Dana N, Fathallah D M, Arnaout M A
Renal Unit, Massachusetts General Hospital, Boston, MA.
Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3106-10. doi: 10.1073/pnas.88.8.3106.
Polymorphonuclear cells and monocytes (phagocytes) are a critical component of host defense against infections. However, these cells also play a significant role in host tissue damage in many noninfectious diseases, such as ischemia-reperfusion injury syndromes and rejection of transplanted organs. The leukocyte adhesion molecule family CD11/CD18 (beta 2 integrins) is critical to the function of polymorphonuclear cells and monocytes in inflammation and injury. Inherited deficiency of CD11/CD18 impairs phagocyte chemotaxis, adhesion and transmigration across endothelium, and clearance of invading microorganisms through phagocytosis and cell-mediated killing. Furthermore, murine monoclonal antibodies directed against the CD11b/CD18 (CR3) heterodimer have been shown to reduce, by 50%-80%, phagocyte-mediated ischemia-reperfusion injury in several organ systems, such as the myocardium, liver, and gastrointestinal tract and to inhibit development of insulin-dependent diabetes mellitus in nonobese diabetic (NOD) mice. Expression of CD11b/CD18 in a soluble and functional form might therefore be potentially useful as an anti-inflammatory agent. We have now expressed a recombinant soluble heterodimeric form of this human beta 2 integrin, normally expressed as two noncovalently associated membrane-bound subunits. The secreted receptor exhibited direct and specific binding to its ligand, iC3b, the major complement C3 opsonin, and inhibited binding of polymorphonuclear cells to recombinant interleukin 1-activated endothelium.
多形核细胞和单核细胞（吞噬细胞）是宿主抵御感染的关键组成部分。然而，这些细胞在许多非感染性疾病（如缺血再灌注损伤综合征和移植器官排斥反应）中的宿主组织损伤中也起着重要作用。白细胞黏附分子家族CD11/CD18（β2整合素）对于多形核细胞和单核细胞在炎症和损伤中的功能至关重要。CD11/CD18的遗传性缺陷会损害吞噬细胞的趋化性、黏附性和跨内皮迁移，以及通过吞噬作用和细胞介导的杀伤清除入侵微生物的能力。此外，针对CD11b/CD18（CR3）异二聚体的鼠单克隆抗体已被证明可使几种器官系统（如心肌、肝脏和胃肠道）中吞噬细胞介导的缺血再灌注损伤减少50%-80%，并抑制非肥胖糖尿病（NOD）小鼠胰岛素依赖型糖尿病的发展。因此，可溶性且具有功能形式的CD11b/CD18的表达可能作为一种抗炎剂具有潜在用途。我们现已表达了这种人β2整合素的重组可溶性异二聚体形式，其通常以两个非共价结合的膜结合亚基形式表达。分泌的受体表现出与其配体iC3b（主要补体C3调理素）的直接特异性结合，并抑制多形核细胞与重组白细胞介素1激活的内皮细胞的结合。
