Graves Scott S, Rezvani Andrew, Sale George, Stone Diane, Parker Maura, Rosinski Steven, Spector Michele, Swearingen Bruce, Kean Leslie, Storb Rainer
Transplantation Biology Program, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Transplantation Biology Program, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Biol Blood Marrow Transplant. 2017 Mar;23(3):420-427. doi: 10.1016/j.bbmt.2016.12.629. Epub 2016 Dec 21.
In long-term survivors of allogeneic hematopoietic cell transplantation (HCT), chronic graft-versus-host disease (GVHD) is the major cause of morbidity and mortality and a major determinant of quality of life. Chronic GVHD responds poorly to current immunosuppressive drugs, and while T cell depletion may be preventive, this gain is offset by increased relapse rates. A significant impediment to progress in treating chronic GVHD has been the limitations of existing animal models. The goal of this study was to develop a reproducible comprehensive model of chronic GVHD in the dog. Ten recipient dogs received 920 cGy total body irradiation, infusion of marrow, and an infusion of buffy coat cells from a dog leukocyte antigen (DLA)-mismatched unrelated donor. Postgrafting immunosuppression consisted of methotrexate (days 1, 3, 6, 11) and cyclosporine. The duration of cyclosporine administration was limited to 80 days instead of the clinically used 180 days. This was done to contain costs, as chronic GVHD was expected to develop at earlier time points. All recipients were given ursodiol for liver protection. One dog had graft failure and 9 dogs showed stable engraftment. Eight of the 9 developed de novo chronic GVHD. Dogs progressed with clinical signs of chronic GVHD over a period of 43 to 164 (median, 88) days after discontinuation of cyclosporine. Target organs showed the spectrum of chronic GVHD manifestations that are typically seen clinically. These included lichenoid changes of the skin, fasciitis, ocular involvement (xerophthalmia), conjunctivitis, bronchiolitis obliterans, salivary gland involvement, gingivitis, esophageal involvement, and hepatic involvement. Peripheral blood lymphocyte surface antigen expression of CD28 and inducible costimulator was elevated in dogs with GHVD compared with those in normal dogs, but not significantly so. Serum levels of IL-8 and monocyte chemotactic protein-1 in GVHD-affected dogs at time of euthanasia were elevated, whereas levels of IL-15 were depressed compared with those in normal dogs. Results indicate that the canine model is well suited for future studies aimed at preventing or treating chronic GVHD.
在异基因造血细胞移植（HCT）的长期存活者中，慢性移植物抗宿主病（GVHD）是发病和死亡的主要原因，也是生活质量的主要决定因素。慢性GVHD对当前的免疫抑制药物反应不佳，虽然去除T细胞可能具有预防作用，但这一益处被复发率增加所抵消。现有动物模型的局限性一直是治疗慢性GVHD取得进展的重大障碍。本研究的目的是建立一种可重复的犬慢性GVHD综合模型。十只受体犬接受了920 cGy的全身照射、骨髓输注以及来自犬白细胞抗原（DLA）不匹配的无关供体的血沉棕黄层细胞输注。移植后免疫抑制包括甲氨蝶呤（第1、3、6、11天）和环孢素。环孢素的给药时间限制为80天，而不是临床使用的180天。这样做是为了控制成本，因为预计慢性GVHD会在更早的时间点出现。所有受体均给予熊去氧胆酸进行肝脏保护。一只犬出现移植失败，9只犬移植稳定。9只犬中有8只发生了新发慢性GVHD。在停用环孢素后的43至164天（中位数为88天）内，犬出现了慢性GVHD的临床症状。靶器官表现出临床上常见的慢性GVHD表现谱。这些表现包括皮肤苔藓样改变、筋膜炎、眼部受累（干眼症）、结膜炎、闭塞性细支气管炎、唾液腺受累、牙龈炎、食管受累和肝脏受累。与正常犬相比，患有GHVD的犬外周血淋巴细胞表面抗原CD28和诱导性共刺激分子的表达有所升高，但升高不显著。安乐死时，受GVHD影响的犬血清白细胞介素-8（IL-8）和单核细胞趋化蛋白-1水平升高，而IL-15水平与正常犬相比降低。结果表明，该犬模型非常适合未来旨在预防或治疗慢性GVHD的研究。
