Prevention of graft vessel disease by combined FTY720/cyclosporine. A treatment in a rat carotid artery transplantation model.
BACKGROUND
Graft vessel disease (GVD) is an important problem often responsible for late graft loss. The effects of FTY720, an immunomodulator with a novel mechanism of action were investigated in combination with cyclosporine A (CsA) in a carotid artery allograft model.


METHODS
A segment of the carotid artery of Lewis rats was replaced by a DA allograft. Seven groups of eight rats were treated for 8 weeks with vehicle (P), CsA 0.3 (C0.3), 1 (C1) or 3 (C3) mg x kg(-1).day(-1) or a combination of CsA 1 with FTY 0.01 (C1F0.01), 0.03 (C1F0.03), and 0.1 (C1F0.1) mg x kg(-1).day(-1). Lumen area was estimated by magnetic resonance imaging, peripheral lymphocyte count and drug concentrations were determined at 1 and 8 weeks. Neointima, media, and lumen area were measured morphometrically. Intimal and adventitial infiltration of mononuclear cells, and medial smooth muscle cells number was assessed using a score.


RESULTS
FTY720 did not influence CsA blood concentrations. FTY720 but not CsA decreased the PLC dose dependently. Magnetic resonance imaging revealed that treatment groups have larger lumen size than group P. Histological and morphometric evaluation showed that all aspects of GVD were dose dependently suppressed by treatment and lumen narrowing was prevented.


CONCLUSIONS
CsA, at clinically relevant blood levels, suppressed GVD only partly. The addition of FTY720 was well tolerated and completely suppressed GVD development. In vivo lumen size did not correlate with the histologically estimated neointimal thickness.
Novartis Pharma Research, Novartis Pharma AG, Basel, Switzerland.
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Z
Nikolova
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Hof
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M
Rudin
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Y
Baumlin
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G
Kraus
R P
RP
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D000818:Animals; D002339:Carotid Arteries / Q000473:pathology / Q000637:transplantation*; D002340:Carotid Artery Diseases / Q000517:prevention & control*; D016572:Cyclosporine / Q000008:administration & dosage* / Q000097:blood; D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D018655:Lymphocyte Count; D008279:Magnetic Resonance Imaging; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D011409:Propylene Glycols / Q000008:administration & dosage* / Q000097:blood; D051381:Rats; D011917:Rats, Inbred Lew; D013110:Sphingosine / Q000031:analogs & derivatives
D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D016572:Cyclosporine; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine