PD-L1– and calcitriol-dependent liposomal antigen-specific regulation of systemic inflammatory autoimmune disease

• DOI: 10.1172/jci.insight.126025
• Publication Date: 2019-09-05T16:00:36Z
• Authors: Ryan Galea; Hendrik J. Nel; Meghna Talekar; Xiao Liu; Joshua D. Ooi; Megan Huynh; Sara Hadjigol; Kate J. Robson; Yi Tian Ting; Suzanne Cole; Karyn Cochlin; Shannon Hitchcock; Bijun Zeng; Suman Yekollu; Martine Boks; Natalie Goh; Helen Roberts; Jamie Rossjohn; Hugh H. Reid; Ben J. Boyd; Ravi Malaviya; David J. Shealy; Daniel G. Baker; Loui Madakamutil; A. Richard Kitching; Brendan J. O’Sull...; Ranjeny Thomas
• Keywords: 570; Anti-Glomerular Basement Membrane Disease; Injections, Subcutaneous; 610; Autoimmunity; CHO Cells; Mouse models; B7-H1 Antigen; Arthritis, Rheumatoid; 03 medical and health sciences; Cricetulus; 0302 clinical medicine; Calcitriol; Antigen presenting cells; Immune Tolerance; Animals; Humans; Antigen Presentation; Immunodominant Epitopes; Cell Differentiation; Dendritic Cells; HLA-DR Antigens; Adoptive Transfer; 3. Good health; Disease Models, Animal; 2700 Medicine; Nephrology; Liposomes; Female; Tolerance; Immunologic Memory

Autoimmune diseases resulting from MHC class II–restricted autoantigen-specific T cell immunity include the systemic inflammatory autoimmune conditions rheumatoid arthritis and vasculitis. While currently treated with broad-acting immunosuppressive drugs, a preferable strategy is to regulate antigen-specific effector cells (Teffs) restore tolerance by exploiting DC antigen presentation. We targeted draining lymph node (dLN) phagocytic DCs using liposomes encapsulating 1α,25-dihydroxyvitamin D3 (calcitriol) antigenic peptide elucidate mechanisms of used responding under resting immunized conditions. PD-L1 expression was upregulated in dLNs relative naive mice. Subcutaneous administration OVA323–339 calcitriol dLN PD-L1hi mice reduced their II expression. OVA323–339/calcitriol suppressed expansion, differentiation, function Teffs induced Foxp3+ IL-10+ peripheral Tregs an manner, which dependent on PD-L1. Peptide/calcitriol modulated CD40 human promoted Treg induction vitro. Liposomes disease-associated peptides severity Goodpasture's vasculitis models suppression memory differentiation function. Accordingly, peptide/calcitriol leverage for regulation induce diseases.