Regulation of transplant arteriosclerosis by CD25+CD4+ T cells generated to alloantigen in vivo

BACKGROUND: CD25CD4 regulatory T cells have been shown to suppress alloimmunity in various experimental settings. Here, we hypothesized that alloantigen-reactive regulatory T cells would reduce the severity of transplant arteriosclerosis. METHODS: CD25CD4 T cells from CBA mice that were pretreated with C57BL/6 (B.6) blood (donor-specific transfusion, DST) and nondepleting anti-CD4 Ab (YTS 177) were cotransferred with naïve CBA CD25CD4"effector" T cells into CBA-rag mice. These animals received aorta transplants from B.6 CD31 donors. CBA wild-type recipients of B.6 aorta grafts were pretreated with 177/DST directly. Some animals received 6×10 CD25CD4 T cells from pretreated mice to augment regulation on day -1. Grafts were harvested on day 30. RESULTS: Luminal occlusion of the graft caused by neointima formation was 29.3±19.4% (n=5) after transfer of effector T cells only. Co-transfer of CD25CD4 regulators reduced occlusion significantly (2.4±3.3%, n=3; P=0.009). This effect was partially abrogated in the presence of a CTLA4 blocking Ab (11.1±4.7%, n=4; P=0.008). Pretreating immunocompetent CBA recipients of B.6 aortic allografts with 177/DST did not reduce transplant arteriosclerosis significantly (43.0±15.7%, n=5 vs. 56.6±16.8%, n=5; 177/DST vs. controls; P=0.22). However, when pretreated primary CBA recipients received an additional transfer of 6 × 10 CD25CD4 T cells procured from other mice pretreated with 177/DST before transplantation, luminal occlusion of the graft was markedly reduced (33.0±7.6%, n=5; P=0.002). CONCLUSION: Regulatory T cells generated in vivo to alloantigen can prevent CD25CD4 T-cell-mediated transplant arteriosclerosis. In immunocompetent recipients, these cells have potential to be used as cellular immunotherapy to control transplant arteriosclerosis.