Modulation of Gamma-Delta T Cells to Regulate Airway Hyperresponsiveness

Abstract

Disclosed is a method for regulation of airway hyperresponsiveness by modulating the action of γδ T cells in a patient. Also disclosed are methods for identifying compounds that regulate airway hyperresponsiveness by modulating γδ T cell action.

1 . A method to reduce airway hyperresponsiveness in a mammal, comprising increasing γδ T cell action in a mammal that has, or is at risk of developing, a respiratory condition associated with airway hyperresponsiveness. 
     
     
         2 . The method of  claim 1 , wherein said step of increasing γδ T cell action comprises increasing the number of γδ T cells in the lung tissue of said mammal. 
     
     
         3 . The method of  claim 2 , wherein said step of increasing comprises removing γδ T cells from said mammal, inducing said γδ T cells to proliferate ex vivo to increase the number of said γδ T cells, and returning said γδ T cells to the lung tissue of said mammal. 
     
     
         4 . The method of  claim 1 , wherein said step of increasing γδ T cell action comprises activating y5 T cells in said mammal. 
     
     
         5 . The method of  claim 4 , wherein said step of activating γδ T cells is performed ex vivo. 
     
     
         6 . The method of  claim 1 , wherein said step of increasing γδ T cell action comprises administering an agent to said mammal that activates γδ T cells in said mammal. 
     
     
         7 .- 14 . (canceled) 
     
     
         15 . The method of  claim 6 , wherein said agent is an antibody that specifically binds to γδ T cell receptor and activates said γδ T cells. 
     
     
         16 . The method of  claim 6 , wherein said agent is an antibody that specifically binds to a γδ T cell receptor (TCR) selected from the group consisting of a murine TCR comprising Vγ4 and a human TCR comprising Vγ1. 
     
     
         17 . The method of  claim 6 , wherein said agent is targeted to γδ T cells in said mammal. 
     
     
         18 . The method of  claim 17 , wherein said agent is targeted to γδ T cells in the lung tissue of said mammal. 
     
     
         19 . The method of  claim 17 , wherein said agent is targeted to γδ T cells having a T cell receptor (TCR) selected from the group consisting of a murine TCR comprising Vγ4 and a human TCR comprising Vγ1. 
     
     
         20 . The method of  claim 17 , wherein said agent comprises: (a) an antibody that specifically binds to a molecule on the cell surface of γδ T cells; and (b) a compound that activates said γδ T cells, wherein said compound is linked to said antibody of (a). 
     
     
         21 . The method of  claim 18 , wherein said compound that activates said γδ T cells is selected from the group consisting of: a protein comprising a peptide having a BiP-binding motif, a glycosylated protein or peptide, polyGT, polyGAT (1:1:1), synthetic GC, synthetic AT, a mycobacterial product, a  Listeria  cell wall product, cardiolipin, TNF-a, and an antibody that specifically binds to a γδ T cell receptor and activates said receptor. 
     
     
         22 . The method of  claim 6 , wherein said agent is administered to the lung tissue of said mammal. 
     
     
         23 . The method of  claim 22 , wherein said agent is administered by a route selected from the group consisting of inhaled, intratracheal and nasal routes. 
     
     
         24 . The method of  claim 6 , wherein said agent is administered to said animal in an amount effective to reduce airway hyperresponsiveness in said animal as compared to prior to administration of said agent. 
     
     
         25 . The method of  claim 6 , wherein said agent is administered with a pharmaceutically acceptable excipient 
     
     
         26 .- 28 . (canceled) 
     
     
         29 . The method of  claim 1 , wherein said step of increasing γδ T cell action decreases airway methacholine responsiveness in said mammal. 
     
     
         30 . The method of  claim 1 , wherein said step of increasing γδ T cell action reduces airway hyperresponsiveness of said mammal such that the FEV 1  value of said mammal is improved by at least about 5%. 
     
     
         31 .- 32 . (canceled) 
     
     
         33 . The method of  claim 1 , wherein said airway hyperresponsiveness is associated with a disease selected from the group consisting of chronic obstructive disease of the airways and asthma. 
     
     
         34 .- 35 . (canceled)