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

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 & 7 others Ravi Malaviya, David J. Shealy, Daniel G. Baker, Loui Madakamutil, A. Richard Kitching, Brendan J. O’Sullivan, Ranjeny Thomas

Research output: Contribution to journalArticleResearchpeer-review

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Abstract

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.

Original languageEnglish
Article numbere126025
Number of pages21
JournalJCI Insight
Volume4
Issue number18
DOIs
Publication statusPublished - 19 Sep 2019

Cite this

Galea, Ryan ; Nel, Hendrik J. ; Talekar, Meghna ; Liu, Xiao ; Ooi, Joshua D. ; Huynh, Megan ; Hadjigol, Sara ; Robson, Kate J. ; Ting, Yi Tian ; Cole, Suzanne ; Cochlin, Karyn ; Hitchcock, Shannon ; Zeng, Bijun ; Yekollu, Suman ; Boks, Martine ; Goh, Natalie ; Roberts, Helen ; Rossjohn, Jamie ; Reid, Hugh H. ; Boyd, Ben J. ; Malaviya, Ravi ; Shealy, David J. ; Baker, Daniel G. ; Madakamutil, Loui ; Richard Kitching, A. ; O’Sullivan, Brendan J. ; Thomas, Ranjeny. / PD-L1– and calcitriol-dependent liposomal antigen-specific regulation of systemic inflammatory autoimmune disease. In: JCI Insight. 2019 ; Vol. 4, No. 18.
@article{d6c9ae0ac77c4ef09806d8fcdf985233,
title = "PD-L1– and calcitriol-dependent liposomal antigen-specific regulation of systemic inflammatory autoimmune disease",
abstract = "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.",
author = "Ryan Galea and Nel, {Hendrik J.} and Meghna Talekar and Xiao Liu and Ooi, {Joshua D.} and Megan Huynh and Sara Hadjigol and Robson, {Kate J.} and Ting, {Yi Tian} and Suzanne Cole and Karyn Cochlin and Shannon Hitchcock and Bijun Zeng and Suman Yekollu and Martine Boks and Natalie Goh and Helen Roberts and Jamie Rossjohn and Reid, {Hugh H.} and Boyd, {Ben J.} and Ravi Malaviya and Shealy, {David J.} and Baker, {Daniel G.} and Loui Madakamutil and {Richard Kitching}, A. and O’Sullivan, {Brendan J.} and Ranjeny Thomas",
year = "2019",
month = "9",
day = "19",
doi = "10.1172/jci.insight.126025",
language = "English",
volume = "4",
journal = "JCI Insight",
issn = "2379-3708",
publisher = "The American Society for Clinical Investigation",
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Galea, R, Nel, HJ, Talekar, M, Liu, X, Ooi, JD, Huynh, M, Hadjigol, S, Robson, KJ, Ting, YT, Cole, S, Cochlin, K, Hitchcock, S, Zeng, B, Yekollu, S, Boks, M, Goh, N, Roberts, H, Rossjohn, J, Reid, HH, Boyd, BJ, Malaviya, R, Shealy, DJ, Baker, DG, Madakamutil, L, Richard Kitching, A, O’Sullivan, BJ & Thomas, R 2019, 'PD-L1– and calcitriol-dependent liposomal antigen-specific regulation of systemic inflammatory autoimmune disease', JCI Insight, vol. 4, no. 18, e126025. https://doi.org/10.1172/jci.insight.126025

PD-L1– and calcitriol-dependent liposomal antigen-specific regulation of systemic inflammatory autoimmune disease. / Galea, Ryan; Nel, Hendrik J.; Talekar, Meghna; Liu, Xiao; Ooi, Joshua D.; Huynh, Megan; Hadjigol, Sara; Robson, Kate J.; Ting, Yi Tian; Cole, Suzanne; Cochlin, Karyn; Hitchcock, Shannon; Zeng, Bijun; Yekollu, Suman; Boks, Martine; Goh, Natalie; Roberts, Helen; Rossjohn, Jamie; Reid, Hugh H.; Boyd, Ben J.; Malaviya, Ravi; Shealy, David J.; Baker, Daniel G.; Madakamutil, Loui; Richard Kitching, A.; O’Sullivan, Brendan J.; Thomas, Ranjeny.

In: JCI Insight, Vol. 4, No. 18, e126025, 19.09.2019.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - PD-L1– and calcitriol-dependent liposomal antigen-specific regulation of systemic inflammatory autoimmune disease

AU - Galea, Ryan

AU - Nel, Hendrik J.

AU - Talekar, Meghna

AU - Liu, Xiao

AU - Ooi, Joshua D.

AU - Huynh, Megan

AU - Hadjigol, Sara

AU - Robson, Kate J.

AU - Ting, Yi Tian

AU - Cole, Suzanne

AU - Cochlin, Karyn

AU - Hitchcock, Shannon

AU - Zeng, Bijun

AU - Yekollu, Suman

AU - Boks, Martine

AU - Goh, Natalie

AU - Roberts, Helen

AU - Rossjohn, Jamie

AU - Reid, Hugh H.

AU - Boyd, Ben J.

AU - Malaviya, Ravi

AU - Shealy, David J.

AU - Baker, Daniel G.

AU - Madakamutil, Loui

AU - Richard Kitching, A.

AU - O’Sullivan, Brendan J.

AU - Thomas, Ranjeny

PY - 2019/9/19

Y1 - 2019/9/19

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85072647654&partnerID=8YFLogxK

U2 - 10.1172/jci.insight.126025

DO - 10.1172/jci.insight.126025

M3 - Article

VL - 4

JO - JCI Insight

JF - JCI Insight

SN - 2379-3708

IS - 18

M1 - e126025

ER -