期刊
JCI INSIGHT
卷 4, 期 18, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.126025
关键词
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资金
- National Health and Medical Research Council (NHMRC) [1071822, 1083192]
- NHMRC Senior Research Fellowship
- Arthritis Queensland
- Arthritis Australia
- National Health and Medical Research Council of Australia [1083192] Funding Source: NHMRC
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 1 alpha.,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 OVA(323-339) and calcitriol targeted dLN PD-L1(hi) DCs of immunized mice and reduced their MHC class II expression. OVA(323)(-3)(39)/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 7 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.
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