Viral serine proteinase inhibitor (SERP-1) effectively decreases the incidence of graft vasculopathy in heterotopic heart allografts.
BACKGROUND
Graft vascular disease (GVD) is the most common cause of late graft failure in solid organ transplantation. Recent studies have shown good efficacy of a novel nontoxic viral-derived serine proteinase inhibitor (SERP-1) in preventing postangioplasty restenosis. The current study was designed to test whether short-term treatment with SERP-1 was effective in reducing the incidence of GVD in a solid organ transplant.


METHODS
Piebald-Virol-Glaxo (PVG) donor hearts were transplanted into August-Copenhagen-Irish (ACI) recipients and observed for 90 days. All recipients (n=60) were treated with microemulsion cyclosporine (CsA) 7.5 mg/kg per gavage from day 0 to day 9 and randomized into 4 groups. SERP-1 was given intravenously. Group I received CsA monotherapy; group II, CsA+SERP-1 1 ng/g (postoperative days 0-9); group III, CsA+SERP-1 10 ng/g (postoperative days 0-9); and group IV, CsA+SERP-1 10 ng/g (postoperative days 0-9, 30, and 60). Graft viability was monitored by palpation, and GVD was assessed by morphometry.


RESULTS
Two animals in group I rejected their allografts on postoperative days 7 and 14, 1 animal in group II rejected the allograft (postoperative day 31), and none in group III and IV rejected the allografts. At 90 days postoperative, 23.8% of all coronary vessels showed evidence of GVD in group I, 18.4% in group II, 12.9% in group III, and 11.8% in group IV. The difference in incidence of GVD was significant between groups I and III (P<0.05) and groups I and IV (P<0.05). Treatment with SERP-1 was well tolerated, and all animals regained weight quickly postsurgery.


CONCLUSIONS
Treatment of allograft recipients with SERP-1 in combination with CsA early after transplantation significantly decreases the incidence of GVD when compared to grafts treated with only CsA. These results demonstrate the clinical potential for this novel serine protease inhibitor to prevent GVD in solid organ transplantation.
Hausen
B
B
Transplantation Immunology, Department of Cardiothoracic Surgery, Falk CVRB, Stanford University Medical Center, 300 Pasteur Drive, Palo Alto, CA 94305-5407, USA. hausen@leland.stanford.edu
Boeke
K
K
Berry
G J
GJ
Morris
R E
RE
D000818:Animals; D003327:Coronary Disease / Q000517:prevention & control*; D016572:Cyclosporine / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D006084:Graft Rejection / Q000209:etiology / Q000473:pathology; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation / Q000009:adverse effects*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D017202:Myocardial Ischemia / Q000209:etiology / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D011182:Postoperative Care; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000627:therapeutic use*; D015843:Serpins / Q000627:therapeutic use*; D013997:Time Factors; D014183:Transplantation, Heterologous; D014184:Transplantation, Homologous; D014764:Viral Proteins / Q000627:therapeutic use*
D007166:Immunosuppressive Agents; D015842:Serine Proteinase Inhibitors; D015843:Serpins; D014764:Viral Proteins; D016572:Cyclosporine