Allograft Inflammatory Factor in Transplant Vasculopathy

移植物动脉硬化是移植后第一年移植器官衰竭的主要原因。 尽管其详细的发病机制尚不清楚，但临床和实验室研究表明，移植动脉硬化源于局部免疫介导的过程，该过程涉及受体单核细胞（巨噬细胞和B和T淋巴细胞起关键作用）与供体器官血管系统细胞之间的相互作用。同种异体移植炎性因子（allograftinflammatoryfactor，aif-1）是一种17 kD的蛋白质，具有EF手型Ca ~（++）结合基序，在大多数正常组织中几乎检测不到。 然而，其表达的巨噬细胞系的细胞显着增加，在同种异体和自身免疫反应，包括血管周围炎症移植心脏，实验性自身免疫性神经炎，和炎症胰腺的糖尿病前期BB大鼠。 关于aif-1在巨噬细胞活化中的功能或其在移植动脉硬化或其他炎症性疾病的发病机制中的特殊作用知之甚少。该提案有三个主要目标：描述aif-1表达的离散疾病相关模式的分子基础，确定aif-1在巨噬细胞生物学中的作用，并评估其在移植动脉硬化发病机制中的重要性。 分子遗传学技术，如腺病毒转导和胚胎干细胞的基因靶向，将被用来产生具有实质上不同的aif-1表达水平的巨噬细胞。 将在体外和体内测试这些细胞的功能。aif-1在移植动脉硬化中的重要性将在缺乏aif-1的小鼠的同种异体移植研究中进行评估。这项工作可能会改善器官移植的长期结果。 控制aif-1表达的遗传元件可能有助于将免疫调节基因产物表达到移植器官的炎症部位。aif-1的功能意义可能在于巨噬细胞，或者它们对其他炎症细胞的调节; aif-1表达如何影响免疫反应可能指向参与移植动脉硬化发展的新的调节途径。

Transplant arteriosclerosis is the major cause of graft organ failure after the first year of transplantation. Although its detailed pathogenesis remains unclear, clinical and laboratory studies indicate that transplant arteriosclerosis stems from a local, immune-mediated process involving interactions between the recipient's mononuclear cells, with critical roles for macrophages and B and T lymphocytes, and cells of the donor organ's vascular system. Allograft inflammatory factor (aif-1), a 17 kD protein bearing an EF hand Ca++-binding motif, is barely detectable in most normal tissues. However, its expression by cells of macrophage lineage increases markedly in both allo- and autoimmune reactions, including perivascular inflammation in transplanted hearts, experimental autoimmune neuritis, and the inflamed pancreas of prediabetic BB rats. Very little is known about the function of aif-1 in macrophage activation or its specific role in the pathogenesis of transplant arteriosclerosis or other inflammatory conditions. This proposal has three major goals: to delineate the molecular basis for the discrete disease-associated pattern of expression of aif-1, to define the role of aif-1 in macrophage biology, and to assess its importance in the pathogenesis of transplant arteriosclerosis. Molecular genetic techniques such as adenoviral transduction and gene targeting of embryonic stem cells will be used to produce macrophages with substantially different levels of aif-1 expression. Function of these cells will be tested both in vitro and in vivo. The importance of aif-1 in transplant arteriosclerosis will be assessed in allograft transplantation studies with mice lacking aif-1. This work may lead to improved longterm outcomes for organ transplantation. The genetic elements controlling aif-1 expression may be useful to direct expression of immunoregulatory gene products to sites of inflammation in transplanted organs. The functional significance of aif-1 likely resides in macrophages, or in their regulation of other inflammatory cells; how aif-1 expression affects the immune response may point to new regulatory pathways involved in the development of transplant arteriosclerosis.