Yi Tai, Cuchara Lisa, Wang Yinong, Koh Kian Peng, Ranjbaran Hooman, Tellides George, Pober Jordan S, Lorber Marc I
Department of Surgery, Section of Organ Transplantation and Immunology, Yale University School of Medicine, New Haven, CT 06510, USA.
Transplantation. 2006 Feb 27;81(4):559-66. doi: 10.1097/01.tp.0000198737.12507.19.
Chronic allograft dysfunction may result from arterial injury, manifest as transplant arteriosclerosis (TA). This represents an important factor limiting long-term outcomes after heart and kidney transplantation; a relationship between acute allograft arterial injury and TA has been suggested. We have used SCID/bg mice bearing transplanted human artery, inoculated with allogeneic human PBMC to study arteriopathy in human vessels. Earlier work demonstrated arteriopathy similar to that observed clinically, and identified interferon-gamma as a mediator of the process. This study evaluated whether sirolimus (SRL), with cyclosporine A (CsA) or alone, affects TA, and examined possible mechanisms of action.
CB17/SCID/bg mice were transplanted with human arteries replacing the abdominal aorta; reconstituted with allogeneic human PBMC. Controls received vehicle alone for comparison with mice given CsA (5 mg/kg/d), SRL (0.1 or 0.5 mg/kg/d), or CsA (5 mg/kg/d) plus SRL (0.1 mg/kg/d). Transplant arteries were examined 28 days later by histology and immunohistochemistry; circulating human interferon-gamma was evaluated by ELISA, and intragraft interferon-gamma mRNA by qRT-PCR.
The characteristic TA was modestly reduced by CsA or low-dose SRL, but eliminated by combination CsA plus SRL or higher dose SRL alone. Circulating interferon-gamma was reduced by CsA, but inhibition was dramatic with SRL alone or combined with CsA. Intragraft interferon-gamma and HLA-DR expression were moderately reduced by CsA or SRL, and eliminated with combined CsA plus SRL.
SRL plus CsA prevented allograft arteriopathy, correlating with suppression of intragraft interferon-gamma, suggesting that SRL effects may result from anti-inflammatory consequences from inhibiting interferon-gamma.
慢性移植器官功能障碍可能由动脉损伤引起，表现为移植动脉硬化（TA）。这是限制心脏和肾脏移植后长期预后的一个重要因素；急性移植器官动脉损伤与TA之间的关系已被提出。我们使用移植了人类动脉的SCID/bg小鼠，接种异体人类外周血单核细胞（PBMC）来研究人类血管的动脉病变。早期研究显示了与临床观察到的类似的动脉病变，并确定γ干扰素是该过程的介导因子。本研究评估西罗莫司（SRL）与环孢素A（CsA）联合使用或单独使用时是否会影响TA，并研究其可能的作用机制。
将CB17/SCID/bg小鼠的腹主动脉用人动脉进行置换；用异体人类PBMC进行重建。对照组仅接受赋形剂，与给予CsA（5mg/kg/天）、SRL（0.1或0.5mg/kg/天）或CsA（5mg/kg/天）加SRL（0.1mg/kg/天）的小鼠进行比较。28天后通过组织学和免疫组织化学检查移植动脉；通过酶联免疫吸附测定（ELISA）评估循环中的人类γ干扰素，通过定量逆转录聚合酶链反应（qRT-PCR）评估移植器官内的γ干扰素信使核糖核酸（mRNA）。
CsA或低剂量SRL可使特征性TA略有减轻，但CsA加SRL联合使用或单独使用高剂量SRL可消除TA。CsA可降低循环中的γ干扰素，但单独使用SRL或与CsA联合使用时抑制作用显著。CsA或SRL可使移植器官内的γ干扰素和人类白细胞抗原-DR（HLA-DR）表达适度降低，而CsA加SRL联合使用可消除这种表达。
SRL加CsA可预防移植器官动脉病变，这与移植器官内γ干扰素的抑制相关，提示SRL的作用可能源于抑制γ干扰素的抗炎效应。
