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Limb Allograft Survival With Costimulation Blockade, T Cell Depletion, and High-Dose Bone Marrow Transplantation
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ABSTRACT
Regimens based on anti-CD40L antibody (MR1), T cell depletion, and bone marrow transplantation have induced tolerance in models of organ and nonvascularized skin transplantation. This study determined the efficacy of such modalities in a limb allograft model.
C57Bl/6 mice were recipients of Balb/c limb allografts. Experimental groups were: group 1, untreated allograft; group 2, treatment with MR1, CD4/8 T cell depletion; group 3, MR1, CD4/8 T cell depletion, high-dose bone marrow transplantation; and group 4, MR1, CD4 T cell depletion, high-dose bone marrow transplantation. High-dose bone marrow transplantation consists of 120 million unseparated bone marrow cells given intraperitoneally on postoperative day 3. MR1 and T cell depletion antibodies are administered at 500 mcg intraperitoneally on days 0, 2, 4, and 6. Additional groups will be studied based on the findings of these initial groups. Histology and immunohistochemistry will be performed on all specimens. Chimerism will be evaluated in recipients with long-term allograft survival by real-time polymerase chain reaction.
Untreated recipients (group 1) rejected their limb allografts after a mean 9 days. Recipients treated with MR1 and complete T cell depletion only (group 2) demonstrate allograft survival to 1 month at this time. Transplant recipients treated with MR1, complete T cell depletion, and high-dose bone marrow transplantation (group 3) also demonstrate limb allograft survival up to 6 weeks presently. These groups will continue to be monitored until signs of rejection are noted.
Brief antibody-based induction regimens are demonstrating promise for the induction of immune unresponsiveness in the limb allograft model. Because a whole limb allograft includes vascularized bone marrow, components such as total body irradiation and bone marrow transplantation, which are required for the survival of organ and nonvascularized skin allografts, may not be necessary in limb transplantation. Because anti-CD40L antibody controls the CD4 T cell response but is less effective against CD8 T cells, partial rather than complete T cell depletion when combined with costimulation blockade may be sufficient for allograft survival.