DeFina Rachel, Christopher Kenneth, He Hongzhen, Mandelbrot Didier, Gu Yongping, Finn Patricia, Perkins David L
Laboratory of Molecular Immunology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, PBB-170, Boston, MA 02115, USA.
J Mol Med (Berl). 2003 Oct;81(10):655-63. doi: 10.1007/s00109-003-0468-1. Epub 2003 Aug 22.
Recent studies affirm costimulatory blockade as a beneficial means of preventing allograft rejection. The precise molecular effects of these pathways, however, are not entirely understood. A striking example is in the costimulatory pathways, 4-1BB/4-1BBL, CD40/CD40L, and B7/CD28. Blocking any one of these prolongs graft survival, yet each operates via distinct immunomodulatory signals. To examine the mechanistic relationships among these signals, our approach was a comprehensive investigation of their molecular constituents. Using a model of heterotopic heart transplantation in mice with a costimulatory pathway deficiency, we analyzed the expression profiles of a large panel of immune and inflammatory genes using ribonuclease protection assays coupled with algorithms. We found that while graft survival was prolonged in all groups, each pathway modulates a unique profile of expressed genes. There were 19 genes, for example, with significant changes in expression compared to the control, yet none of these were similarly modulated in all three groups. Our study reveals that despite similar delays of allograft rejection, the molecular basis for this effect is distinct in all three costimulatory pathways. Furthermore, we underscore the existence of numerous molecular mechanisms affecting graft survival. This, in turn, provides crucial implications for clinical treatment post-transplant where inhibitors would be designed to target multiple mechanisms.
近期研究证实，共刺激阻断是预防同种异体移植排斥反应的一种有效手段。然而，这些信号通路的确切分子效应尚未完全明确。一个显著的例子是共刺激信号通路，如4-1BB/4-1BBL、CD40/CD40L和B7/CD28。阻断其中任何一条通路均可延长移植物存活时间，但每条通路通过不同的免疫调节信号发挥作用。为了研究这些信号之间的机制关系，我们采用的方法是对其分子组成进行全面研究。利用共刺激信号通路缺陷的小鼠异位心脏移植模型，我们结合算法，采用核糖核酸酶保护试验分析了大量免疫和炎症基因的表达谱。我们发现，虽然所有组的移植物存活时间均延长，但每条通路调节的基因表达谱各不相同。例如，与对照组相比，有19个基因的表达发生了显著变化，但在所有三个组中，这些基因的调节方式并不相同。我们的研究表明，尽管同种异体移植排斥反应的延迟相似，但这三种共刺激信号通路产生这种效应的分子基础各不相同。此外，我们强调存在多种影响移植物存活的分子机制。这反过来又为移植后的临床治疗提供了关键启示，即设计抑制剂时应针对多种机制。
