alpha4beta1-integrin blockade and cyclosporine decreases the prevalence and severity of transplant vasculopathy in a rat transplant model.
BACKGROUND
Transplant vasculopathy leads to neointimal proliferation of allograft arteries, and alpha4beta1-integrin (very late antigen-4 [VLA-4]) seems to play an important role in the pathogenesis. This study evaluates the effect of a new, synthetic, VLA-4 blocker (S3429) on transplant vasculopathy in a rat cardiac transplant model.


METHODS
After transplantation (Lewis to Fisher), rats were divided randomly into 6 therapy groups: Group 1, n = 14, saline solution (vehicle); Group 2, n = 14, 3 mg/kg/day cyclosporine; Group 3, n = 21, 10 mg/kg/day S3429 + 3 mg/kg/day cyclosporine; Group 4, n = 21, 5 mg/kg/day S3429 + 3 mg/kg/day cyclosporine; Group 5: n = 21, 10 mg/kg/day S3429; Group 6, n = 21, 5 mg/kg/day S3429. Cyclosporine was given continuously until rats were killed. S3429 was either given for the entire study time or was discontinued after 20 days and animals were killed at Day 80. Twenty-eighty days after grafting, we assessed vasculopathy prevalence and mean vessel occlusion in coronary arteries.


RESULTS
Cyclosporine decreased the prevalence of vasculopathy and mean vessel occlusion compared with controls. We observed a further decrease in prevalence and mean vessel occlusion with 80 days of therapy with S3429 and cyclosporine. After discontinuing S3429 therapy at Day 20, prevalence and mean vessel occlusion increased to values seen in cyclosporine-treated animals at Day 80. S3429 alone decreased mean vessel occlusion only within the first 20 days compared with controls but had no effect on the prevalence of vasculopathy.


CONCLUSIONS
Because of the further decrease with S3429 therapy and the dramatic increase after discontinuation of S3429 therapy, we conclude that blocking VLA-4 receptors may prevent the development of transplant vasculopathy.
Richter
M H C
MH
Heart Center, University of Leipzig, Leipzig, Germany. drrichter@gmx.net
Wehner
V
V
Kock
M
M
Falk
V
V
Richter
H
H
Stilz
H U
HU
Lippek
F
F
Schollmann
H J
HJ
Gummert
J F
JF
Mohr
F W
FW
D000818:Animals; D003327:Coronary Disease / Q000453:epidemiology / Q000517:prevention & control*; D016572:Cyclosporine / Q000627:therapeutic use*; D004195:Disease Models, Animal; D016027:Heart Transplantation / Q000009:adverse effects*; D006827:Hydantoins / Q000627:therapeutic use*; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D015995:Prevalence; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D012720:Severity of Illness Index
D006827:Hydantoins; D039041:Integrin alpha4beta1; D010671:Phenylurea Compounds; C501869:S 3429; D016572:Cyclosporine