Blocking leukocyte emigration and inflammation by interfering with cd99/hec2

Abstract

The present invention provides methods and compositions for modulating transendothelial migration (TEM) of leukocytes. In particular, inhibition of TEM can provide a potent therapeutic approach to treating inflammatory conditions. The invention specifically relates to the discovery that CD99 mediates TEM, because blocking CD99 on either endothelial cells or monocytes bloks migration 80-90%. In conjunction with PECAM inhibitors, TEM blockade approaches 100%. CD99 is involved in a step in TEM that is distal to the step controlled by PECAM.

1 - 33 . (canceled)  
   
   
       34 . A method of inhibiting transendothelial migration (TEM) of leukocytes in a subject, comprising administering to the subject a CD99 binding inhibitor, wherein the CD99 binding inhibitor comprises a soluble CD99 molecule, and wherein CD99-mediated leukocyte transmigration through the endothelium is inhibited.  
   
   
       35 . The method according to  claim 34 , wherein the CD99 is located on endothelial cells.  
   
   
       36 . The method according to  claim 34 , wherein the CD99 is located on the leukocytes.  
   
   
       37 . The method according to  claim 34  wherein the TEM occurs between activated endothelial cells.  
   
   
       38 . The method according to  claim 37 , wherein the activated endothelial cells are activated as a result of contact with a pro-inflammatory cytokine selected from the group consisting of tumor necrosis factor (TNF) and interleukin-1 (IL-1).  
   
   
       39 . The method according to  claim 34 , wherein the TEM occurs across endothelial cells in a tissue selected from the group consisting of arterial endothelium, venous endothelium, venular endothelium, and post-capillary venular endothelium.  
   
   
       40 . The method according to  claim 34 , wherein TEM occurs into a site of inflammation.  
   
   
       41 . The method according to  claim 34 , wherein inhibiting CD99-mediated transmigration of leukocytes comprises contacting the leukocytes, the endothelium, or both with a soluble CD99 molecule.  
   
   
       42 . A method of treating an inflammatory condition in a subject, wherein the inflammatory condition is mediated by transendothelial migration (TEM) of leukocytes, the method comprising administering to the subject in need thereof a CD99 binding inhibitor, wherein the CD99 binding inhibitor comprises a soluble CD99 molecule, and wherein CD99-mediated leukocyte TEM is inhibited.  
   
   
       43 . The method according to  claim 42 , wherein the TEM occurs across endothelial cells in a tissue selected from the group consisting of arterial endothelium, venous endothelium, capillary endothelium, venular endothelium, and post-capillary venular endothelium.  
   
   
       44 . The method according to  claim 42 , wherein the inflammatory condition is an acute inflammatory condition.  
   
   
       45 . The method according to  claim 42 , wherein the inflammatory condition results from an infection.  
   
   
       46 . The method according to  claim 42 , wherein the inflammatory condition is a chronic inflammatory condition.  
   
   
       47 . The method according to  claim 42 , wherein inhibiting CD99-mediated TEM comprises contacting the leukocytes, the endothelium, or both with a soluble CD99 molecule.