Allogeneic stem cell transplantation (alloSCT) is utilised to cure haematological malignancies through a combination of conditioning regimen intensity and immunological disease control via the graft versus tumour (GVT) effect. Currently, conventional myeloablative chemotherapeutic or chemoradiation conditioning regimens are associated with significant side effects including graft versus host disease (GVHD), infection, and organ toxicity. Conversely, more tolerable reduced intensity conditioning (RIC) regimens are associated with unacceptably higher rates of disease relapse, partly through an excess incidence of mixed chimerism. Improvement in post-alloSCT outcomes therefore depends on promotion of the GVT effect whilst simultaneously reducing conditioning-related toxicity. We have previously shown that this could be achieved through BCL-2 inhibition, and in this study, we explored the modulation of JAK1/2 as a strategy to lower the barrier to donor engraftment in the setting of RIC. We investigated the impact of short-term treatment of BCL2 (venetoclax) or JAK1/2 (ruxolitinib) inhibition on recipient natural killer and T cell immunity and the subsequent effect on donor engraftment. We identified striking differences in mechanism of action of these two drugs on immune cell subsets in the bone marrow of recipients, and in the regulation of MHC class-II and interferon-inducible gene expression, leading to different rates of GVHD. This study demonstrates that the repurposed use of ruxolitinib or venetoclax can be utilised as pre-transplant immune-modulators to promote the efficacy of alloSCT, whilst reducing its toxicity.

同种异体干细胞移植 (alloSCT) 用于通过结合预处理方案强度和免疫疾病控制来治愈血液系统恶性肿瘤 通过移植物抗肿瘤（GVT）效应。目前，传统的清髓性化疗或放化疗预处理方案与显着的副作用相关，包括移植物抗宿主病 (GVHD)、感染和器官毒性。相反，更可耐受的降低强度调节 (RIC) 方案与高得不可接受的疾病复发率相关，部分原因是混合嵌合体的发生率过高。因此，alloSCT 后结果的改善取决于促进 GVT 效应，同时减少与条件相关的毒性。我们之前已经表明，这可以通过 BCL-2 抑制来实现，在本研究中，我们探索了 JAK1/2 的调节作为降低 RIC 环境中供体植入障碍的策略。我们研究了 BCL2 (venetoclax) 或 JAK1/2 (ruxolitinib) 抑制的短期治疗对受体自然杀伤细胞和 T 细胞免疫的影响以及随后对供体植入的影响。我们发现这两种药物对受体骨髓中免疫细胞亚群的作用机制存在显着差异，在调节 MHC II 类和干扰素诱导基因表达方面存在显着差异，导致 GVHD 发生率不同。这项研究表明，重新使用 ruxolitinib 或 venetoclax 可用作移植前免疫调节剂，以提高 alloSCT 的功效，同时降低其毒性。我们发现这两种药物对受体骨髓中免疫细胞亚群的作用机制存在显着差异，在调节 MHC II 类和干扰素诱导基因表达方面存在显着差异，导致 GVHD 发生率不同。这项研究表明，重新使用 ruxolitinib 或 venetoclax 可用作移植前免疫调节剂，以提高 alloSCT 的功效，同时降低其毒性。我们发现这两种药物对受体骨髓中免疫细胞亚群的作用机制存在显着差异，在调节 MHC II 类和干扰素诱导基因表达方面存在显着差异，导致 GVHD 发生率不同。这项研究表明，重新使用 ruxolitinib 或 venetoclax 可用作移植前免疫调节剂，以提高 alloSCT 的功效，同时降低其毒性。