背景:在急性髓系白血病(AML)的异基因造血干细胞移植中,供体T细胞通过移植物抗白血病(GVL)效应对抗白血病,同时,它们还存在通过与受体细胞相互作用引发危及生命的移植物抗宿主病(GVHD)的风险。GVHD的发作取决于供体T细胞和受体抗原呈递细胞(APC)之间的相互作用,激发T细胞激活。然而,缺乏平衡GVHD和GVL的有效方法。
方法:在我们的研究中,我们通过将聚阳离子胺化明胶和聚阴离子藻酸盐层叠到T细胞表面来制作纳米胶囊,检查其基本生理功能的潜在变化。随后,我们建立了AML小鼠模型,并用骨髓细胞(BMC)联合包裹T细胞移植治疗,以研究包裹T细胞的GVL和抗GVHD作用.体外共培养被用来探索封装对免疫突触的影响,共刺激分子,和肿瘤杀伤途径。
结果:将BMC与选择性包裹在AML小鼠体内的供体T细胞联合移植可显着减轻GVHD症状,同时保留基本的GVL效应。封装的T细胞通过阻碍与受体APC的免疫突触的形成来发挥免疫调节作用,从而下调共刺激信号,如CD28-CD80、ICOS-ICOSL、和CD40L-CD40。接受包囊T细胞移植的小鼠供体Ly-5.1-BMC细胞数量显着增加,伴随着穿孔素和颗粒酶B的体内表达水平不变。虽然在单细胞纳米封装后在体外观察到供体T细胞在肿瘤微环境中的细胞毒性的瞬时抑制,随后恢复正常的抗肿瘤活性,归因于包封的囊泡壳的选择性渗透性和材料降解。此外,在白血病肿瘤细胞中仍观察到凋亡蛋白和FAS-FAS配体通路在正常水平的表达。
结论:封装的供体T细胞通过早期免疫分离使与APC的共刺激信号最小化,从而有效缓解GVHD,同时保留GVL效应。随后降解纳米胶囊恢复T细胞对AML细胞的细胞毒性功效,由细胞毒性途径介导。使用移植封装的T细胞提供了抑制GVHD同时保持GVL效应的有希望的策略。
BACKGROUND: In allogeneic-hematopoietic stem cell transplantation for acute myeloid leukemia (AML), donor T cells combat leukemia through the graft-versus-leukemia (GVL) effect, while they also pose a risk of triggering life-threatening graft-versus-host disease (GVHD) by interacting with recipient cells. The onset of GVHD hinges on the interplay between donor T cells and recipient antigen-presenting cells (APCs), sparking T-cell activation. However, effective methods to balance GVHD and GVL are lacking.
METHODS: In our study, we crafted nanocapsules by layering polycationic aminated gelatin and polyanionic alginate onto the surface of T cells, examining potential alterations in their fundamental physiological functions. Subsequently, we established an AML mouse model and treated it with transplantation of bone marrow cells (BMCs) combined with encapsulated T cells to investigate the GVL and anti-GVHD effects of encapsulated T cells. In vitro co-culture was employed to probe the effects of encapsulation on immune synapses, co-stimulatory molecules, and tumor-killing pathways.
RESULTS: Transplantation of BMCs combined with donor T cells selectively encapsulated onto AML mice significantly alleviates GVHD symptoms while preserving essential GVL effects. Encapsulated T cells exerted their immunomodulatory effects by impeding the formation of immune synapses with recipient APCs, thereby downregulating co-stimulatory signals such as CD28-CD80, ICOS-ICOSL, and CD40L-CD40. Recipient mice receiving encapsulated T-cell transplantation exhibited a marked increase in donor Ly-5.1-BMC cell numbers, accompanied by unaltered in vivo expression levels of perforin and granzyme B. While transient inhibition of donor T-cell cytotoxicity in the tumor microenvironment was observed in vitro following single-cell nanoencapsulation, subsequent restoration to normal antitumor activity ensued, attributed to selective permeability of encapsulated vesicle shells and material degradation. Moreover, the expression of apoptotic proteins and FAS-FAS ligand pathway at normal levels was still observed in leukemia tumor cells.
CONCLUSIONS: Encapsulated donor T cells effectively mitigate GVHD while preserving the GVL effect by minimizing co-stimulatory signaling with APCs through early immune isolation. Subsequent degradation of nanocapsules restores T-cell cytotoxic efficacy against AML cells, mediated by cytotoxic pathways. Using transplant-encapsulated T cells offers a promising strategy to suppress GVHD while preserving the GVL effect.