Blocking platelet/endothelial cell adhesion molecule 1 (PECAM) inhibits disease progression and prevents joint erosion in established collagen antibody-induced arthritis.

Collagen antibody-induced arthritis is a robust murine model of arthritis that histologically recapitulates the inflammatory characteristics of rheumatoid arthritis including pannus formation and destruction of articular cartilage and bone. PECAM is a molecule expressed by both leukocytes and endothelial cells that has been shown to play a major role in the extravasation of leukocytes into sites of inflammation. Genetic deletion of many molecules will blunt the onset and progression of arthritis in murine models, as will administration of various anti-inflammatory therapies given prior to the onset of disease. However, patients seek medical attention when symptomatic, which means that the disease is well established. We investigated whether blocking PECAM interactions would inhibit progression of established disease in the collagen antibody-induced arthritis model. We report that treatment of symptomatic mice with a PECAM-Fc chimera significantly reduced inflammation and virtually eliminated cartilage and bone destruction. The results suggest that therapies that block PECAM function may be beneficial in the treatment of established arthritis.

CD99 is essential for leukocyte diapedesis in vivo.

Recruitment of leukocytes into inflamed tissue requires migration of leukocytes from the blood stream across the endothelial lining and the basement membrane of the local blood vessels. CD99 in humans is a 32-kDa highly O-glycosylated cell surface protein expressed on most leukocytes. The authors recently found CD99 to be expressed in leukocytes and at human endothelial cell contacts. Human CD99 is involved in homophilic interaction between the two cell types and participates in the transendothelial migration of monocytes and polymorphonuclear neutrophils (PMNs) in vitro. To test the role of CD99 in vivo, the authors cloned murine CD99 (muCD99), expressed it in vitro, and generated a blocking monoclonal antibody against it. We first showed that muCD99 is expressed on mouse leukocytes as well as enriched at the endothelial cell borders. Transfection of cells with muCD99 imparts on them the ability to aggregate in a CD99-dependent homophilic manner. Cells expressing muCD99 did not bind to cells expressing murine or human platelet endothelial call adhesion molecule (PECAM) or human CD99. In the thioglycollate peritonitis model of inflammation, anti-CD99 monoclonal antibody blocked the recruitment of neutrophils and monocytes by over 40% and 80%, respectively, at 18 h. Microscopy showed that this blocking occurred at the luminal surface of venules. The authors conclude that CD99 plays a major role in the emigration of leukocytes in vivo.