Modulation of systemic memory T cell trafficking

Abstract

Methods are provided to specifically modulate the trafficking of systemic memory T cells, particularly CD4+ T cells, without affecting naive T cells or intestinal memory T cells. It is shown that systemic memory T cells, which are characterized as CD45Ra − , and integrin α4β7 − , express high levels of CCR4. Ligands of CCR4, such as TARC or MDC, act as an adhesion trigger, wherein upon CCR4 binding, these cells undergo integrin-dependent arrest to the appropriate vascular receptor(s). This arrest acts to localize the cells at the target site. The methods of the invention manipulate this triggering, and CCR4 mediated chemotaxis, to affect the localization of T cells in targeted tissues. In one embodiment of the invention, the active agent is a CCR4 agonist, that acts to enhance T cell localization. In an alternative embodiment, the agent is an antagonist that blocks CCR4 biological activity. An advantage of the invention is the selectivity for systemic memory T cells, without affecting native T cells or intestinal memory T cells.

1 . A method of screening comprising: 
 assessing an effect of an agent on a cell expressing CCR4 in the presence of TARC or MDC.    
     
     
         2 . The method of  claim 1 , wherein the cell expressing CCR4 is a T cell.  
     
     
         3 . The method of  claim 1 , wherein the effect is binding of TARC or MDC to the cell.  
     
     
         4 . The method of  claim 1 , wherein the effect is adhesion of the cell.  
     
     
         5 . A method of modulating the trafficking of CCR4 +  leukocytes, comprising: 
 modulating the interaction between CCR4 and MDC or TARC.    
     
     
         6 . The method of  claim 5 , wherein the leukocyte is a lymphocyte.  
     
     
         7 . The method of  claim 6 , wherein the lymphocyte is a T cell.  
     
     
         8 . The method of  claim 7 , wherein the T cell is CD4 + .  
     
     
         9 . The method of  claim 7 , wherein the T cell is CD8 + .  
     
     
         10 . The method of  claim 5 , wherein the modulated interaction affects adhesion of the CCR4 +  leukocytes.  
     
     
         11 . The method of  claim 5 , wherein the modulated interaction affects chemotaxis of the CCR4 30   leukocytes.  
     
     
         12 . The method of  claim 5 , wherein the interaction is modulated by CCR4 agonist activity.  
     
     
         13 . The method of  claim 5 , wherein the interaction is modulated by CCR4 antagonist activity.  
     
     
         14 . A method of treating inflammatory disease, comprising: 
 interfering with the interaction between CCR4 and TARC or MDC.    
     
     
         15 . The method of  claim 14 , wherein the inflammatory disease is an inflammatory skin disease.  
     
     
         16 . The method of  claim 14 , wherein the method comprises administering to a patient an effective amount of a CCR4 antagonist.  
     
     
         17 . The method of  claim 16 , wherein the CCR4 antagonist is an antibody.  
     
     
         18 . The method of  claim 17 , wherein the antibody binds to CCR4.  
     
     
         19 . The method of  claim 16 , wherein the administration provides for a prolonged localized concentration of the CCR4 antagonist.  
     
     
         20 . The method of  claim 19 , wherein the localized concentration of the CCR4 antagonist is vascular.