ovalbumin and Anti-Glomerular-Basement-Membrane-Disease

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

Topics: Adoptive Transfer; Animals; Anti-Glomerular Basement Membrane Disease; Antigen Presentation; Arthritis, Rheumatoid; B7-H1 Antigen; Calcitriol; Cell Differentiation; CHO Cells; Cricetulus; Dendritic Cells; Disease Models, Animal; Female; HLA-DR Antigens; Humans; Immune Tolerance; Immunodominant Epitopes; Immunologic Memory; Injections, Subcutaneous; Liposomes; Lymph Nodes; Mice; Mice, Transgenic; Ovalbumin; Peptide Fragments; Phagocytosis; Severity of Illness Index; T-Lymphocytes

Podocytes are essential to the structure and function of the glomerular filtration barrier; however, they also exhibit increased expression of MHC class II molecules under inflammatory conditions, and they remove Ig and immune complexes from the glomerular basement membrane (GBM). This finding suggests that podocytes may act as antigen-presenting cells, taking up and processing antigens to initiate specific T cell responses, similar to professional hematopoietic cells such as dendritic cells or macrophages. Here, MHC-antigen complexes expressed exclusively on podocytes of transgenic mice were sufficient to activate CD8+ T cells in vivo. In addition, deleting MHC class II exclusively on podocytes prevented the induction of experimental anti-GBM nephritis. Podocytes ingested soluble and particulate antigens, activated CD4+ T cells, and crosspresented exogenous antigen on MHC class I molecules to CD8+ T cells. In conclusion, podocytes participate in the antigen-specific activation of adaptive immune responses, providing a potential target for immunotherapies of inflammatory kidney diseases and transplant rejection.

Topics: Adaptive Immunity; Animals; Anti-Glomerular Basement Membrane Disease; Antigen Presentation; Antigen-Presenting Cells; CD8-Positive T-Lymphocytes; Cell Communication; Female; Glomerular Basement Membrane; Glomerular Filtration Barrier; Graft Rejection; Histocompatibility Antigens Class II; Immunoglobulin G; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Knockout; Microspheres; Ovalbumin; Phagocytosis; Podocytes