LAUSR

Hematopoietic stem cell transplantation (HSCT) has many potential applications beyond current standard indications, including treatment of autoimmune disease, gene therapy, and transplant tolerance induction. However, severe myelosuppression and other toxicities after myeloablative conditioning regimens have hampered wider clinical use. To achieve donor hematopoietic stem cell (HSC) engraftment, it appears essential to establish niches for the donor HSCs by depleting the host HSCs. To date, this has been achievable only by nonselective treatments such as irradiation or chemotherapeutic drugs. An approach that is capable of more selectively depleting host HSCs is needed to widen the clinical application of HSCT. Here, we show in a clinically relevant nonhuman primate model that selective inhibition of B cell lymphoma 2 (Bcl-2) promoted hematopoietic chimerism and renal allograft tolerance after partial deletion of HSCs and effective peripheral lymphocyte deletion while preserving myeloid cells and regulatory T cells. Although Bcl-2 inhibition alone was insufficient to induce hematopoietic chimerism, the addition of a Bcl-2 inhibitor resulted in promotion of hematopoietic chimerism and renal allograft tolerance despite using only half of the dose of total body irradiation previously required. Selective inhibition of Bcl-2 is therefore a promising approach to induce hematopoietic chimerism without myelosuppression and has the potential to render HSCT more feasible for a variety of clinical indications. Description Selective Bcl-2 inhibition promotes engraftment of hematopoietic stem cells, inducing hematopoietic chimerism without myelosuppression. Tolerating transplant Hematopoietic stem cell transplant (HSCT) is an effective treatment option for patients with hematological cancers. However, its uses outside of oncology have been limited because of graft rejection caused by the conditioning regimen that non-selectively depletes host hematopoietic stem cells (HSCs). Prior work has indicated that inhibition of B cell lymphoma-2 (Bcl-2) may promote hematopoietic chimerism induction and allograft tolerance without a myelosuppressive conditioning regimen, but these studies were done in rodents. Here, Sasaki et al. showed that, in nonhuman primates, selective Bcl-2 inhibition in combination with minimal total body irradiation selectively deleted HSCs and lymphocytes, allowing for successful hematopoietic chimerism and renal allograft tolerance without myelosuppressive complications. Together, these findings suggest that selective Bcl-2 inhibition could be a clinically useful addition to HSCT conditioning regimens. —CM