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Titolo:
An antagonist IL-15/Fc protein prevents costimulation blockade-resistant rejection
Autore:
Ferrari-Lacraz, S; Zheng, XX; Kim, YS; Li, YS; Maslinski, W; Li, XC; Strom, TB;
Indirizzi:
Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Immunol,Dept Med, Boston, MA 02215 USA Harvard Univ Boston MA USA 02215 v Immunol,Dept Med, Boston, MA 02215 USA
Titolo Testata:
JOURNAL OF IMMUNOLOGY
fascicolo: 6, volume: 167, anno: 2001,
pagine: 3478 - 3485
SICI:
0022-1767(20010915)167:6<3478:AAIPPC>2.0.ZU;2-J
Fonte:
ISI
Lingua:
ENG
Soggetto:
CD8(+) T-CELLS; ALLOGRAFT-REJECTION; ACTIVATION TRANSCRIPTS; IL-2 RECEPTOR; IN-VIVO; CD40; MICE; HOMEOSTASIS; EXPRESSION; TOLERANCE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
38
Recensione:
Indirizzi per estratti:
Indirizzo: Strom, TB Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Immunol,Dept Med, Res N,Room 380,POB 15707, Boston, MA 02215 USA Harvard Univ ResN,Room 380,POB 15707 Boston MA USA 02215 15 USA
Citazione:
S. Ferrari-Lacraz et al., "An antagonist IL-15/Fc protein prevents costimulation blockade-resistant rejection", J IMMUNOL, 167(6), 2001, pp. 3478-3485

Abstract

IL-15 is a powerful T cell growth factor (TCGF) with particular importancefor the maintenance of CD8(+) T cells. Because costimulation blockade doesnot result in universal tolerance, we hypothesized that "escape" from costimulation blockade might represent a CD8(+) and IL-I 5/IL-15R(+)-dependent process. For this analysis, we have used an IL-15 mutant/Fc gamma 2a protein, a potentially cytolytic protein that is also a high-affinity receptor site specific antagonist for the IL-15R alpha receptor protein, as a therapeutic agent. The IL-15-related fusion protein was used as monotherapy or in combination with CTLA4/Fc in murine islet allograft models. As monotherapies, CTLA4/Fc and an IL-15 mutant/Fc gamma 2a were comparably effective in a semiallogeneic model system, and combined treatment with IL-15 mutant/Fc gamma 2a plus CTLA4/Fc produced universal permanent engraftment. In a fully MHC-mismatched strain combination known to be refractory to costimulation blockade treatment, combined treatment with both fusion proteins proved to be highly effective; > 70% of recipients were tolerized. The analysis revealedthat the IL-15 mutant/Fc treatment confers partial protection from both CD4(+) and CD8(+) T cell graft infiltration. In rejections occurring despite CTLA4/Fc treatment, concomitant treatment with the IL-15 mutant/Fc gamma 2aprotein blocked a CD8(+) T cell-dominated rejection processes. This protection was linked to a blunted proliferative response of alloreactive T cellsas well silencing of CTL-related gene expression events. Hence, we have demonstrated that targeting the IL-15/IL-15R pathway represents a new and potent strategy to prevent costimulation blockade-resistant CD8(+) T cell-driven rejection.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 05/04/20 alle ore 03:52:10