造血干细胞移植（HSCT）除了已有的标准适应症外，还有许多潜在应用，包括治疗自身免疫性疾病，基因治疗和移植容忍诱导。但是，在肆虐的骨髓抑制和其他有毒反应之后，通过骨髓消融调理方案来扩大其临床应用遇到了困难。为了实现供体造血干细胞（HSC）移植，建立供体HSC的生存环境似乎是必要的，通过消除宿主HSC来实现。迄今为止，这只能通过不可选择的治疗，如放射线或化学治疗药物实现。需要一种能够更有选择性地消除宿主HSC的方法来扩大HSCT的临床应用。在临床相关的非人灵长类动物模型中，我们表明，选择性抑制B细胞淋巴瘤2（Bcl-2）在部分删除HSC和有效的外周淋巴细胞删除的同时促进了造血嵌合体和肾脏移植耐受性，并保留了骨髓细胞和调节性T细胞。尽管仅仅使用Bcl-2抑制剂是不足以诱导造血嵌合体的，但加入Bcl-2抑制剂的结果促进了造血嵌合体和肾脏移植耐受性，尽管仅仅使用以前所必需的半剂量全身放射线。因此，选择性抑制Bcl-2是一种有前途的方法，可以在不抑制造血功能的情况下诱导造血嵌合体，并且有可能使HSCT对多种临床适应症更为可行。

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.