CTLA4-Ig-Based Conditioning Regimen to Induce Tolerance to Cardiac Allografts

BackgroundTransplant rejection and toxicity associated with chronic immunosuppressive therapy remain a major problem. Mixed hematopoietic chimerism has been shown to produce tolerance to solid organ transplants. However, currently available protocols to induce mixed hematopoietic chimerism invariably require toxic pre-conditioning. In this study, we investigated a non-toxic CTLA4-Ig-based protocol to induce donor-specific tolerance to cardiac allografts in rats.MethodsFully mismatched, 4 to 6 week old ACI (RT1.Aa) and Wistar Furth (RT1.Au) rats were used as cell/organ donors and recipients, respectively. Recipients were treated with CTLA4-Ig 2 mg/kg/day (on days 0, 2, 4, 6, 8), tacrolimus 1 mg/kg/day (daily, from days 0 to 9), and a single dose of anti-lymphocyte serum (10 mg) on day 10, soon after total body irradiation (300 cGy) and donor bone marrow (100 × 106 T-cell depleted cells) transplantation (BMT). Six weeks after BMT, chimeric animals received heterotopic heart transplants.ResultsHematopoietic chimerism was 18.8 ± 10.6% at day 30, and was stable (24 ± 10%) at 1 year post-BMT; there was no graft versus host disease. Chimeric recipients (RT1.Au) permanently accepted (>360 days) donor-specific (RT1.Aa; n = 6) hearts, yet rapidly rejected (<9 days) third-party hearts (RT1.Al; n = 5). Graft (heart) tolerant (>100 days) recipients accepted donor-specific secondary skin grafts (>200 days) while rejected the third-party skin grafts (<9 days). Lymphocytes of graft tolerant animals demonstrated hyporesponsiveness in mixed lymphocyte cultures in a donor-specific manner. Tolerant graft histology showed no obliterative arteriopathy or chronic rejection.ConclusionsThe CTLA4-Ig based conditioning regimen with donor BMT produced mixed chimerism and induced donor- specific tolerance to cardiac allografts.