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 - 73 . (canceled) 
     
     
         74 . 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 the 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 the clonal T cell population from the mixed population of T cells.   
     
     
         75 . The method of  claim 74 , further comprising expanding the remaining mixed population of T cells. 
     
     
         76 . The method of  claim 75 , 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 the remaining T cells. 
     
     
         77 . A population of T cells generated according to the method of  claim 74 . 
     
     
         78 . The method of  claim 74 , wherein the pro-apoptotic composition comprises allogeneic or xenogeneic cells. 
     
     
         79 . A method for treating autoimmune disease in a patient comprising administering to the patient the population of T cells of  claim 77 . 
     
     
         80 . The method of  claim 76 , wherein one agent is an antibody or a fragment thereof, and another agent is an antibody or a fragment thereof. 
     
     
         81 . The method of  claim 76 , wherein one agent is an anti-CD3 antibody and another agent is an anti-CD28 antibody. 
     
     
         82 . 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, and   (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 the sensitized T cells, wherein the exposure of the sensitized T cells to the surface is for a time sufficient to induce apoptosis of the sensitized T cells;   thereby eliminating the sensitized T cells from the population.   
     
     
         83 . The method of  claim 82 , wherein step (b) further comprises exposing the population of cells to the surface for a time sufficient to stimulate at least a portion of the remaining T cells and wherein the at least a portion of the remaining cells proliferates. 
     
     
         84 . The method of  claim 82 , wherein the 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 the T cell, wherein the ligation by the first and second agent induces proliferation of the T cell. 
     
     
         85 . A population of T cells generated according to the method of  claim 82 . 
     
     
         86 . The method of  claim 82 , wherein the exposure of the cells to the surface is for a time sufficient to increase polyclonality. 
     
     
         87 . A method for generating a substantially pure population of CD3+/CD28+ T cells from a population of T cells, 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.   
     
     
         88 . A composition comprising an in vitro, mixed population of T cells comprising polyclonal T cells and antigen-specific T cells,
 wherein the polyclonal T cells are capable of expanding and the antigen-specific T cells are not capable of expanding.   
     
     
         89 . The composition of  claim 88 , further comprising a surface having attached thereto agents with binding activity to cell surface moieties on the surfaces of T cells in the mixed population,
 wherein the agents having binding affinity for CD3 protein complexes and CD28 proteins, and.   
     
     
         90 . The composition of  claim 89 , wherein the ratio of surface to cells is at least 5:1 
     
     
         91 . The composition of  claim 89 , wherein one of the agents is an anti-CD3 antibody or an anti-CD3 antibody fragment. 
     
     
         92 . The composition of  claim 89 , wherein one of the agents is an anti-CD28 antibody or an anti-CD28 antibody fragment.