Session Type: ACR Poster Session C
Session Time: 9:00AM-11:00AM
Current treatments to control autoimmune arthritis and vasculitis use broadly immunosuppressive drugs, associated with undesirable side effects. Antigen-specific immunological tolerance strategies are preferable to control both cellular and humoral immune responses in autoimmune diseases, using the natural process of antigen presentation by dendritic cells (DCs) to control the balance of regulatory T cells (Treg) relative to pathogenic effector (Teff) T cells and B cells. In a phase I clinical trial, intradermally-injected autologous DCs exposed to citrullinated peptides and BAY11-7082 reduced circulating Teff and increased the ratio of Treg to Teff in rheumatoid arthritis. However, simpler strategies are desirable for widespread clinical use. In skin draining lymph nodes (dLN), migratory but not resident DCs are required for tolerance. We developed a strategy for passive targeting of DCs in situ after s.c. delivery of a nanoparticulate liposome formation encapsulating peptide and NF-kB inhibitor.
Egg phosphatidylcholine liposomes encapsulating 1,25 dihydroxycholecalciferol (calcitriol) and OVA323-339 or aggrecan89-103 peptide were prepared by thin film hydration. Distribution of DiI-labeled liposomes was assessed with in vivo imaging and flow cytometry. DO11.10 OVA-specific memory T cells were generated ex vivo. The response of transferred T cells to liposomes administered i.v. or s.c. was assessed by flow cytometry. Proteoglycan-induced arthritis (PGIA) was induced with recombinant human proteoglycan and DDA adjuvant. IAd-aggrecan tetramers identified aggrecan-specific T cells.
Liposomes encapsulating calcitriol and peptide were 90-130 nm. After s.c. administration, liposomes encapsulating calcitriol and peptide rapidly distributed to the subcapsular sinus then penetrated dLN, with the majority taken up by CD11b+CD11c+MHC class II+ migratory DCs. Two s.c. injections of OVA323-336/calcitriol liposomes suppressed antigen-specific CD4+ T cell expansion and IFN-g production and induced antigen-specific Foxp3+ peripheral (p)Treg. The induced pTreg suppressed proliferation of and promoted IL-10 production by a second cohort of OVA-specific Teff. In the proteoglycan-induced arthritis (PGIA) model, s.c. aggrecan89-103/calcitriol but not OVA323-339/calcitriol liposomes prevented disease development and suppressed the severity of established arthritis, associated with reduced autoreactive T cell expansion and reduced memory and follicular-helper T cell differentiation relative to naïve T cells.
Skin migratory DCs are targeted and tolerized by calcitriol-peptide liposomes, triggering “infectious” antigen-specific tolerance mechanisms to regulate autoimmune arthritis.
To cite this abstract in AMA style:Galea R, Nel H, Talekar M, Cole S, Cochlin K, Hitchcock S, Zeng B, Yekollu S, Rossjohn J, Reid H, Malaviya R, Shealy D, O'Sullivan B, Thomas R. Skin Migratory Dendritic Cells Targeted and Tolerized By Calcitriol-Peptide Liposomes Supress Antigen-Specific Autoreactive T Cell Expansion and Memory Differentiation to Regulate Autoimmune Arthritis [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/skin-migratory-dendritic-cells-targeted-and-tolerized-by-calcitriol-peptide-liposomes-supress-antigen-specific-autoreactive-t-cell-expansion-and-memory-differentiation-to-regulate-autoimmune-arthritis/. Accessed .
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/skin-migratory-dendritic-cells-targeted-and-tolerized-by-calcitriol-peptide-liposomes-supress-antigen-specific-autoreactive-t-cell-expansion-and-memory-differentiation-to-regulate-autoimmune-arthritis/