Regulatory t cells suppress autoimmunity

Abstract

The invention provides methods for producing an autoantigen-specific regulatory T cell enriched composition, and resultant compositions and methods for use.

1 . A method of modulating an autoimmune response in a subject, said method comprising:
 obtaining a population of subject-compatible cells;   producing a predetermined autoantigen-specific regulatory T cell enriched composition from said population of cells; and   introducing said composition into said subject to modulate said autoimmune response in said subject.   
     
     
         2 . The method according to  claim 1 , wherein said population of cells is obtained from said subject. 
     
     
         3 . The method according to  claim 1 , wherein said population of cells is obtained from a donor distinct from said subject. 
     
     
         4 . The method according to  claim 1 , wherein said population of cells is harvested from peripheral blood. 
     
     
         5 . The method according to  claim 1 , wherein said producing step comprises expanding said antigen-specific regulatory T cells. 
     
     
         6 . The method according to  claim 5 , wherein said expanding is achieved by contacting said population of cells with an autoantigen-specific regulatory T cell stimulatory composition. 
     
     
         7 . The method according to  claim 5 , wherein regulatory T cells are enriched from said population of cells prior to said expanding step. 
     
     
         8 . The method according to  claim 5 , wherein regulatory T cells are enriched from said population after said expanding step. 
     
     
         9 . The method according to  claim 6 , wherein said stimulatory composition comprises an MHC class II/autoantigenic peptide complex. 
     
     
         10 . The method according to  claim 6 , wherein said stimulatory composition comprises a costimulatory agent. 
     
     
         11 . The method according to  claim 10 , wherein said costimulatory agent is an agonist antibody. 
     
     
         12 . The method according to  claim 11 , wherein said agonist antibody binds to CD28. 
     
     
         13 . The method according to  claim 6 , wherein said stimulatory composition comprises a second regulatory T cell stimulatory agent. 
     
     
         14 . A composition comprising:
 a population of natural cells wherein at least 50% of said cells of said composition are autoantigen-specific regulatory T cells.   
     
     
         15 . The composition according to  claim 14 , wherein said autoantigen-specific regulatory T cells are specific for autoantigenic peptides presented in MHC class II molecules of Table A. 
     
     
         16 . The composition according to  claim 14 , wherein said autoantigen-specific regulatory T cells are effective at modulating an autoimmune response when administered to a subject. 
     
     
         17 . A method of adoptive cellular immunotherapy, the method comprising the steps of:
 extracting a mixed population of T cells from a patient diagnosed with diabetes mellitus and presenting an indication of impaired glucose homoeostasis selected from fasting plasma glucose (FPG), post-prandial glucose (PPG), and glucose tolerance (GTT);   isolating from the population a subpopulation comprising >98% CD4 + CD25 +  T cells (Treg cells) by negative and positive immuno-selection and cell sorting;   expanding the Treg cells of the subpopulation at least 100-fold by contacting the subpopulation with effective amounts of (i) a TCR/CD3 activator selected from a multivalent antibody and ligand for TCR/CD3; (ii) a TCR costimulator activator selected from a multivalent antibody and ligand for CD28; and (iii) IL-2, wherein the effective amount of IL-2 is 200 to 2500 IU IL-2/ml, to obtain ex vivo expanded Treg cells;   introducing into the patient 10 7  to 10 11  of the ex vivo expanded Treg cells; and   detecting a resultant improvement in the impaired glucose homoeostasis.   
     
     
         18 . The method of  claim 17 , wherein the improvement is selected from an FPG of 110 mg/dL or less, a 2-hour PPG of 140 mg/dL or less, and a GTT of 140 mg/dL or less 2 hours after a 75-g glucose load. 
     
     
         19 . The method of  claim 17 , wherein the TCR/CD3 activator is an anti-CD3 antibody, and the TCR costimulator activator is an anti-CD28 antibody, wherein the anti-CD3 and anti-CD28 antibodies are immobilized on paramagnetic beads provided in a Treg cell:bead ratio of between 1:1 and 1:2. 
     
     
         20 . The method of  claim 17 , wherein the TCR/CD3 activator is an MHC-peptide multimer, wherein the peptide is a diabetes-associated autoantigen peptide and the diabetes-associated autoantigen is selected from glutamic acid decarboxylase (GAD), an islet cell autoantigen (ICA) and insulin, the TCR costimulator activator is an anti-CD28 antibody, and introducing step introduces into the patient 10 7  to 10 9  of the ex vivo expanded Treg cells.