A new nucleic acid-based agent inhibits cytotoxic T lymphocyte-mediated immune disorders.
J Allergy Clin Immunol
; 132(3): 713-722.e11, 2013 Sep.
Article
em En
| MEDLINE
| ID: mdl-23791505
ABSTRACT
BACKGROUND:
Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and graft-versus-host disease (GVHD) are distinct immune reactions elicited by drugs or allogeneic antigens; however, they share a pathomechanism with the activation of cytotoxic T lymphocytes (CTLs). CTLs produce cytotoxic proteins, cytokines, chemokines, or immune alarmins, such as granulysin (GNLY), leading to the extensive tissue damage and systemic inflammation seen in patients with SJS/TEN or GVHD. Currently, there is no effective therapeutic agent specific for CTL-mediated immune disorders.OBJECTIVES:
By targeting GNLY(+) CTLs, we aimed to develop a nucleic acid-based agent consisting of an anti-CD8 aptamer with GNLY small interfering RNA (siRNA).METHODS:
We performed systematic evolution of ligands using exponential enrichment to select and identify effective anti-CD8 aptamers. We developed an aptamer-siRNA chimera using a "sticky bridge" method by conjugating the aptamer with siRNA. We analyzed the inhibitory effects of the aptamer-siRNA chimera on CTL responses in patients with SJS/TEN or GVHD.RESULTS:
We identified a novel DNA aptamer (CD8AP17s) targeting CTLs. This aptamer could be specifically internalized into human CTLs. We generated the CD8AP17s aptamer-GNLY siRNA chimera, which showed a greater than 79% inhibitory effect on the production of GNLY by drug/alloantigen-activated T cells. The CD8AP17s aptamer-GNLY siRNA chimera decreased cytotoxicity in in vitro models of both SJS/TEN (elicited by drug-specific antigen) and GVHD (elicited by allogeneic antigens).CONCLUSIONS:
Our results identified a new nucleic acid-based agent (CD8 aptamer-GNLY siRNA chimera) that can significantly inhibit CTL-mediated drug hypersensitivity, such as that seen in patients with SJS/TEN, as well as the alloreactivity seen in patients with GVHD. This study provides a novel therapeutic strategy for CTL-mediated immune disorders.Palavras-chave
Alloreactivity; CD8; CON; CTL; Cytotoxic T lymphocyte; Dissociation constant; GNLY; GVHD; Graft-versus-host disease; Granulysin; K(d); NF-κB; NK; Natural killer; Nonsilencing control; Nuclear factor κB; RNA interference; RNAi; SEAP; SELEX; SJS; Secreted embryonic alkaline phosphatase; Single-stranded DNA; Small interfering RNA; Stevens-Johnson syndrome; Systematic evolution of ligands by exponential enrichment; T-cell receptor; TCR; TEN; Toxic epidermal necrolysis; aptamer; drug hypersensitivity; graft-versus-host disease; granulysin; nucleic acidbased therapeutics; siRNA; ssDNA; systematic evolution of ligands by exponential enrichment; toxic epidermal necrolysis
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Linfócitos T Citotóxicos
/
Antígenos de Diferenciação de Linfócitos T
/
Antígenos CD8
/
RNA Interferente Pequeno
/
Aptâmeros de Nucleotídeos
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
J Allergy Clin Immunol
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Taiwan