| Objective To investigated a non-toxic AdCTLA4-Ig-based protocol for non-myeloablative allogeneic hematopoietic cell transplantation to induce donor-specific tolerance to hind limb allografts in rats.Methods Fully mismatched, 4 to 8 week old Brown Norway(RT1n )and Lewis(RT11 ) rats were used as cell/organ donors and recipients, respectively. Recipients were treated with AdCTLA4-Ig(5×109 PFU,days -30,0,30), standard immunosuppressive therapy( MP:10 mg/kg/d,MMF: 20mg/kg/d,RAPA: 0.2mg/kg/d;days -33～100), soon after total body irradiation (3Gy, day -30) and donor bone marrow (100×106,day -30) transplantation (BMT). 30 days after BMT, chimeric animals received hind limb transplantations. And 100 days after hind limb transplantations, immunosuppressive therapy was changed for low-dosed CsA (8 mg/kg/d,days 100～),until the allografts were rejected.Results In Group C , hematopoietic chimerism was(38.8±10.6%)at day 0, and was stabl(e29.3±11.9%)at 330 days post-BMT; and there was no graft versus host disease in both Group C and Group D. When the standard immunosuppressive therapy was stopped and changed for low-dosed CsA, chimeric recipients(Lewis,RT11) permanently accepted (>200 days) donor specific (Brown Norway,RT1n) hind limb allografts in Group C, yet rapidly rejected in Group A (8±2d), Group B (18±3d) and in Group C(20±2d). Lymphocytes of graft tolerant animals demonstrated hyporesponsiveness in mixed lymphocyte cultures in a donor-specific manner in Group C. Tolerant graft histology showed no obliterative arteriopathy or chronic rejection.Conclusion The AdCTLA4-Ig based conditioning regimen with donor BMT produced stable mixed chimerism and induced donor- specific tolerance to hind limb allografts.
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