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BACKGROUND: CD25+CD4+ 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: CD25+CD4+ 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 CD25-CD4+"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 6x10(5) CD25+CD4+ 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 CD25+CD4+ 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 x 10(5) CD25+CD4+ 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 CD25-CD4+ T-cell-mediated transplant arteriosclerosis. In immunocompetent recipients, these cells have potential to be used as cellular immunotherapy to control transplant arteriosclerosis.

Original publication

DOI

10.1097/01.tp.0000265446.61754.d2

Type

Journal article

Journal

Transplantation

Publication Date

15/06/2007

Volume

83

Pages

1459 - 1465

Keywords

Adoptive Transfer, Animals, Antibodies, Antigens, CD, Antigens, Differentiation, Aorta, Arteriosclerosis, Blood Transfusion, CD4 Antigens, CTLA-4 Antigen, Endothelium, Vascular, Immunocompetence, Interleukin-2 Receptor alpha Subunit, Isoantigens, Mice, Mice, Inbred C57BL, Mice, Inbred CBA, Mice, Knockout, T-Lymphocytes, Regulatory, Tissue Donors, Tissue Transplantation, Transplantation, Homologous