Prevention of allograft heart valve failure in a rat model.
OBJECTIVE
Allograft heart valves are commonly used in cardiac surgery. Despite mounting evidence that these valves are immunogenic, leading to premature failure, current clinical practice does not attempt to minimize or control such a response. The objective of this study was to evaluate immune modulatory approaches to ameliorate allograft valve failure in a rat model.


METHODS
Aortic valve grafts were implanted infrarenally into Lewis rat recipients (n = 32). There were 4 transplant groups: syngeneic grafts (Lewis to Lewis), untreated allografts (Brown Norway to Lewis), allograft recipients treated with cyclosporine (INN: ciclosporin) (10 mg/kg per day for 7 or 28 days), and allograft recipients treated with anti-alpha4 integrin and anti-beta2 integrin monoclonal antibodies for 7 days. At 7 and 28 days the valves were examined for structural integrity and cellular infiltration.


RESULTS
Both cyclosporine and anti-alpha4/beta2 integrin treatment resulted in significant reduction in leaflet infiltration by macrophages (ED1(+)), T cells (CD3(+)), and CD8(+) T cells at 7 days with preservation of structural integrity when compared with control allografts. Twenty-eight days after implantation, daily treatment with cyclosporine preserved leaflet structural integrity and inhibited cellular infiltration. However, a short course of cyclosporine (7 days) failed to prevent destruction of the valves at 28 days.


CONCLUSIONS
Immune modulatory approaches aimed at T-cell activation or trafficking decrease leaflet cellular infiltration and prevent allograft valve structural failure. However, short-course therapy does not appear to be sufficient and must be maintained to allow long-term preservation of leaflet structural integrity (28 days).
Légaré
J F
JF
Departments of Surgery, Pathology, and Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.
Ross
D B
DB
Issekutz
T B
TB
Ruigrok
W
W
Creaser
K
K
Hirsch
G M
GM
Lee
T D
TD
D000704:Analysis of Variance; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001021:Aortic Valve / Q000276:immunology / Q000637:transplantation*; D016572:Cyclosporine / Q000276:immunology / Q000627:therapeutic use; D005434:Flow Cytometry; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control*; D019918:Heart Valve Prosthesis Implantation; D007124:Immunoenzyme Techniques; D007166:Immunosuppressive Agents / Q000276:immunology / Q000627:therapeutic use*; D016023:Integrins / Q000276:immunology / Q000627:therapeutic use; D008297:Male; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D016023:Integrins; D016572:Cyclosporine