| Autor: |
Li, Z., Benghiat, F. S., Charbonnier, L. Marie, Kubjak, C., Rivas, M. N., Cobbold, S. P., Waldmann, H., De Wilde, V., Petein, M., Schuind, F., Goldman, M., Le Moine, A. |
| Zdroj: |
American Journal of Transplantation; December 2008, Vol. 8 Issue: 12 p2527-2536, 10p |
| Abstrakt: |
The growing development of composite tissue allografts (CTA) highlights the need for tolerance induction protocols. Herein, we developed a mouse model of heterotopic limb allograft in a stringent strain combination in which potentially tolerogenic strategies were tested taking advantage of donor stem cells in the grafted limb. BALBc allografts were transplanted into C57BL6 mice treated with anti-CD154 mAb, nondepleting anti-CD4 combined to either depleting or nondepleting anti-CD8 mAbs. Some groups received additional rapamycin. Both depleting and nondepleting mAb combinations without rapamycin only delayed limb allograft rejection, whereas the addition of rapamycin induced long-term allograft survival in both combinations. Nevertheless, robust donor-specific tolerance, defined by the acceptance of a fresh donor-type skin allograft and simultaneous rejection of third-party grafts, required initial CD8T-cell depletion. Mixed donor-recipient chimerism was observed in lymphoid organs and recipient bone marrow of tolerant but not rejecting animals. Tolerance specificity was confirmed by the inability to produce IL-2, IFN-? and TNF-? in MLC with donor antigen while significant alloreactivity persisted against third- party alloantigens. Collectively, these results show that robust CTA tolerance and mixed donor-recipient chimerism can be achieved in response to the synergizing combination of rapamycin, transient CD8T-cell depletion and costimulationcoreceptor blockade. |
| Databáze: |
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