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Titolo:
Genetic heterogeneity in the toxicity to systemic adenoviral gene transferof interleukin-12
Autore:
Mazzolini, G; Narvaiza, I; Perez-Diez, A; Rodriguez-Calvillo, M; Qian, C; Sangro, B; Ruiz, J; Prieto, J; Melero, I;
Indirizzi:
Univ Navarra, Sch Med, Dept Internal Med, Gene Therapy Unit, E-31080 Pamplona, Spain Univ Navarra Pamplona Spain E-31080 herapy Unit, E-31080 Pamplona, Spain
Titolo Testata:
GENE THERAPY
fascicolo: 4, volume: 8, anno: 2001,
pagine: 259 - 267
SICI:
0969-7128(200102)8:4<259:GHITTT>2.0.ZU;2-U
Fonte:
ISI
Lingua:
ENG
Soggetto:
INTERFERON-GAMMA PRODUCTION; HERPES-SIMPLEX VIRUS; ANTITUMOR IMMUNITY; EXPRESSING INTERLEUKIN-12; HEPATOCELLULAR-CARCINOMA; INTRATUMORAL INJECTION; CELL RESPONSES; NITRIC-OXIDE; IL-12; INDUCTION;
Keywords:
interleukin-12; toxicity; interferon-gamma; adenovirus;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
38
Recensione:
Indirizzi per estratti:
Indirizzo: Melero, I Univ Navarra, Sch Med, Dept Internal Med, Gene Therapy Unit, Irunlarrea 1,E-31080 Pamplona, Spain Univ Navarra Irunlarrea 1 Pamplona SpainE-31080 amplona, Spain
Citazione:
G. Mazzolini et al., "Genetic heterogeneity in the toxicity to systemic adenoviral gene transferof interleukin-12", GENE THER, 8(4), 2001, pp. 259-267

Abstract

Despite the efficacy of IL-12 in cancer experimental models, clinical trials with systemic recombinant IL-12 showed unacceptable toxicity related to endogenous IFN gamma production. We report that systemic administration of a recombinant adenovirus encoding IL-12 (AdCMVmIL-12) has a dramatically different survival outcome in a number of mouse pure strains over a wide range of doses. For instance at 2.5 x 10(9) p.f.u., systemic AdCMVmIL-12 killedall C57BL/6 mice but spared all BALB/c mice. Much higher IFN gamma concentrations in serum samples of C57BL/6 than in those from identically treated BALB/c were found Causes for heterogeneous toxicity can be traced to differences among murine strains in the levels of gene transduction achieved in the liver, as assessed with adenovirus coding for reporter genes. In accordance, IL-12 serum concentrations are higher in susceptible mice. In addition, sera from C57BL/6 mice treated with AdCMVmIL-12 showed higher levels of IL-18, a well-known IFN gamma inducer. Interestingly, lethal toxicity in C57BL/6 mice was abolished by administration of blocking anti-IFN gamma mAbs and also by simultaneous depletion of T cells, NK cells, and macrophages. These observations together with the great dispersion of IFN gamma produced by human PBMCs upon in vitro stimulation with IL-12, or infection with recombinant adenovirus encoding IL-12, suggest that patients might also show heterogeneous degrees of toxicity in response to IL-12 gene transfer.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 02/06/20 alle ore 21:55:37