Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida; Division of Transplantation and Cellular Therapy, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida.
Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, Florida.
Transplant Cell Ther. 2022 Jun;28(6):303.e1-303.e7. doi: 10.1016/j.jtct.2022.03.012. Epub 2022 Mar 14.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is complicated by graft- versus-host disease (GVHD), which causes immune dysfunction and further delays immune reconstitution through its effects on primary and secondary lymphoid organs. Treatments to prevent GVHD and improve immune recovery following allo-HSCT are needed. Post-transplantation cyclophosphamide (PTCy) is a well-established and clinically widely used method for GVHD prophylaxis after HLA-matched as well as haploidentical allo-HSCT, as well as a promising strategy in the setting of mismatched unrelated donor allo-HSCT. Recently, regulatory T cells (Tregs), a critical subset for immune homeostasis and tolerance induction, have been evaluated for use as GVHD prophylaxis in experimental models and clinical trials. Natural killer (NK) cells are one of the first lymphoid populations to reconstitute following allo-HSCT and are important mediators of protective immunity against pathogens, and are also critical for limiting post-transplantation relapse of hematologic cancers. Several reports have noted that a delay in NK cell recovery may occur following experimental mouse allo-HSCT as well as after clinical allo-HSCT. Here we examined how 2 treatment strategies, PTCy and donor expanded Tregs (TrED), in experimental MHC-matched allo-HSCT affect NK recovery. Our experiments show that both strategies improved NK cell numbers, with PTCy slightly better than TrED, early after allo-HSCT (1 month) compared with untreated allo-HSCT recipients. Importantly, NK cell IFN-γ production and cytotoxic function, as reflected by CD107 expression as well as in vivo killing of NK-sensitive tumor cells, were improved using either PTCy or TrED versus control allo-HSCT recipients. In conclusion, both prophylactic treatments were found to be beneficial for NK recovery and NK cell function following MHC-matched minor antigen-mismatched experimental allo-HSCT. Improved NK recovery could help provide early immunity toward tumors and pathogens in these transplant recipients.
异基因造血干细胞移植（allo-HSCT）会并发移植物抗宿主病（GVHD），它通过对初级和次级淋巴器官的影响导致免疫功能障碍，并进一步延迟免疫重建。需要预防 GVHD 并改善 allo-HSCT 后的免疫恢复的治疗方法。环磷酰胺（PTCy）是一种经过充分验证且在临床上广泛应用的方法，可用于 HLA 匹配和半相合 allo-HSCT 后的 GVHD 预防，以及在 mismatched 无关供体 allo-HSCT 中也是一种有前途的策略。最近，调节性 T 细胞（Tregs），一种对免疫稳态和诱导耐受至关重要的亚群，已在实验模型和临床试验中被评估用于 GVHD 预防。自然杀伤（NK）细胞是 allo-HSCT 后第一个重建的淋巴细胞群之一，是针对病原体的保护性免疫的重要介质，对于限制移植后血液系统恶性肿瘤的复发也至关重要。有几项报道指出，在实验性小鼠 allo-HSCT 后以及临床 allo-HSCT 后，NK 细胞恢复可能会延迟。在这里，我们研究了在实验性 MHC 匹配 allo-HSCT 中，PTCy 和供体扩增的 Tregs（TrED）这两种治疗策略如何影响 NK 恢复。我们的实验表明，与未治疗的 allo-HSCT 受者相比，两种策略都能在 allo-HSCT 后早期（1 个月）改善 NK 细胞数量，PTCy 略优于 TrED。重要的是，与对照 allo-HSCT 受者相比，无论是使用 PTCy 还是 TrED，NK 细胞 IFN-γ 的产生和细胞毒性功能（反映为 CD107 的表达以及体内杀伤 NK 敏感肿瘤细胞）都得到了改善。总之，在 MHC 匹配的次要抗原不匹配实验性 allo-HSCT 后，两种预防性治疗均有益于 NK 恢复和 NK 细胞功能。NK 恢复的改善可能有助于为这些移植受者提供针对肿瘤和病原体的早期免疫。
