lesions with imiquimod did not deplete macrophages

11、, but rather stimulated macrophage infiltration due to cytokine release.,a Transmission electron-microscopic images of macrophages show autophagosome formation after imiquimod treatment for 7days. b Images of SMCs shown autophagosome formation after imiquimod treatment,I, intima; M, media; a, VCAM-1

12、; b, T cells; c, macrophages,These in vivo results seem to be in contrast with our invitro ndings (imiquimod induced autophagic death). The contradictory effects of imiquimod in vivo versus in vitro might be misleading because the level of autophagy induced by both conditions could be entirely diffe

13、rent.,TLR7/8 agonists as vaccine adjuvants,Imiquimod and similar analogs have vaccine adjuvant activity came from studies demonstrating the ability of these molecules to activate APCs, induce immune modulatory cytokines and activate B- and T-cell responses.,Mice vaccinated intradermally with microneedles coated with imiquimod and H1N1 HA induced IFN-producing T-cell response, high levels of IgG2 and protective immunity following a lethal challenge w