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.

IL-27 Is Essential for Suppression of Experimental Allergic Asthma by the TLR7/8 Agonist R848 (Resiquimod)

“…PD-L1 is a ligand for the negative costimulatory molecule PD-1, and this signaling pathway has been shown to compromise functions of Ag-specific T cells (61). Through upregulation of PD-L1, IFN-g leads to induction of tolerogenic properties in DCs (43,58), which acquire the capability to effectively suppress T cell responses in a PD-L1/PD-1-dependent manner (42,62,63). Furthermore, the ability of IL-27 as an inducer of tolerogenic DCs was recently confirmed in a clinical study in chronic obstructive pulmonary disease that provided evidence that IL-27-exposed DCs induced regulatory T cells in obstructive pulmonary disease patients (64).…”

Combination immunotherapy with TLR agonists and checkpoint inhibitors suppresses head and neck cancer

“…RNA was isolated from SCC7, MEER, and RAW264.7 murine macrophage cells using RNeasy Plus kit (QIAGEN) and was reverse-transcribed using iScript (Bio-Rad). qPCR analyses using Taqman Gene Expression Assay (Thermo Fisher Scientific) were performed by CFX-Connect Real-Time System (Bio-Rad) as described previously (76). Primers purchased from Thermo Fisher Scientific are described in Supplemental Table 4.…”

Tolerogenic Dendritic Cells from Poorly Compensated Type 1 Diabetes Patients Have Decreased Ability To Induce Stable Antigen-Specific T Cell Hyporesponsiveness and Generation of Suppressive Regulatory T Cells

“…To test that our protocol for generating tolDCs led to diabetes prevention in vivo, tolDCs were generated from bone marrow cells of NOD mice by using dexamethasone and vitamin D 2 . Previous studies showed that to prevent diabetes onset and induce Agspecific tolerance in animal model of diabetes, Ag supply might not be required in DC-based therapies for T1D (31)(32)(33)(34). It is suggested that unpulsed DCs could pick up diabetogenic Ags in vivo and present them in a tolerogenic fashion (35).…”