Combination Treatment with Antigen-Specific Dual-Sized Microparticle System Plus Anti-CD3 Immunotherapy Fails to Synergize to Improve Late-Stage Type 1 Diabetes Prevention in Nonobese Diabetic Mice.
ACS Biomater Sci Eng
; 6(10): 5941-5958, 2020 10 12.
Article
em En
| MEDLINE
| ID: mdl-33320581
ABSTRACT
Type 1 diabetes (T1D) pathophysiology, while incompletely understood, has in part been attributed to aberrant presentation of self-antigen plus proinflammatory costimulation by professional antigen-presenting cells (APCs). Therapies targeting dendritic cells (DCs) offer an avenue to restore antigen-specific tolerance by promoting presentation of self-antigen in an anti-inflammatory or suppressive context. Here, we describe a subcutaneously administered, dual-sized biodegradable microparticle (MP) platform that includes phagocytosable (â¼1 µm) and nonphagocytosable (â¼30 µm) MPs to deliver pro-tolerogenic factors both intra- and extracellularly, as well as the T1D-associated autoantigen, insulin, to DCs for amelioration of autoimmunity. This MP platform resulted in increased recruitment of DCs, suppressive skewing of DC phenotype with diminished expression of CD86 and MHC-II, increased regulatory T cell (Treg) frequency, and upregulated expression of the checkpoint inhibitor programmed cell death protein 1 (PD-1) on T cells. When administered concomitantly with anti-CD3 antibody, which provides transient T cell depletion while preserving Treg populations, in 12-week-old nonobese diabetic (NOD) mice, regulatory immune populations persisted out to 20 weeks of age; however, combination anti-CD3 and dual-sized MP (dMP) therapy failed to synergistically inhibit diabetes onset.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
1_ASSA2030
/
6_ODS3_enfermedades_notrasmisibles
Base de dados:
MEDLINE
Assunto principal:
Diabetes Mellitus Experimental
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Diabetes Mellitus Tipo 1
Limite:
Animals
Idioma:
En
Revista:
ACS Biomater Sci Eng
Ano de publicação:
2020
Tipo de documento:
Article