A new nucleic acid–based agent inhibits cytotoxic T lymphocyte–mediated immune disorders - 02/09/13
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.
Le texte complet de cet article est disponible en PDF.Key words : Alloreactivity, aptamer, CD8, drug hypersensitivity, graft-versus-host disease, granulysin, nucleic acid–based therapeutics, Stevens-Johnson syndrome, systematic evolution of ligands by exponential enrichment, toxic epidermal necrolysis
Abbreviations used : CON, CTL, GNLY, GVHD, Kd, NF-κB, NK, RNAi, SEAP, SELEX, siRNA, SJS, ssDNA, TCR, TEN
Plan
| Supported by grants from the National Science Council, Taiwan (NSC98-2320-B-010-002-MY3, NSC98-2314-B-182A-027-MY3, NSC101-2320-B-010-072-MY3, NSC101-2321-B-010-027-, NSC101-2325-B-001-038-), the Taiwan Ministry of Education (Aim for the Top University Plan, National Yang-Ming University), and Academia Sinica (AS-99-TP-B12), Taiwan. |
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| Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
Vol 132 - N° 3
P. 713 - septembre 2013 Retour au numéro
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