Differential effects of everolimus and cyclosporine A on intimal alpha-actin-positive cell dynamics of carotid allografts in mice.
BACKGROUND
We recently demonstrated that donor medial cells are replaced by smooth muscle alpha-actin (SMA)-expressing host cells in murine carotid allografts. In this study, we investigated neointimal cell dynamics including effects of cyclosporine A (CsA) and everolimus (SDZ RAD, Certican). To obtain a functional readout, we measured the effects of these treatments on cardiac allografts.


METHODS
Heterotopic heart allotransplantation was performed between C57BL/6 (B6) and BALB/c (B/c) mice. Orthotopic carotid artery allotransplantation was performed between B6 and B/c mice expressing green fluorescent protein (GFP). Both strains served as donors and recipients. Groups of mice were treated for 4 and 8 weeks (heart and carotid recipients, respectively) with placebo, CsA 20 mg/kg per day, or everolimus 1.0 mg/kg per day using Alzet minipumps. At 2, 4, and 8 weeks, carotid grafts were harvested for histology.


RESULTS
In the GFP-B/c to B6 strain combination, everolimus but not CsA significantly reduced neointima formation and accumulation of SMA-positive host (non-GFP) cells at doses that did not fully suppress heart rejection. In the B6 to GFP-B/c strain combination, everolimus and CsA strongly prevented heart rejection under treatment, partly suppressed neointima formation, and completely prevented SMA-positive host (GFP) cell accumulation.


CONCLUSIONS
Donor-derived cells expressing SMA never appear in the neointima, and such cells are completely recipient derived. Adequate immunosuppression delays or prevents the disappearance of donor cells and the appearance of host cells in the graft, a phenomenon apparently associated with the neointima formation. Even immunosuppression sufficient to prevent heart allograft rejection under treatment completely, diminishes neointima formation only by approximately 50%.
Matsumoto
Yuji
Y
Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland.
Hof
Akiko
A
Baumlin
Yves
Y
Müller
Matthias
M
Hof
Robert P
RP
D000199:Actins / Q000378:metabolism*; D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects / Q000502:physiology / Q000637:transplantation*; D016572:Cyclosporine / Q000097:blood / Q000494:pharmacology*; D000068338:Everolimus; D049452:Green Fluorescent Proteins; D016027:Heart Transplantation / Q000502:physiology*; D007166:Immunosuppressive Agents / Q000097:blood / Q000494:pharmacology; D008164:Luminescent Proteins / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020123:Sirolimus / Q000031:analogs & derivatives / Q000097:blood / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D014184:Transplantation, Homologous / Q000502:physiology*; D017539:Tunica Intima / Q000187:drug effects / Q000502:physiology / Q000637:transplantation*
D000199:Actins; D007166:Immunosuppressive Agents; D008164:Luminescent Proteins; D049452:Green Fluorescent Proteins; D016572:Cyclosporine; D000068338:Everolimus; D020123:Sirolimus