School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia; Molecular Horizons, University of Wollongong, NSW 2522, Australia; Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia.
School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia; Molecular Horizons, University of Wollongong, NSW 2522, Australia; Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia.
Int Immunopharmacol. 2019 Jul;72:479-486. doi: 10.1016/j.intimp.2019.04.037. Epub 2019 Apr 30.
Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative method for blood cancers and other blood disorders, but is limited by the development of graft-versus-host disease (GVHD). GVHD results in inflammatory damage to the host liver, gastrointestinal tract and skin, resulting in high rates of morbidity and mortality in HSCT recipients. Activation of the A receptor has been previously demonstrated to reduce disease in allogeneic mouse models of GVHD. This study aimed to investigate the effect of A activation on disease development in a humanised mouse model of GVHD. Immunodeficient non-obese diabetic-severe combined immunodeficiency-interleukin (IL)-2 receptor γ (NSG) mice injected with human (h) peripheral blood mononuclear cells (hPBMCs), were treated with either the A agonist CGS 21680 or control vehicle. Contrary to the beneficial effect of A activation in allogeneic mouse models, CGS 21680 increased weight loss, and failed to reduce the clinical score or increase survival in this humanised mouse model of GVHD. Moreover, CGS 21680 reduced T regulatory cells and increased serum human IL-6 concentrations. Conversely, CGS 21680 reduced serum human tumour necrosis factor (TNF)-α concentrations and leukocyte infiltration into the liver, indicating that A activation can, in part, reduce molecular and histological GVHD in this model. Notably, CGS 21680 also prevented healthy weight gain in NSG mice not engrafted with hPBMCs suggesting that this compound may be suppressing appetite or metabolism. Therefore, the potential benefits of A activation in reducing GVHD in HSCT recipients may be limited and confounded by adverse impacts on weight, decreased T regulatory cell frequency and increased IL-6 production.
同种异体造血干细胞移植 (HSCT) 是治疗血液癌和其他血液疾病的一种方法，但受移植物抗宿主病 (GVHD) 的发展限制。GVHD 导致宿主肝脏、胃肠道和皮肤发生炎症性损伤，导致 HSCT 受者的发病率和死亡率居高不下。先前已经证明，A 受体的激活可减少同种异体 GVHD 小鼠模型中的疾病。本研究旨在研究 A 激活对 GVHD 人源化小鼠模型中疾病发展的影响。注射人外周血单核细胞 (hPBMC) 的免疫缺陷非肥胖糖尿病-严重联合免疫缺陷-白细胞介素 (IL)-2 受体 γ (NSG) 小鼠用 A 激动剂 CGS 21680 或对照载体处理。与 A 激活在同种异体小鼠模型中的有益作用相反，CGS 21680 增加了体重减轻，并且未能降低该 GVHD 人源化小鼠模型的临床评分或增加存活率。此外，CGS 21680 减少了 T 调节细胞并增加了血清人白细胞介素 6(IL-6)浓度。相反，CGS 21680 降低了血清人肿瘤坏死因子 (TNF)-α 浓度和白细胞浸润到肝脏，表明 A 激活可以部分减少该模型中的分子和组织学 GVHD。值得注意的是，CGS 21680 还阻止了未植入 hPBMC 的 NSG 小鼠的健康体重增加，表明该化合物可能会抑制食欲或新陈代谢。因此，A 激活在降低 HSCT 受者 GVHD 中的潜在益处可能受到限制，并受到对体重、T 调节细胞频率降低和 IL-6 产生增加的不利影响的影响。
