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


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.
Department of Surgery, Section of Organ Transplantation and Immunology, Yale University School of Medicine, New Haven, CT 06510, USA.
Tai
T
Yi
Lisa
L
Cuchara
Yinong
Y
Wang
Kian Peng
KP
Koh
Hooman
H
Ranjbaran
George
G
Tellides
Jordan S
JS
Pober
Marc I
MI
Lorber
D000818:Animals; D001158:Arteries / Q000473:pathology / Q000637:transplantation*; D016572:Cyclosporine / Q000627:therapeutic use*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D007371:Interferon-gamma / Q000187:drug effects / Q000502:physiology*; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000502:physiology; D051379:Mice; D016513:Mice, SCID; D020123:Sirolimus / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014183:Transplantation, Heterologous / Q000473:pathology; D014184:Transplantation, Homologous / Q000473:pathology*
D007166:Immunosuppressive Agents; D007371:Interferon-gamma; D016572:Cyclosporine; D020123:Sirolimus