Robust limb allograft tolerance in mice
Induction of robust limb allograft tolerance in mice
For obvious reasons, composite tissue allografts (CTA) could make good use of tolerance induction protocols.
A mouse model of heterotopic limb allograft was developed in a stringent strain combination and tolerogenic strategies were tested taking advantage of donor stem cells in the grafted bone. Co-stimulation blockade with anti-CD154 mAb, non-depleting anti-CD4 combined to depleting anti-CD8 mAbs and rapamycin were used. With this treatment, robust donor-specific tolerance, defined by the acceptance of a fresh donor-type skin allograft and simultaneous rejection of third party grafts was achieved. Robust tolerance required an early but only transient CD8+ T cell depletion. Tolerance was accompanied with mixed donor-recipient haematopoietic chimerism (mainly NK, B and T cells) in lymphoid organs and recipient bone marrow. In mixed lymphocyte culture, recipient T cells from tolerant animals were unable to produce significant amounts of IL-2, IFN-γ and TNF-α in the presence of donor alloantigens, while anti-third party alloreactivity persisted. The percentage of specific v-β T cell subtypes were decreased in tolerant versus ungrafted animals, illustrating the alteration of T cell repertoire in the context of mixed allogeneic chimerism. We conclude that robust tolerance to composite tissue allograft can be achieved in response to the synergizing combination of rapamycin, transient CD8+ T cell depletion, co-stimulation/co-receptor blockade and intact vascularised donor bone marrow transplantation.
Legend to the figure: Tolerance of a BALB/c composite tissue allograft with the white skin flap in the right groin fossa of a C57BL/6 recipient.
This work was published by Li Z. et al from the Institute for Medical Immunology, Université Libre de Bruxelles, Bruxelles, Belgium (Li Z, Benghiat FS, Charbonnier LM, Kubjak C, Rivas MN, Cobbold SP, Waldmann H, De Wilde V, Petein M, Schuind F, Goldman M, Le Moine A. CD8+ T-Cell depletion and rapamycin synergize with combined coreceptor/stimulation blockade to induce robust limb allograft tolerance in mice. Am J Transplant. 2008 Dec;8(12):2527-36. Epub 2008 Oct 6).