Methods for eliminating at least a substantial portion of a clonal antigen-specific memory t cell subpopulation

Abstract

The present invention relates generally to methods for stimulating T cells, and more particularly, to methods to eliminate undesired (e.g., autoreactive, alloreactive, pathogenic) subpopulations of T cells from a mixed population of T cells, thereby restoring the normal immune repertoire of said T cells. The present invention also relates to compositions of cells, including stimulated T cells having restored immune repertoire and uses thereof.

1 . A method for eliminating at least a substantial portion of a clonal T cell subpopulation from a mixed population of T cells from an individual, comprising,
 exposing a population of cells, wherein at least a portion thereof comprises T cells, to one or more pro-apoptotic or growth inhibiting compositions wherein said exposure induces apoptosis or growth inhibition in at least a substantial portion of at least one clonal T cell population present in the mixed population of T cells;   thereby eliminating at least a substantial portion of said clonal T cell population from the mixed population of T cells.   
     
     
         2 . The method of  claim 1  further comprising expanding the remaining mixed population of T cells. 
     
     
         3 . The method of  claim 2  wherein the remaining mixed population of cells is expanded by exposing the remaining mixed population of cells to a surface wherein the surface has attached thereto one or more agents that ligate a cell surface moiety of at least a portion of the remaining T cells and stimulates said remaining T cells. 
     
     
         4 . The method of  claim 3 , wherein said surface has attached thereto a first agent that ligates a first T cell surface moiety of a T cell, and the same or a second surface has attached thereto a second agent that ligates a second moiety of said T cell, wherein said ligation by the first and second agent induces proliferation of said T cell. 
     
     
         5 . A population of T cells generated according to the method of  claim 1 . 
     
     
         6 . The method of  claim 1  wherein the pro-apoptotic or growth inhibiting composition comprises an autoantigen. 
     
     
         7 .- 13 . (canceled) 
     
     
         14 . A method for treating autoimmune disease in a patient comprising administering to the patient the population of T cells of  claim 5 . 
     
     
         15 .- 24 . (canceled) 
     
     
         25 . A method for eliminating at least a substantial portion of a clonal T cell subpopulation from a mixed population of T cells from an individual, comprising,
 (a) exposing a population of cells wherein at least a portion thereof comprises T cells to one or more compositions that sensitize at least a portion of the T cells to further activation or stimulation,   (b) exposing the population of cells to a surface wherein the surface has attached thereto one or more agents that ligate a cell surface moiety of at least a portion of the sensitized T cells and stimulates said sensitized T cells, wherein the exposure of said sensitized T cells to said surface is for a time sufficient to induce apoptosis of said sensitized T cells;   thereby eliminating said sensitized T cells from the population.   
     
     
         26 . The method of  claim 25  wherein step (b) further comprises exposing said population of cells to said surface for a time sufficient to stimulate at least a portion of the remaining T cells and wherein said at least a portion of the remaining cells proliferates. 
     
     
         27 . The method of  claim 25 , wherein said surface has attached thereto a first agent that ligates a first T cell surface moiety of a T cell; and the same or a second surface has attached thereto a second agent that ligates a second moiety of said T cell, wherein said ligation by the first and second agent induces proliferation of said T cell. 
     
     
         28 . The method of  claim 26  wherein the exposure of said cells to said surface is for a time sufficient to increase polyclonality. 
     
     
         29 .- 54 . (canceled) 
     
     
         55 . A method for generating a substantially pure population of CD3+/CD28+ T cells from a population of T cells from an individual, comprising:
 exposing a population of cells, wherein at least a portion thereof comprises T cells, ex vivo to a composition that stimulates and/or selects surface CD3 and CD28 molecules;   thereby generating a substantially pure population of CD3+/CD28+ T cells.   
     
     
         56 .- 57 . (canceled) 
     
     
         58 . The method of  claim 55  further comprising expanding said CD3+CD28+ T cells for a time sufficient such that the percentage of contaminating CD3+/CD28− T cells is less than about 5%. 
     
     
         59 . The method of  claim 55  further comprising expanding said CD3+CD28+ T cells for a time sufficient such that the percentage of contaminating CD3+/CD28− T cells is less than about 1%. 
     
     
         60 . The method of  claim 55  any one of  claims 55   57  further comprising expanding said CD3+CD28+ T cells for a time sufficient such that the percentage of contaminating CD3+/CD28− T cells is less than 0.1%. 
     
     
         61 . The method of  claim 55  wherein the CD3 molecule is stimulated using an anti-CD3 antibody and the CD28 molecule is stimulated using an anti-CD28 antibody. 
     
     
         62 .- 73 . (canceled)