*Purpose: Mixed chimerism (MC) induction via non-myeloablative conditioning and bone marrow transplantation (BMT) induces tolerance to solid organs. Our standard MC induction protocol in cynomologous macaques achieves transient MC lasting 20 – 60 days, with T-cell chimerism of 5%. We established an induction protocol that yields higher and longer lasting MC in rhesus macaques as an operational tolerance model to kidney transplantation.

*Methods: Conditioning with total body irradiation (125cGy), thymic irradiation (7Gy), anti-CD154 mAbs and horse ATG followed by combined allogeneic MHC-mismatched BMT/kidney transplant and 1 month of cyclosporine, after which all immunosuppression (IS) was withdrawn. 3 rhesus macaques underwent this regimen and their mixed chimerism development as well as bone marrow engraftment was compared with 3 cynomolgous macaques receiving our standard induction protocol (Table 1).

*Results: Rhesus macaques developed multilineage MC that was high in peak percentage (>90%) and showed T-cell chimerism >10% (Figure1). Bone marrow engraftment was evident after IS withdrawal and persisted significantly longer compared to cynomolgus controls. One animal developed long-term multilineage chimerism >30% for 5 months (ongoing). During the chimeric period, recipients showed donor-specific hyporesponsiveness in MLR and Elispot. No animal developed graft-versus-host disease. Animals accepted their donor kidney graft for 150 days and longer.

*Conclusions: While a similar induction regimen in other species has historically failed to achieve permanent chimerism, this protocol shows the development of higher chimerism overall, T-cell chimerism >10%, bone marrow engraftment after IS withdrawal and persistent macrochimerism for >5 months. The rhesus macaque as a more robust species harbors significant advantages as a NHP model for tolerance induction in solid organ transplantation.

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