Methods of modulating antigen-specific T cell activity

Abstract

The present invention is directed to artificial antigen presenting cells and methods of making artificial antigen presenting cells. Such artificial antigen presenting cells may be used in certain methods of isolating and expanding T cell populations as well as modulating T cell responses. Additionally, the present invention provides novel methods for the identification and isolation of antigen-specific T cells. The methods provide for the construction of liposomes containing MHC:peptide complexes, accessory molecules, co-stimulatory molecules, adhesion molecules, and other molecules irrelevant to T cell binding or modulation that are used in the binding of artificial antigen presenting cells to solid support systems that may be used in the retrieval and identification of antigen-specific T cells. Additionally, the present invention is directed to devices and methods for treating conditions which would benefit from modulation of T cell response, for example, autoimmune disorders, allergies, cancers, viral infections, and graft rejection.

1 - 11 . (canceled)  
     
     
         12 . A method of modulating antigen-specific T cells, comprising: 
 a) contacting a population of T cells with artificial antigen presenting cells that comprise: 
 i. a liposome comprising a lipid bilayer comprised of neutral phospholipids and cholesterol;  
 ii. at least one GM-1 ganglioside molecule disposed in the lipid bilayer;  
 iii. a cholera toxin β subunit bound to a GM-1 ganglioside molecule;  
 iv. an MHC component loaded with an antigen of interest, wherein the antigen-loaded MHC component is bound to the cholera toxin β subunit;  
 v. an accessory molecule that can stabilize an interaction between a T cell receptor and the antigen-loaded MHC component; and  
 vi. an immunomodulatory molecule; and  
   b) incubating said T cells with said artificial antigen presenting cells so as modulate an activity of T cells specific for the antigen of interest:    
     
     
         13 . A method according to  claim 12  wherein the population of antigen-specific T cells are enriched for reactivity with the antigen of interest.  
     
     
         14 . A method according to  claim 13  wherein the enrichment occurs by isolating T cells specific for the antigen of interest from a biological sample containing T cells.  
     
     
         15 . A method according to  claim 13  wherein the biological sample is selected from the group consisting of whole blood, blood cells, blood plasma, and tissue.  
     
     
         16 . A method according to  claim 14  wherein the isolation of T cells specific for the antigen of interest comprises: 
 a) contacting a biological sample containing T cells suspected of being specific for the antigen of interest with an artificial antigen presenting cell that presents the antigen of interest so as to form complexes comprised of T cells specific for the antigen of interest and artificial antigen presenting cells that present the antigen of interest, wherein the artificial antigen presenting cells comprise: 
 i. a liposome comprising a lipid bilayer, wherein the lipid bilayer is comprised of neutral phospholipids and cholesterol;  
 ii. at least one GM-1 ganglioside molecule disposed in the lipid bilayer;  
 iii. a cholera toxin β subunit bound to a GM-1 ganglioside molecule;  
 iv. an MHC component loaded with the antigen of interest, wherein the antigen-loaded MHC component is bound to the cholera toxin β subunit; and  
 v. an accessory molecule that can stabilize an interaction between a T cell receptor and the antigen-loaded MHC component; and  
   b) isolating T cells specific for the antigen of interest from the complexes, if any.    
     
     
         17 . A method according to  claim 12  wherein the T cells are CD4 T cells.  
     
     
         18 . A method according to  claim 12  wherein the CD4 T cells are selected from the group consisting of Th0 cells; Th1 cells, Th2 cells, and Th3 cells.  
     
     
         19 . A method according to  claim 18  wherein the modulation comprises shifting the relative populations of CD4 T cells such that a greater percentage of the CD4 T cells are Th0 cells after modulation than before modulation.  
     
     
         20 . A method according to  claim 18  wherein the modulation comprises shifting the relative populations of CD4 T cells such that a greater percentage of the CD4 T cells are Th1 cells after modulation than before modulation.  
     
     
         21 . A method according to  claim 17  wherein the modulation comprises shifting the relative populations of CD4 T cells such that a greater percentage of the CD4 T cells are Th2 cells after modulation than before modulation.  
     
     
         22 . A method according to  claim 17  wherein the modulation comprises shifting the relative populations of CD4 T cells such that a greater percentage of the CD4 T cells are Th3 cells after modulation than before modulation.  
     
     
         23 . A method according to  claim 12  wherein the modulation results in altering the phenotype of the antigen-specific T cells.  
     
     
         24 . A method according to  claim 12  wherein the modulation results in inducing apoptosis of the antigen-specific T cells.  
     
     
         25 . A method according to  claim 12  wherein the modulation results in inducing anergy in the antigen-specific T cells.  
     
     
         26 . A method according to  claim 12  wherein the modulation results in proliferation of the antigen-specific T cells.  
     
     
         27 . A method according to  claim 12  wherein the immunomodulatory molecule is selected from the group consisting of a cytokine, a cytokine receptor, a chemokine, and a chemokine receptor.  
     
     
         28 . A method according to  claim 12  wherein the immunomodulatory molecule is selected from the group consisting of a B7-1 molecule, a B7-2 molecule, and an OX40 molecule.  
     
     
         29 . A method according to  claim 12  wherein the modulated antigen-specific T cells are useful for treating a T cell-mediated disease.  
     
     
         30 . A method according to  claim 30  wherein the T cell-mediated disease is selected from the group consisting of graft versus host disease, an autoimmune disease, an allergy, a cancer, and viral infection.