Journal Article

Induction of Tolerogenic Dendritic Cells by a PEGylated TLR7 Ligand for Treatment of Type 1 Diabetes

Promessi, Victor J., Carson, Dennis A., Shyu, Luke, Hayashi, Tomoko, Crain, Brian, Cottam, Howard B., Sheng, Caroline, Corr, Maripat, Kang, McNancy, Yao, Shiyin

2015

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adoptive Transfer / Animals / Antigens / Apoptosis / Arthritis / Autoimmune diseases / B cells / B7-H1 Antigen - genetics / B7-H1 Antigen - metabolism / Bone marrow / Cancer / CD11c antigen / CD80 antigen / CD86 antigen / Cell activation / Cytokines / Cytokines - metabolism / Dendritic cells / Dendritic Cells - drug effects / Dendritic Cells - immunology / Dendritic Cells - metabolism / Diabetes / Diabetes mellitus / Diabetes mellitus (insulin dependent) / Diabetes Mellitus, Type 1 - genetics / Diabetes Mellitus, Type 1 - immunology / Diabetes Mellitus, Type 1 - metabolism / Diabetes Mellitus, Type 1 - therapy / Diabetes therapy / Disease Models, Animal / Female / Gene Expression / Hyperglycemia / Immune Tolerance / Immunity, Innate / Immunomodulation / Immunoregulation / Inflammation / Inflammation Mediators - metabolism / Insulitis / Interleukin 1 / Islet cells / Laboratory animals / Leukocytes, Mononuclear - drug effects / Leukocytes, Mononuclear - immunology / Leukocytes, Mononuclear - metabolism / Ligands / Lymph nodes / Lymphocyte Activation - immunology / Lymphocytes / Lymphocytes T / Major histocompatibility complex / Mice / Mice, Inbred NOD / Mice, Knockout / Modulation / Pancreas / Pancreatic beta cells / PD-L1 protein / Phenotype / Phenotypes / Polyethylene glycol / Rodents / T cell receptors / T cells / T-Lymphocyte Subsets - drug effects / T-Lymphocyte Subsets - immunology / T-Lymphocyte Subsets - metabolism / TLR7 protein / Toll-Like Receptor 7 - genetics / Toll-Like Receptor 7 - metabolism / Toll-like receptors / Type 1 diabetes