Targeting apoptosis to induce stable mixed haematopoietic chimerism and long-term allograft survival without myelosuppressive conditioning in mice

Induction of mixed hematopoietic chimerism results in donor-specific immunological tolerance by apoptosismediated deletion of donor-reactive lymphocytes. A broad clinical application of this approach is currently hampered by limited predictability and toxicity of the available conditioning protocols. We developed a new therapeutic approach to induce mixed chimerism and tolerance by a direct pharmacological modulation of the intrinsic apoptosis pathway in peripheral T cells. The pro-apoptotic small molecule Bcl-2 inhibitor ABT737 promoted mixed chimerism induction and reversed the anti-tolerogenic effect of calcineurin inhibitors by boosting the critical role of the pro-apoptotic Bcl-2 factor Bim. A short conditioning protocol with ABT-737 in combination with costimulation-blockade and low-dose cyclosporine A resulted in a complete deletion of peripheral donor-reactive lymphocytes and was sufficient to induce mixed chimerism and robust systemic tolerance across full MHC barriers, without myelosuppression and by using moderate doses of bone marrow cells. Thus, immunological tolerance can be achieved by direct modulation of the intrinsic apoptosis pathway in peripheral lymphocytes – a new approach to translate immunological tolerance into clinically applicable protocols. For personal use only. on October 4, 2017. by guest www.bloodjournal.org From