C - Chemistry – Metallurgy – 12 – N
Patent
C - Chemistry, Metallurgy
12
N
C12N 15/12 (2006.01) A01K 67/027 (2006.01) A61K 31/70 (2006.01) A61K 35/14 (2006.01) A61K 38/17 (2006.01) A61K 39/00 (2006.01) A61K 39/395 (2006.01) A61K 48/00 (2006.01) C07K 14/705 (2006.01) C07K 16/28 (2006.01) C12N 5/10 (2006.01) C12N 15/13 (2006.01) A61K 35/12 (2006.01) A61K 38/00 (2006.01)
Patent
CA 2326671
The invention provides means and methods for inhibiting T-cell mediated rejection of a xenotransplanted organ by blocking the delivery of co- stimulatory signal 2 (the B7/CD28 interaction) in order to prevent the activation of xenoreactive T-cells in the recipient. In a first aspect, co- stimulation is prevented by administration to the organ recipient of a soluble form of CTLA-4 from the xenogeneic donor organism. This preferentially binds B7 on the xenograft and blocks the interaction between B7 on the xenogeneic donor cells and CD28 on recipient T-cells. In a second aspect, co-stimulation is antagonised by expressing a ligand for CTLA-4 on the xenogeneic donor cells. This ligand binds to CTLA-4 on activated T-cells of the recipient and antagonises signal 2. In a third aspect, co-stimulation is prevented by expressing recipient organism MHC class II on the surface of the cells of the xenogeneic donor organ. The donor cells are thus able to present xenoantigens to a recipient T-cell in the context of self-MHC class II. If the donor cells do not express B7, or if B7 is blocked, the xenoreactive recipient T-cell becomes anergic.
L'invention concerne des procédés et moyens d'inhibition du rejet induit par les lymphocytes T d'un organe xénogreffé, consistant à bloquer l'apport du signal 2 co-activateur (interaction B7/CD28) de manière à empêcher l'activation des lymphocytes T xénoréactifs chez le receveur. Dans un premier aspect, on empêche la co-activation en administrant au receveur de l'organe une forme soluble de CTLA-4 provenant de l'organisme du donneur xénogène, ce qui fixe B7, de manière préférentielle, sur la xénogreffe et bloque l'interaction entre B7 des cellules du donneur xénogène et CD28 des lymphocytes T du receveur. Dans un second aspect, on antagonise la co-activation en faisant s'exprimer un ligand de CTLA-4 sur les cellules du donneur xénogène. Ce ligand se fixe sur CTLA-4 sur les lymphocytes T activés du receveur et antagonise le signal 2. Dans un troisième aspect, on empêche la co-activation en faisant s'exprimer le CMH de classe II de l'organisme du receveur, sur la surface des cellules de l'organe du donneur xénogène. Les cellules du donneur sont alors capables de présenter des xéno-antigènes aux lymphocytes T du receveur, dans le contexte du CMH de classe II autonome. Si les cellules du donneur n'expriment pas B7, ou si B7 est bloqué, les lymphocytes T du receveur xénoréactif deviennent anergiques.
Dorling Anthony
Lechler Robert Ian
Imperial College Innovations Limited
Norton Rose Or S.e.n.c.r.l. S.r.l./llp
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