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. METHOD: 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).

T lymphocytes mediate leaflet destruction and allograft aortic valve failure in rats.

BACKGROUND: Allograft heart valves are commonly used in cardiac surgery but ultimately fail. This situation is most acute in children. This study addresses the role of T cell-mediated immune damage in allograft valve failure. METHODS: Syngeneic (Lewis to Lewis) or allogeneic (Brown Norway to Lewis) aortic valve grafts were implanted infrarenally into Lewis rat recipients (n = 24). Allogeneic valve grafts were also implanted into T cell-deficient rats (nude; n = 12). At 7, 14, and 28 days the valves were explanted and examined for structural integrity and cellular infiltration. RESULTS: Syngeneic grafts maintained normal leaflet structure with little leaflet immune infiltration. Allografts showed leaflet infiltration (7 days), significant leaflet thickening, progressively decreased cellularity (14 days), and leaflet destruction (28 days). Infiltrates contained CD43+, CD3+, and CD8+ cells. Allografts in T cell-deficient rats showed none of the above changes and maintained normal structural integrity. CONCLUSIONS: Allograft heart valves in the rat model undergo T cell-mediated immune rejection, resulting in structural failure.