Session Name: Tolerance / Immune Deviation
Session Date & Time: None. Available on demand.
*Purpose: Immunologic tolerance of renal allograft has been achieved by induction of hematopoietic chimerism through donor bone marrow transplantation (DBMT). The myeloablative and genetic toxicity associated with DBMT conditioning hampers widespread application of tolerance protocols. To this end, we have recently shown that the addition of selective BCL-2 inhibition with Venetoclax (Vtx) to our nonmyeloablative conditioning regimen can promote chimerism and allograft tolerance without myelosuppression. To establish the Vtx-based regimen for clinical application, the necessity of all aspects of the protocol for combined kidney and bone marrow transplantation was evaluated individually.
*Methods: Cynomolgus monkeys received various regimens which included low dose total body irradiation (TBI), local TI and ATG pre-CKBMT, followed by a short course of anti-CD154 mAb and Cyclosporine. The study groups consisted of 6 arms. Group A and B received no Vtx, but 3GyTBI and 1.5Gy TBI. Groups C,D,E and F all received Vtx but 1.5Gy TBI, no TBI, no TI, or no CoB, respectively.
*Results: All recipients of the conventional regimen, Group A, achieved chimerism and long-term allograft tolerance but experienced severe transient pancytopenia. With reduced TBI (1.5Gy) without Vtx, all recipients failed to develop chimerism and ¾ rejected by day 167. By adding Vtx, all three recipients achieved excellent chimerism (Fig. 1) and renal allograft tolerance without pancytopenia. Without TBI or CoB, all recipients failed to develop chimerism and rejected kidney allografts. Without TI, all three recipients failed to achieve tolerance despite successful development of chimerism. In this group, early repopulation of recent thymic emigrants and naive T cells were observed.
*Conclusions: TBI dose was reduced by adding Vtx, leading to successful chimerism and allograft tolerance without myelosuppression. Minimal TBI, TI, and CoB appeared to be essential in the protocol with selective Bcl-2 inhibition.
To cite this abstract in AMA style:Lassiter G, Hirose T, Sasaki H, Ma D, Oura T, Dehnadi A, Cosimi A, Cippa P, Fehr T, Kawai T. Selective Bcl-2 Inhibition for Induction of Mixed Chimerism and Renal Allograft Tolerance without Myelosupression [abstract]. Am J Transplant. 2021; 21 (suppl 3). https://atcmeetingabstracts.com/abstract/selective-bcl-2-inhibition-for-induction-of-mixed-chimerism-and-renal-allograft-tolerance-without-myelosupression/. Accessed June 11, 2021.
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