The University of Texas MD Anderson Cancer Center, UTHealth Graduate School of Biomedical Sciences, Houston, TX, United States.
Department of Hematopoietic Biology and Malignancy, Division of Cancer Medicine, MD Anderson Cancer Center, Houston, TX, United States.
Front Immunol. 2022 Jun 1;13:893659. doi: 10.3389/fimmu.2022.893659. eCollection 2022.
Allogeneic stem cell transplantation is a curative immunotherapy where patients receive myeloablative chemotherapy and/or radiotherapy, followed by donor stem cell transplantation. Graft versus host disease (GVHD) is a major complication caused by dysregulated donor immune system, thus a novel strategy to modulate donor immunity is needed to mitigate GVHD. Tissue damage by conditioning regimen is thought to initiate the inflammatory milieu that recruits various donor immune cells for cross-priming of donor T cells against alloantigen and eventually promote strong Th1 cytokine storm escalating further tissue damage. Bilirubin nanoparticles (BRNP) are water-soluble conjugated of bilirubin and polyethylene glycol (PEG) with potent anti-inflammatory properties through its ability to scavenge reactive oxygen species generated at the site of inflammation. Here, we evaluated whether BRNP treatment post-transplantation can reduce initial inflammation and subsequently prevent GVHD in a major histocompatibility (MHC) mismatched murine GVHD model. After myeloablative irradiation, BALB/c mice received bone marrow and splenocytes isolated from C57BL/6 mice, with or without BRNP (10 mg/kg) daily on days 0 through 4 post-transplantation, and clinical GVHD and survival was monitored for 90 days. First, BRNP treatment significantly improved clinical GVHD score compared to untreated mice (3.4 vs 0.3, p=0.0003), and this translated into better overall survival (HR 0.0638, p=0.0003). Further, BRNPs showed a preferential accumulation in GVHD target organs leading to a reduced systemic and local inflammation evidenced by lower pathologic GVHD severity as well as circulating inflammatory cytokines such as IFN-γ. Lastly, BRNP treatment post-transplantation facilitated the reconstitution of CD4 iNK T cells and reduced expansion of proinflammatory CD8α iNK T cells and neutrophils especially in GVHD organs. Lastly, BRNP treatment decreased ICOS or CTLA-4 T cells but not PD-1 T cells suggesting a decreased level of T cell activation but maintaining T cell tolerance. In conclusion, we demonstrated that BRNP treatment post-transplantation ameliorates murine GVHD diminishing the initial tissue damage and subsequent inflammatory responses from immune subsets.
同种异体干细胞移植是一种治愈性免疫疗法，患者接受大剂量化疗和/或放疗，然后接受供体干细胞移植。移植物抗宿主病（GVHD）是由供体免疫系统失调引起的主要并发症，因此需要一种新的调节供体免疫的策略来减轻 GVHD。预处理方案引起的组织损伤被认为启动了炎症环境，该环境招募各种供体免疫细胞，对供体 T 细胞进行同种异体抗原的交叉呈递，并最终促进强烈的 Th1 细胞因子风暴，进一步加重组织损伤。胆红素纳米颗粒（BRNP）是胆红素与聚乙二醇（PEG）的水溶性共轭物，通过清除炎症部位产生的活性氧，具有强大的抗炎特性。在这里，我们评估了移植后 BRNP 治疗是否可以减少初始炎症，并随后在主要组织相容性（MHC）不匹配的小鼠 GVHD 模型中预防 GVHD。在大剂量照射后，BALB/c 小鼠接受来自 C57BL/6 小鼠的骨髓和脾细胞，在移植后第 0 天至第 4 天每天接受或不接受 BRNP（10mg/kg）治疗，并监测 90 天的临床 GVHD 和存活情况。首先，与未治疗的小鼠相比，BRNP 治疗显著改善了临床 GVHD 评分（3.4 与 0.3，p=0.0003），这转化为更好的总生存（HR 0.0638，p=0.0003）。此外，BRNPs 优先在 GVHD 靶器官中积累，导致全身和局部炎症减少，证据是病理 GVHD 严重程度降低以及循环炎症细胞因子如 IFN-γ。最后，移植后 BRNP 治疗促进了 CD4 iNK T 细胞的重建，并减少了促炎 CD8α iNK T 细胞和中性粒细胞的扩增，特别是在 GVHD 器官中。最后，BRNP 治疗减少了 ICOS 或 CTLA-4 T 细胞，但不减少 PD-1 T 细胞，这表明 T 细胞激活水平降低，但维持 T 细胞耐受。总之，我们证明了移植后 BRNP 治疗可改善小鼠 GVHD，减轻初始组织损伤和随后免疫亚群的炎症反应。
