Human allograft arterial injury is ameliorated by sirolimus and cyclosporine and correlates with suppression of interferon-gamma

• Published in: Transplantation Vol. 81; no. 4; p. 559
• Main Authors: Yi, Tai, Cuchara, Lisa, Wang, Yinong, Koh, Kian Peng, Ranjbaran, Hooman, Tellides, George, Pober, Jordan S, Lorber, Marc I
• Format: Journal Article
• Language: English
• Published: United States 27.02.2006
• Subjects: Animals; Arteries - pathology; Arteries - transplantation; Cyclosporine - therapeutic use; Humans; Immunosuppressive Agents - pharmacology; Immunosuppressive Agents - therapeutic use; Interferon-gamma - drug effects; Interferon-gamma - physiology; Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - physiology; Mice; Mice, SCID; Sirolimus - therapeutic use; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Transplantation, Heterologous - pathology; Transplantation, Homologous - pathology
• ISSN: 0041-1337
• 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.