Sirolimus (rapamycin) halts and reverses progression of allograft vascular disease in non-human primates.
BACKGROUND
Current immunosuppressive protocols fail to prevent chronic rejection often manifested as graft vascular disease (GVD) in solid organ transplant recipients. Several new immunosuppressants including sirolimus, a dual function growth factor antagonist, have been discovered, but studies of drug efficacy have been hampered by the lack of a model of GVD in primates, as a prelude to clinical trials. As described earlier, we have developed a novel non-human primate model of GVD where progression of GVD is quantified by intravascular ultrasound (IVUS).


METHODS
Twelve cynomolgus monkeys underwent aortic transplantation from blood group compatible but mixed lymphocyte reaction-mismatched donors. To allow the development of GVD in the allograft, no treatment was administered for the first 6 weeks. Six monkeys were treated orally with sirolimus from day 45 after transplantation to day 105.


RESULTS
Progression of GVD measured as change in intimal area from day 42 to 105 was halted in sirolimus-treated monkeys compared to untreated monkeys (P<0.001, general linear model). On day 105, the intimal area +/- SEM was 3.7+/-1.0 and 6.4+/-0.5 mm2, respectively (P<0.05, t test). The magnitude of allograft intimal area on day 105 correlated inversely with sirolimus trough levels (R2=0.67, P<0.05). Regression of the intimal area was seen in four of six sirolimus-treated monkeys, which was significantly different from the untreated monkeys (P<0.05).


CONCLUSIONS
Our results in the first non-human primate model of GVD showed that treatment with sirolimus not only halted the progression of preexisting GVD but also was associated with partial regression. Sirolimus trough blood levels were correlated with efficacy. Therefore, sirolimus has the potential to control clinical chronic allograft rejection.
Ikonen
T S
TS
Department of Cardiothoracic Surgery, Transplantation Immunology, Stanford University, CA 94305, USA.
Gummert
J F
JF
Hayase
M
M
Honda
Y
Y
Hausen
B
B
Christians
U
U
Berry
G J
GJ
Yock
P G
PG
Morris
R E
RE
D000199:Actins; D000818:Animals; D001012:Aorta, Abdominal / Q000637:transplantation*; D004396:Coloring Agents; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000188:drug therapy / Q000517:prevention & control; D016027:Heart Transplantation / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008252:Macaca fascicularis; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000737:chemistry; D020123:Sirolimus / Q000627:therapeutic use*; D014184:Transplantation, Homologous / Q000473:pathology
D000199:Actins; D004396:Coloring Agents; D007166:Immunosuppressive Agents; D020123:Sirolimus