title: Induction of Tolerogenic Dendritic Cells by a PEGylated TLR7 Ligand for Treatment of Type 1 Diabetes.
abstract: Autoimmune diabetes mellitus (DM) results from the destruction of pancreatic islet cells by activated T lymphocytes, which have been primed by activated dendritic cells (DC). Individualized therapy with ex vivo DC manipulation and reinfusion has been proposed as a treatment for DM, but this treatment is limited by cost, and requires specialized facilities. A means of in situ modulation of the DC phenotype in the host would be more accessible. Here we report a novel innate immune modulator, 1Z1, generated by conjugating a TLR7 ligand to six units of polyethylene glycol (PEG), which skews DC phenotype in vivo. 1Z1 was less potent in inducing cytokine production by DC than the parent ligand in vitro and in vivo. In addition, this drug only modestly increased DC surface expression of activation markers such as MHC class II, CD80, and CD86; however, the expression of negative regulatory molecules, such as programmed death ligand 1 (PD-L1), and interleukin-1 receptor-associated kinase M (IRAK-M) were markedly increased. In vivo transfer of 1Z1 treated DC into prediabetic NOD mice delayed pancreatic insulitis. Daily administration of 1Z1 effectively prevented the clinical onset of hyperglycemia and reduced histologic islet inflammation. Daily treatment with 1Z1 increased PD-L1 expression in the CD11c(+) population in peri-pancreatic lymph nodes; however, it did not induce an increase in regulatory T cells. Pharmaceutical modulation of DC maturation and function in situ, thus represents an opportunity to treat autoimmune disease.
authors.affiliation: Moores Cancer Center, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0695, United States of America.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Hayashi
authors.affiliation: Moores Cancer Center, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0695, United States of America.
authors.forename: Shiyin
authors.initials: S
authors.lastname: Yao
authors.affiliation: Moores Cancer Center, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0695, United States of America.
authors.forename: Brian
authors.initials: B
authors.lastname: Crain
authors.affiliation: Moores Cancer Center, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0695, United States of America.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Promessi
authors.affiliation: Moores Cancer Center, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0695, United States of America.
authors.forename: Luke
authors.initials: L
authors.lastname: Shyu
authors.affiliation: Moores Cancer Center, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0695, United States of America.
authors.forename: Caroline
authors.initials: C
authors.lastname: Sheng
authors.affiliation: Moores Cancer Center, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0695, United States of America.
authors.forename: McNancy
authors.initials: M
authors.lastname: Kang
authors.affiliation: Moores Cancer Center, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0695, United States of America.
authors.forename: Howard B
authors.initials: HB
authors.lastname: Cottam
authors.affiliation: Moores Cancer Center, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0695, United States of America.
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Carson
authors.affiliation: Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0663, United States of America.
authors.forename: Maripat
authors.initials: M
authors.lastname: Corr
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D060890:B7-H1 Antigen / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000628:therapy; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D007108:Immune Tolerance; D007113:Immunity, Innate; D056747:Immunomodulation; D018836:Inflammation Mediators / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D010641:Phenotype; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000378:metabolism*
chemical_list: D060890:B7-H1 Antigen; D016207:Cytokines; D018836:Inflammation Mediators; D008024:Ligands; D051199:Toll-Like Receptor 7