Conjugation of Transforming Growth Factor Beta to Antigen-Loaded Poly(lactide-co-glycolide) Nanoparticles Enhances Efficiency of Antigen-Specific Tolerance

被引：69

作者：

Casey, Liam M. ^{[1
]}

Pearson, Ryan M. ^{[2
,7
]}

Hughes, Kevin R. ^{[2
]}

Liu, Jeffrey M. H. ^{[2
,3
]}

Rose, Justin A. ^{[1
]}

North, Madeleine G. ^{[2
]}

Wang, Leon Z. ^{[2
]}

Lei, Mei ^{[2
]}

Miller, Stephen D. ^{[4
,5
,6
]}

Shea, Lonnie D. ^{[1
,2
]}

机构：

[1] Univ Michigan, Dept Chem Engn, 2300 Hayward Ave, Ann Arbor, MI 48105 USA

[2] Univ Michigan, Dept Biomed Engn, 1119 Carl A Gerstacker Bldg,2200 Bonisteel Blvd, Ann Arbor, MI 48109 USA

[3] Northwestern Univ, Interdisciplinary Biol Sci Program, Evanston, IL 60208 USA

[4] Northwestern Univ, Chem Life Proc Inst CLP, Evanston, IL 60208 USA

[5] Northwestern Univ, Feinberg Sch Med, Dept Microbiol Immunol, 6-713 Tarry Bldg,303 East Chicago Ave, Chicago, IL 60611 USA

[6] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA

[7] Cour Pharmaceut, Northbrook, IL 60062 USA

来源：

BIOCONJUGATE CHEMISTRY | 2018年 / 29卷 / 03期

关键词：

EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; DENDRITIC CELLS; IN-VIVO; IMMUNE TOLERANCE; TOLEROGENIC NANOPARTICLES; BONE-MARROW; TRANSPLANTATION; INDUCTION; DELIVERY;

D O I：

10.1021/acs.bioconjchem.7b00624

中图分类号：

Q5 [生物化学];

学科分类号：

071010 ; 081704 ;

摘要：

Current strategies for treating autoimmunity involve the administration of broad-acting immunosuppressive agents that impair healthy immunity. Intravenous (i.v.) administration of poly(lactide-co-glycolide) nanoparticles (NPs) containing disease-relevant antigens (Ag-NPs) have demonstrated antigen (Ag)-specific immune tolerance in models of autoimmunity. However, subcutaneous (s.c.) delivery of Ag-NPs has not been effective. This investigation tested the hypothesis that codelivery of the immunomodulatory cytokine, transforming growth factor beta 1 (TGF-beta), on Ag-NPs would modulate the immune response to Ag-NPs and improve the efficiency of tolerance induction. TGF-beta was coupled to the surface of Ag-NPs such that the loadings of Ag and TGF-beta were independently tunable. The particles demonstrated bioactive delivery of Ag and TGF-beta in vitro by reducing the inflammatory phenotype of bone marrow-derived dendritic cells and inducing regulatory T cells in a coculture system. Using an in vivo mouse model for multiple sclerosis, experimental autoimmune encephalomyelitis, TGF-beta codelivery on Ag-NPs resulted in improved efficacy at lower doses by i.v. administration and significantly reduced disease severity by s.c. administration. This study demonstrates that the codelivery of immunomodulatory cytokines on Ag-NPs may enhance the efficacy of Ag-specific tolerance therapies by programming Ag presenting cells for more efficient tolerance induction.

引用

页码：813 / 823

页数：11

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