A new and clinically relevant murine model of solid-organ transplant aspergillosis.
A new and clinically relevant murine model of solid-organ transplant aspergillosis.
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DOI：
10.1242/dmm.010330
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发表时间：
2013-05
影响因子：
4.3
通讯作者：
Armstrong-James D
中科院分区：
文献类型：
--
作者：
Herbst S;Shah A;Carby M;Chusney G;Kikkeri N;Dorling A;Bignell E;Shaunak S;Armstrong-James D
侵袭性真菌感染（IFIs）是器官移植患者死亡的主要原因。鼠氢化可的松介导的肺曲霉菌病免疫抑制模型常用于这些患者的IFIs。然而，该模型没有考虑钙调磷酸酶抑制剂对IFIs或真菌钙调磷酸酶途径的移植免疫的影响，这是毒力和抗真菌药物耐药性所必需的。为了解决这两个问题，一个新的和临床相关的移植免疫抑制模型他克莫司（FK 506）和氢化可的松相关的肺曲霉菌病的开发。我们首先对406例肺移植患者的IFIs进行了表征。这表明，所有肺曲霉病患者的免疫抑制与钙调磷酸酶抑制剂和类固醇。小鼠药代动力学研究表明，理想剂量1 mg/kg/天的FK 506腹腔给药产生的血谷水平在人体治疗范围内（5-12 ng/ml）。与仅使用氢化可的松的免疫抑制相比，使用FK 506和氢化可的松的移植相关免疫抑制模型中肺曲霉菌病的死亡率增加。肺组织病理学显示中性粒细胞浸润和气管支气管炎，这与24小时时肺肿瘤坏死因子-α（TNFα）、JE（人MCP-1的同源物）和KC（人IL-8的同源物）减少有关，但在真菌负荷高时，48小时时肺TNFα、JE和KC增加。此外，FK 506在体外直接损害肺泡巨噬细胞中的真菌杀伤，在5 ng/ml的低浓度下，FK 506介导的体外烟曲霉放射状生长抑制。总之，这些结果表明，FK 506的免疫抑制活性超过其体内抗真菌活性。这些观察结果表明，FK 506损害先天免疫应答，并导致与类固醇联合使用时对IFIs的易感性增加。这种新的和临床相关的侵袭性曲霉病小鼠模型是一个有价值的除了进一步研究真菌免疫和抗真菌治疗在器官移植。
Invasive fungal infections (IFIs) are a major cause of death in organ transplant patients. The murine hydrocortisone-mediated immunosuppression model of pulmonary aspergillosis is commonly used to characterise IFIs in these patients. However, this model does not take into account the effects of calcineurin inhibitors on transplant immunity to IFIs or the fungal calcineurin pathway, which is required for both virulence and antifungal drug resistance. To address these two issues, a new and clinically relevant transplant immunosuppression model of tacrolimus (FK506) and hydrocortisone-associated pulmonary aspergillosis was developed. We first characterised IFIs in 406 patients with a lung transplant. This showed that all of the patients with pulmonary aspergillosis were immunosuppressed with calcineurin inhibitors and steroids. Murine pharmacokinetic studies demonstrated that an ideal dose of 1 mg/kg/day of FK506 intraperitoneally produced blood trough levels in the human therapeutic range (5–12 ng/ml). There was increased mortality from pulmonary aspergillosis in a transplant-relevant immunosuppression model using both FK506 and hydrocortisone as compared with immunosuppression using hydrocortisone only. Lung histopathology showed neutrophil invasion and tracheobronchitis that was associated with reduced lung tumour necrosis factor-α (TNFα), JE (homologue of human MCP-1) and KC (homologue of human IL-8) at 24 hours, but increased lung TNFα, JE and KC at 48 hours when fungal burden was high. Furthermore, FK506 directly impaired fungal killing in alveolar macrophages in vitro, with FK506-mediated inhibition of the radial growth of Aspergillus fumigatus in vitro occurring at the low concentration of 5 ng/ml. Taken together, these findings show that the immunosuppressive activity of FK506 outweighs its antifungal activity in vivo. These observations demonstrate that FK506 impairs innate immune responses and leads to an incremental increase in susceptibility to IFIs when it is combined with steroids. This new and clinically relevant mouse model of invasive aspergillosis is a valuable addition to the further study of both fungal immunity and antifungal therapy in organ transplantation.
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影响因子：
4.9
作者：
Sheppard, Donald C.;Graybill, John R.;Filler, Scott G.
通讯作者：
Filler, Scott G.
DOI：
10.1086/652768
发表时间：
2010-06-15
期刊：
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
影响因子：
--
作者：
Baddley JW;Andes DR;Marr KA;Kontoyiannis DP;Alexander BD;Kauffman CA;Oster RA;Anaissie EJ;Walsh TJ;Schuster MG;Wingard JR;Patterson TF;Ito JI;Williams OD;Chiller T;Pappas PG
通讯作者：
Pappas PG
影响因子：
6.4
作者：
High, KP;Washburn, RG
通讯作者：
Washburn, RG
影响因子：
4.6
作者：
Fishman, Jay A.
通讯作者：
Fishman, Jay A.
影响因子：
11.4
作者：
Odom, A;Muir, S;Heitman, J
通讯作者：
Heitman, J