Background: While costimulation blockade (CoB) has improved renal allograft function in clinical studies, this comes at the cost of increased rates of early rejection. These rejection episodes are often successfully treated with steroid therapy. Methotrexate (MTX) is used for prophylaxis against graft-vs.-host disease in bone marrow transplant and is approved for use in combination with CTLA4-Ig (abatacept) in rheumatoid arthritis. The successful use of these agents in combination with CoB suggests they may be used for prophylaxis against rejection in renal transplantation. We hypothesized these agents would synergize with CoB to prolong allograft survival in non-human primates.

Methods: Following nephrectomy, nine size-matched Rhesus macaques underwent renal transplantation. All recipients received induction immunosuppression with a tapering course of methylprednisolone. Maintenance therapy was abatacept. Six animals additionally received induction therapy with MTX (5mg/m²). MHC disparity was evaluated by 454 pyrosequencing. Serum creatinine levels were used to monitor graft function. Flow cytometry of peripheral blood cells and CMV PCR were performed weekly.

Results: Three animals received steroids and abatacept. Graft survival was 35, >96, and >110 days with two animals continuing with normal renal function. One animal had a brief rise in creatinine one week post-transplant following a missed steroid dose. Five animals receiving the base regimen plus MTX had graft survival of 30, 65, 164, 224, and >391 days. A sixth animal receiving the MTX regimen lost its graft at day 6 after two consecutive missed steroid doses. Historical controls receiving abatacept and donor-specific transfusion had graft survival of 20-30 days. Neither regimen depleted circulating T cells nor adversely affected protective immunity against CMV. Review of MHC typing revealed similarly disparate pairings in both treatment groups.

Conclusions: We conclude that the addition of steroid induction prolongs renal allograft survival beyond abatacept alone. The addition of MTX may prolong graft survival further, though conclusive results are pending. The loss of one graft and decreased renal function in another following missed steroid doses indicates the importance of the steroid component early in the postoperative period. These results warrant further study of these agents in combination with CoB.

« Back to 2013 American Transplant Congress