Selective Bcl-2 inhibition promotes hematopoietic chimerism and allograft tolerance without myelosuppression in nonhuman primates.
Selective Bcl-2 inhibition promotes hematopoietic chimerism and allograft tolerance without myelosuppression in nonhuman primates.
复制标题
选择性 Bcl-2 抑制可促进非人灵长类动物的造血嵌合和同种异体移植耐受，而不会产生骨髓抑制。
DOI：
10.1126/scitranslmed.add5318
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发表时间：
2023
影响因子：
17.1
通讯作者：
Colv
中科院分区：
文献类型：
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作者：
Sasaki,Hajime;Hirose,Takayuki;Oura,Tetsu;Otsuka,Ryo;Rosales,Ivy;Ma,David;Lassiter,Grace;Karadagi,Ahmad;Tomosugi,Toshihide;Dehnadi,Abbas;Matsunami,Masatoshi;RajuPaul,Susan;Reeves,PatrickM;Hanekamp,Isabel;Schwartz,Samuel;Colv
造血干细胞移植(HSCT)除了目前的标准适应症外，还有许多潜在的应用，包括治疗自身免疫性疾病、基因治疗和诱导移植耐受。然而，清髓性预适应方案后的严重骨髓抑制和其他毒性阻碍了更广泛的临床应用。为了实现供者造血干细胞(HSC)的植入，通过耗尽宿主HSCs来为供者HSCs建立生态位似乎是必不可少的。到目前为止，只有通过放射或化疗药物等非选择性治疗才能实现这一点。需要一种能够更选择性地消耗宿主HSCs的方法来扩大HSCT的临床应用。在这里，我们在一个临床相关的非人类灵长类动物模型中显示，选择性抑制B细胞淋巴瘤2(Bcl2)促进了造血嵌合体和肾移植耐受，在部分删除HSCs和有效的外周淋巴细胞缺失的同时保留了髓系细胞和调节性T细胞。虽然单独抑制Bcl2不足以诱导造血嵌合体，但添加Bcl2抑制剂可促进造血嵌合体和肾移植耐受，尽管仅使用先前所需全身照射剂量的一半。因此，选择性抑制Bcl2是一种很有前途的方法，可以在不抑制骨髓抑制的情况下诱导造血嵌合体，并有可能使HSCT在各种临床适应症中更加可行。
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.