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

Ryan Galea^1,2, Hendrik Nel^1,2, Meghna Talekar^1,2, Suzanne Cole³, Karyn Cochlin⁴, Shannon Hitchcock⁵, Bijun Zeng^1,2, Suman Yekollu^1,2, Jamie Rossjohn⁶, Hugh Reid⁷, Ravi Malaviya⁵, Dave Shealy⁸, Brendan O'Sullivan^1,2 and Ranjeny Thomas^1,2, ¹Dendright Pty Ltd, Brisbane, Australia, ²University of Queensland Diamantina Institute, Brisbane, Australia, ³Immunology, Janssen Research and Development, Spring House, PA, ⁴Immunology, Janssen Research and Development, Springhouse, PA, ⁵Janssen Research and Development, Springhouse, PA, ⁶Infection and Immunity Program, Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia, ⁷Monash University, Melbourne, Australia, ⁸Janssen Research and Development, Spring House, PA

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: animal models and tolerance, Dendritic cells, nanomedicine, rheumatoid arthritis

Session Information

Date: Tuesday, November 7, 2017

Title: T Cell Biology and Targets in Autoimmune Disease Poster II

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose:

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.

Methods:

Egg phosphatidylcholine liposomes encapsulating 1,25 dihydroxycholecalciferol (calcitriol) and OVA_323-339 or aggrecan_89-103 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.

Results:

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. aggrecan_89-103/calcitriol but not OVA_323-339/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.

Conclusion:

Skin migratory DCs are targeted and tolerized by calcitriol-peptide liposomes, triggering “infectious” antigen-specific tolerance mechanisms to regulate autoimmune arthritis.

Disclosure: R. Galea, None; H. Nel, None; M. Talekar, None; S. Cole, Janssen, 3; K. Cochlin, Janssen Pharmaceutica Product, L.P., 3; S. Hitchcock, Johnson & Johnson, 3; B. Zeng, None; S. Yekollu, None; J. Rossjohn, Janssen Pharmaceutica Product, L.P., 2,Janssen Pharmaceutica Product, L.P., 5; H. Reid, Janssen Pharmaceutica Product, L.P., 2,Janssen Pharmaceutica Product, L.P., 5; R. Malaviya, Johnson & Johnson, 3,Johnson & Johnson, 1; D. Shealy, Johnson & Johnson, 1; B. O'Sullivan, None; R. Thomas, Janssen Pharmaceutica Product, L.P., 2,Janssen Pharmaceutica Product, L.P., 5.

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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