A peptide mimic of selectin ligands abolishes in vivo inflammation but has no effect on the rat heart allograft survival1.
Acute heart allograft rejection is characterized by leukocyte infiltration and myocyte damage, key elements in the histological grading of rejection. The induction of selectins and their ligands on the graft postcapillary venular endothelium increases leukocyte tethering to, rolling on, and extravasation through the endothelium into graft parenchyma. We have characterized peptide mimicking selectin ligands by screening phage peptide libraries using anti-Lewis A antibodies and E-selectin as target molecules. The effect of this selectin- binding peptide, IELLQAR, on the prevention of inflammation and tissue damage and on the prolongation of graft survival in inbred DA (RT1a) rat heart allografts transplanted to WF (RT1v) recipients was tested. Bovine serum albumin (0.1%, solvent), VTSIAQA (control peptide), or IELLQAR were either continuously infused into the peritoneum via osmotic mini pumps or injected twice daily IV. Treatment with bovine serum albumin and VTSIAQA did not alter the number of graft infiltrating leukocytes or the histological grade of acute rejection, all scored as grade 4. On the contrary, the selectin binding peptide, IELLQAR, dose-dependently reduced inflammation and at the highest dose (6.0 mg/kg per day) eliminated the majority of graft infiltrating leukocytes, reduced the histological grade from 4 to 1B, but had no effect on graft survival. These data indicate that the intensity of inflammation related to the allograft rejection does not correlate to the graft survival.
Department of Bacteriology and Immunology, Pathology, and Transplantation Laboratory, Haartman Institute, University of Helsinki, Finland.
Risto
R
Renkonen
Michiko N
MN
Fukuda
Lubomir
L
Petrov
Timo
T
Paavonen
Jutta
J
Renkonen
Pekka
P
Häyry
Minoru
M
Fukuda
D000818:Animals; D006084:Graft Rejection / Q000188:drug therapy; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation; D008024:Ligands; D018716:Molecular Mimicry; D009205:Myocarditis / Q000188:drug therapy* / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011920:Rats, Inbred WF; D019087:Selectins / Q000737:chemistry; D015996:Survival Rate; D014184:Transplantation, Homologous
D008024:Ligands; D009842:Oligopeptides; D019087:Selectins; C404394:isoleucyl-glutamyl-leucyl-leucyl-glutaminyl-alanyl-arginine