An injectable synthetic immune-priming center mediates efficient T-cell class switching and T-helper 1 response against B cell lymphoma.
J Control Release
; 155(2): 184-92, 2011 Oct 30.
Article
em En
| MEDLINE
| ID: mdl-21708196
ABSTRACT
Patients with malignant non-Hodgkin's lymphomas (NHL) of B-cell lineages relapse despite initial anti-tumor response to chemotherapy or antibody treatments. Failure to eliminate the tumor is often because of inadequate priming, low cell numbers and suboptimal phenotype of effector T cells. Here we describe a new biomaterial-based controlled-release paradigm to treat weakly immunogenic NHLs by in-situ amplifying the number of functional, antigen-specific T-helper 1 (Th1) cells following immunotherapy. An injectable, synthetic immune priming center (sIPC) consisting of an in-situ crosslinking, chemokine-carrying hydrogel and both DNA- and siRNA dual-loaded microparticles, is reported. This sIPC chemo attracts a large number of immature dendritic cells (DCs) at the site of administration and efficiently co-delivers both DNA antigens and interleukin-10 (IL10)-silencing siRNA to those cells. Using a murine model of A20 B cell lymphoma, we demonstrate that combination of DNA-antigen delivery and IL10 silencing, synergistically activate recruited immature DCs and cause a strong shift towards Th1 response while suppressing Th2 and Th17 cytokines. sIPC-based immunotherapy showed 45% more CD8+ cytotoxic T cell (CTL) response and 53% stronger CD4+ CTL activity compared to naked DNA vaccine. In addition, in-vivo sIPC immunization induced significant protection (p<0.01) against subsequent tumor challenge. Such a multi-modal, injectable system that simultaneously delivers chemokines, siRNA and DNA antigens to DCs marks a new approach to in-situ priming and modulation during immunotherapy and could provide effective vaccination strategies against cancers and infectious diseases.
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Base de dados:
MEDLINE
Assunto principal:
DNA
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Portadores de Fármacos
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Linfoma de Células B
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Células Th1
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Quimiocinas
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Vacinas Anticâncer
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RNA Interferente Pequeno
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article