A Clinically Feasible Approach to Induce Delayed Tolerance in Recipients of Prior Kidney or Vascularized Composite Allotransplants

Background. Mixed chimerism induces donor-specific tolerance to kidney and vascularized composite allotransplants (VCA). However, simultaneous kidney or VCA and bone marrow transplantation (BMT) is problematic because of the combined risk and time required for conditioning. Here, we developed a delayed tolerance induction strategy with mixed chimerism through BMT in prior kidney or VCA recipients. Methods. Wistar Furth rats that received kidney transplantation (KTx) or VCA from allogeneic August-Copenhagen Irish donors were maintained on immunosuppression (IS) for 8 weeks. These recipients were then conditioned with anti-alpha beta-T-cell receptor and anti-CD8 monoclonal antibodies, total body irradiation, cyclosporine A and mycophenolate mofetil (12 doses), and antilymphocyte serum (one dose); and transplanted with T-cell-depleted donor marrow. All IS was discontinued on day 11 after BMT. Results. Cyclosporine A monotherapy prevented acute rejection of KTx or VCA. However, all allografts were rejected after IS withdrawal in KTx or VCA recipients who were conditioned but did not receive BMT. After delayed BMT, mixed chimerism was initially achieved in all KTx or VCA recipients with 200-, 300-, and 400-cGy total body irradiation. Long-term tolerance to KTx or VCA was achieved in most of these recipients with total IS withdrawal. The tolerance achieved with delayed BMT was donor specific as confirmed by acceptance of donor skin and rejection of third-party skin graft. Conclusions. IS-free donor-specific tolerance can be successfully induced with delayed BMT to previous recipients of kidney transplantation or VCA. These findings have significant clinical implications for transplant recipients who receive an organ from either a living donor or a deceased donor with frozen bone marrow cells available.