UC San Diego

Type 1 Diabetes (T1D) is an autoimmune disease characterized by T-cell mediated destruction of the insulin-producing pancreatic islets. The activation of dendritic cells (DCs) contributes to initiating and perpetuating this inflammatory process as well as in other autoimmune disorders. It has been shown previously that low dose stimulation with a synthetic TLR7 ligand (1V136) led to TLR hyporesponsiveness and suppressed DC activation. A new TLR7 ligand was synthesized through conjugation to six units of polyethylene glycol (1Z1) and the effects of 1Z1 on DC phenotype and function were characterized. 1Z1 did not stimulate proinflammatory cytokine production in comparison to the parent compound, 1V136, but still induced refractory status to subsequent TLR7 stimulation. DCs treated with 1Z1 exhibited a semi- matured phenotype and had decreased CD4+ T cell activation function. Daily 1Z1 administration to prediabetic non- obese diabetic (NOD) mice significantly delayed the onset of disease and reduced immune cell infiltration into the pancreatic islets. 1Z1 increased programmed death-1 ligand 1 (PD-L1) expression on CD11c+ DCs in the local lymph nodes. 1Z1 treatment neither caused any adverse effects such as weight loss or cytokine storm in vivo nor induced B cell proliferation in vitro. In summary, chronic 1Z1 treatment induced suppressive phenotype and functionality in DCs which reduced pancreatic T cell activation in prediabetic NOD mice. 1Z1 may be a novel treatment for DC- mediated organ-specific inflammatory diseases