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Biotech / Medical : Biotransplant(BTRN) -- Ignore unavailable to you. Want to Upgrade?

To: Micawber who wrote (1006)	9/5/2001 4:18:35 PM
From: keokalani'nui	Respond to of 1475

The Journal of Immunology, 2001, 167: 3478-3485. Copyright © 2001 by The American Association of Immunologists An Antagonist IL-15/Fc Protein Prevents Costimulation Blockade-Resistant Rejection1 Sylvie Ferrari-Lacraz, Xin Xiao Zheng, Yon Su Kim2, Yongsheng Li, Wlodzimierz Maslinski3, Xian Chang Li and Terry B. Strom4 Department of Medicine, Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215 IL-15 is a powerful T cell growth factor (TCGF) with particular importance for the maintenance of CD8+ T cells. Because costimulation blockade does not result in universal tolerance, we hypothesized that "escape" from costimulation blockade might represent a CD8+ and IL-15/IL-15R+-dependent process. For this analysis, we have used an IL-15 mutant/Fc2a protein, a potentially cytolytic protein that is also a high-affinity receptor site specific antagonist for the IL-15R 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/Fc2a were comparably effective in a semiallogeneic model system, and combined treatment with IL-15 mutant/Fc2a 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 revealed that 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/Fc2a protein blocked a CD8+ T cell-dominated rejection processes. This protection was linked to a blunted proliferative response of alloreactive T cells as 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 ___________________ Wilder