Treatment with a rho kinase inhibitor improves survival from graft-versus-host disease in mice after MHC-haploidentical hematopoietic cell transplantation.
Treatment with a rho kinase inhibitor improves survival from graft-versus-host disease in mice after MHC-haploidentical hematopoietic cell transplantation.
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DOI：
10.1016/j.bbmt.2014.04.029
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发表时间：
2014-08
期刊：
影响因子：
--
通讯作者：
Schwartz DH
中科院分区：
文献类型：
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作者：
Iyengar S;Zhan C;Lu J;Korngold R;Schwartz DH
急性移植物抗宿主病（GVHD）是异基因造血细胞移植（HCT）的主要并发症，也是移植后100天内非复发性死亡的主要原因。虽然GVHD可以通过从供体造血干细胞群体中广泛去除成熟供体T细胞来预防，但这样做消除了也由供体T细胞介导的任何潜在的同种异体移植物抗肿瘤（GVT）效应，并导致不可接受的癌症复发率。将GVHD发展与GVT反应分开的这个问题的一个潜在解决方案是防止肠道（IT）中T细胞介导的GVHD，同时保持靶向表达宿主同种异体抗原的残余肿瘤细胞的供体T细胞的全身性抗宿主同种异体反应性。我们在MHC半相合骨髓移植的C3 H → B6 C3 F1小鼠模型中检测了口服和腹腔注射抗炎rho激酶抑制剂法舒地尔预防GVHD的能力。法舒地尔治疗的抗-thy-1 mAb + C′治疗的骨髓（ATBM）细胞+T细胞接受者的90天存活率为73%，而未治疗的ATBM + T细胞接受者的90天存活率为25%（P < .0001）。严重的初始体重减轻在两组中相似，但在治疗动物中观察到较少的腹泻，并且法舒地尔治疗的存活动物比未治疗的存活动物恢复更多的体重。皮肤炎症在第2周和第8周之间发生并消退，在治疗和未治疗的存活动物中具有相似的严重程度和动力学，表明持续的同种异体反应性。法舒地尔处理小鼠移植后第10天的脾细胞（含成熟供体T细胞）和第98天的脾细胞（含成熟供体和从头胸腺衍生T细胞）显示出对宿主亲本抗原的同种异体反应性，分别通过体外IFN-γ产生和同种异体刺激增殖轮次进行评估。这些数据支持这样的观点，即用rho激酶抑制剂靶向治疗IT可以改善致死性GVHD，同时保留全身同种异体反应性。结果还表明，在法舒地尔治疗和未治疗的同种异体ATBM + T细胞的长期存活者中，对GVHD的IT特异性耐受或抗性的机制相似。
Acute graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic cell transplantation (HCT) and the main cause of nonrelapse mortality during the first 100 days post-transplant. Although GVHD can be prevented by extensive removal of mature donor T cells from the donor hematopoietic stem cell population, doing so eliminates any potential allogeneic graft-versus-tumor (GVT) effect also mediated by donor T cells and results in unacceptable rates of cancer relapse. One potential solution to this problem of separating GVHD development from a GVT response is to prevent T cell–mediated GVHD in the intestinal tract (IT) while preserving systemic antihost alloreactivity of donor T cells that target residual tumor cells expressing host alloantigens. We examined the ability of the anti-inflammatory rho kinase inhibitor, fasudil, given orally and intraperitoneally, to prevent GVHD in a C3H → B6C3F1 mouse model of MHC-haploidentical bone marrow transplantation. Fasudil-treated recipients of anti-thy-1 mAb + C′ treated bone marrow (ATBM) cells plus T cells had a 73% 90-day survival compared with 25% among untreated ATBM + T cell recipients (P < .0001). Severe initial weight loss was similar in the 2 groups, but less diarrhea was observed among treated animals, and fasudil-treated survivors recovered more weight than untreated survivors. Skin inflammation occurred and resolved between weeks 2 and 8 with similar severity and kinetics in both treated and untreated surviving animals, indicating persistent alloreactivity. Day 10 posttransplantation splenocytes from fasudil-treated mice, containing mature donor T cells, and day 98 splenocytes, containing mature donor and de novo thymus-derived T cells, exhibited alloreactivity against host parental antigens, as assessed by in vitro IFN-γ production and rounds of allostimulated proliferation, respectively. These data support the idea that targeted treatment of the IT with rho kinase inhibitors can ameliorate lethal GVHD while preserving systemic alloreactivity. The results also suggest that similar mechanisms of IT-specific tolerance or resistance to GVHD operate in fasudil-treated and untreated long-term survivors of allogeneic ATBM + T cells.