Bcl-2 Inhibition with Venetoclax Promotes Induction of Mixed Chimerism and Renal Allograft Tolerance Without Severe Myelosuppression in Non-human Primates

Abstract

Abstract Background Specific Bcl-2 inhibition has been shown to promote mixed chimerism and allograft tolerance without myelosuppressive conditioning in murine models. We extended this approach to nonhuman primates in combined kidney and bone marrow transplantation (CKBMT). Methods In Group A, recipients received CKBMT with the regimen including total body irradiation (TBI,3 Gy) thymic irradiation (TI, 7Gy) and ATG, followed by a short course of anti-CD154 antibody and cyclosporine. In Group B, TBI was reduced to 1.5Gy. In Group C, peri-transplant Bcl-2 inhibitor (Venetoclax) was added to Group B regimen. In Group D, Group C regimen without TBI. In Group E, Group C regimen without TI. Results 7/8 recipients in Group A developed transient chimerism and achieved long-term renal allograft survival without immunosuppression. However, these recipients developed transient but severe pancytopenia between days 10–17 post CKBMT. Both recipients in Group B failed to develop chimerism. By adding Venetoclax to Group B regimen, 3/3 Group C recipients developed significantly higher and longer mixed chimerism without severe myelosuppression. These three recipients also achieved long-term immunosuppression free renal allograft survival without rejection (>316, >575, >239 days). In Group D, both recipients failed to develop chimerism and rejected their allografts on days 140 and 120. Although three Group E recipients successfully developed chimerism, all rejected their renal allografts on days 100, 97, 163 with early recovery of CD31+ naive T cells. Conclusion Enhancement of intrinsic apoptosis with Bcl-2 inhibition is a promising strategy to achieve robust mixed chimerism and allograft tolerance with reduced myelosuppressive conditioning.