Ensminger S M, Spriewald B M, Witzke O, Morrison K, van Maurik A, Morris P J, Rose M L, Wood K J
Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Headington, United Kingdom.
Transplantation. 2000 Sep 27;70(6):955-63. doi: 10.1097/00007890-200009270-00013.
It has recently been shown that, although anti-CD154 induces CD4+ T-cell tolerance, it is unable to prevent allograft rejection mediated by CD8+ T cells. We have also shown that anti-CD154 monotherapy does not protect the graft from the development of transplant arteriosclerosis even in the absence of CD8+ T cells. This study was designed to investigate and characterize possible mechanisms responsible for the development of transplant arteriosclerosis after CD154 blockade in the absence of CD8+ T cells.
C57BL/6 (H2b) recipients received a fully MHC-mismatched BALB/c donor aorta (H2d). Animals were either treated with anti-CD154 monoclonal antibody (mAb) in the presence or absence of CD8 T cells. Histology, morphometric measurements, immunohistochemistry, and the production of alloantibodies (IgM, IgG1, IgG2a) were analyzed on days 14, 30, and 50 after transplantation. Cytokine production within the graft was investigated by competitive reverse transcription-polymerase chain reaction on day 14.
Combined treatment with anti-CD154 and a depleting CD8 mAb resulted in a delay in the development of transplant arteriosclerosis (intimal proliferation: 33+/-10% vs. 67+/-11% untreated control, day 30) but ultimately did not prevent its progression (intimal proliferation: 55+/-10% vs. 78+/-9% untreated control, day 50). Although there was a significant decrease in the number of CD4+, CD11b+, and CD40+ graft-infiltrating cells and a reduction in the formation of donor-specific IgG1 alloantibodies in recipients treated with anti-CD154 and anti-CD8 mAbs, mRNA for interleukin (IL)-4 was increased, suggesting a shift in the intragraft cytokine profile towards a Th2-like pattern.
Our data provide evidence that short-term CD154 blockade is insufficient to prevent transplant arteriosclerosis, even in combination with CD8+ T-cell depletion. Moreover, the increased expression of the Th2 cytokine interleukin-4 within the graft may be responsible for the development of transplant arteriosclerosis in the long term.
最近的研究表明，尽管抗CD154可诱导CD4 + T细胞耐受，但它无法预防由CD8 + T细胞介导的同种异体移植排斥反应。我们还表明，即使在没有CD8 + T细胞的情况下，抗CD154单一疗法也不能保护移植物免于移植性动脉硬化的发展。本研究旨在调查和表征在没有CD8 + T细胞的情况下，CD154阻断后移植性动脉硬化发展的可能机制。
C57BL / 6（H2b）受体接受完全MHC不匹配的BALB / c供体主动脉（H2d）。动物在有或没有CD8 T细胞的情况下用抗CD154单克隆抗体（mAb）治疗。在移植后第14、30和50天分析组织学、形态测量、免疫组织化学和同种异体抗体（IgM、IgG1、IgG2a）的产生。在第14天通过竞争性逆转录-聚合酶链反应研究移植物内的细胞因子产生。
抗CD154与消耗性CD8 mAb联合治疗导致移植性动脉硬化发展延迟（内膜增生：33±10％对未治疗对照的67±11％，第30天），但最终未能阻止其进展（内膜增生：55±10％对未治疗对照的78±9％，第50天）。尽管在用抗CD154和抗CD8 mAb治疗的受体中，CD4 +、CD11b +和CD40 +移植物浸润细胞的数量显著减少，并且供体特异性IgG1同种异体抗体的形成减少，但白细胞介素（IL）-4的mRNA增加，表明移植物内细胞因子谱向Th2样模式转变。
我们的数据提供了证据，即短期CD154阻断不足以预防移植性动脉硬化，即使与CD8 + T细胞耗竭联合使用也是如此。此外，移植物内Th2细胞因子白细胞介素-4表达的增加可能是长期移植性动脉硬化发展的原因。
