Warnecke Gregor, Bushell Andrew, Nadig Satish N, Wood Kathryn J
Transplantation Research Immunology Group, Nuffield Department of Surgery, John Radcliffe Hospital, University of Oxford, Oxford, UK.
Transplantation. 2007 Jun 15;83(11):1459-65. doi: 10.1097/01.tp.0000265446.61754.d2.
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.
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.
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).
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.
在各种实验环境中，CD25⁺CD4⁺调节性T细胞已被证明可抑制同种异体免疫。在此，我们假设同种异体抗原反应性调节性T细胞会降低移植性动脉硬化的严重程度。
将用C57BL/6（B.6）血液（供体特异性输血，DST）和非清除性抗CD4抗体（YTS 177）预处理的CBA小鼠的CD25⁺CD4⁺T细胞与未活化的CBA CD25⁻CD4⁺“效应”T细胞共转移到CBA-rag⁻/⁻小鼠体内。这些动物接受来自B.6 CD31⁻/⁻供体的主动脉移植。B.6主动脉移植物的CBA野生型受体直接用177/DST进行预处理。一些动物在第-1天接受来自预处理小鼠的6×10⁵个CD25⁺CD4⁺T细胞以增强调节作用。在第30天收获移植物。
仅转移效应T细胞后，由新生内膜形成导致的移植物管腔闭塞为29.3±19.4%（n = 5）。CD25⁺CD4⁺调节性T细胞的共转移显著降低了闭塞率（2.4±3.3%，n = 3；P = 0.009）。在存在CTLA4阻断抗体的情况下，这种效应部分被消除（11.1±4.7%，n = 4；P = 0.008）。用177/DST预处理B.6主动脉同种异体移植物的有免疫活性的CBA受体并不能显著降低移植性动脉硬化（43.0±15.7%，n = 5 vs. 56.6±16.8%，n = 5；177/DST vs. 对照组；P = 0.22）。然而，当预处理的初级CBA受体在移植前额外接受从其他用177/DST预处理的小鼠获得的6×10⁵个CD25⁺CD4⁺T细胞的转移时，移植物的管腔闭塞明显降低（33.0±7.6%，n = 5；P = 0.002）。
体内针对同种异体抗原产生的调节性T细胞可预防CD25⁻CD4⁺T细胞介导的移植性动脉硬化。在有免疫活性的受体中，这些细胞有潜力用作控制移植性动脉硬化的细胞免疫疗法。
