期刊
TRANSPLANTATION
卷 81, 期 4, 页码 559-566出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/01.tp.0000198737.12507.19
关键词
transplant arteriosclerosis; allograft arteriopathy; sirolimus; interferon-gamma
资金
- NHLBI NIH HHS [P01 HL 70295] Funding Source: Medline
Background. 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. Methods. CB17/SCID/bg mice were transplanted with human arteries replacing the abdominal aorta; reconstituted with allogencic human PBMC. Controls received vehicle alone for comparison with mice given CsA (5 mg/kg/d), SRI, (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 immunohistochemisty; circulating human interferon-gamma was evaluated by ELISA, and intragraft interferon-gamma mRNA by qRT-PCR. Results. 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. Conclusions. 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.
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