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 respon sible for late graft loss. The effects of FTY720, an immunomodulator with a novel mechanism of action were investigated in combination with cyclospori ne 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 vehicl e (P), CsA 0.3 (C0.3), 1 (C1) or 3 (C3) mg.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.kg(-1 ).day(-1). Lumen area was estimated by magnetic resonance imaging, peripher al lymphocyte count and drug concentrations were determined at 1 and 8 week s. Neointima, media, and lumen area were measured morphometrically. Intimal and adventitial infiltration of mononuclear cells, and medial smooth muscl e 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 an d morphometric evaluation showed that all aspects of GVD were dose dependen tly 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 histologica lly estimated neointimal thickness.