Tolerogenic synthetic nanocarriers for generating cd8+ regulatory t cells

Abstract

Disclosed are synthetic nanocarrier methods, and related compositions, comprising administering MHC Class I-restricted and/or MHC Class II-restricted epitopes of an antigen and immunosuppressants in order to generate tolerogenic immune responses against the antigen, such as the generation of antigen-specific CD8+ regulatory T cells.

1 . A method comprising:
 (A) administering to a subject:
 (i) a first population of synthetic nanocarriers coupled to immunosuppressants, and 
 (ii) a second population of synthetic nanocarriers coupled to MHC Class I-restricted and/or MHC Class II-restricted epitopes of an antigen in an amount effective to generate antigen-specific CD8+ regulatory T cells in the subject; or 
   (B) generating antigen-specific CD8+ regulatory T cells in a subject by administering:
 (i) a first population of synthetic nanocarriers coupled to immunosuppressants, and 
 (ii) a second population of synthetic nanocarriers coupled to MHC Class I-restricted and/or MHC Class II-restricted of an antigen; or 
   (C) administering to a subject, according to a protocol that was previously shown to generate antigen-specific CD8+ regulatory T cells in one or more test subjects:
 (i) a first population of synthetic nanocarriers coupled to immunosuppressants, and 
 (ii) a second population of synthetic nanocarriers coupled to MHC Class I-restricted and/or MHC Class II-restricted epitopes of an antigen. 
   
     
     
         2 - 3 . (canceled) 
     
     
         4 . The method of  claim 1 , wherein the first population and the second population are the same population. 
     
     
         5 . (canceled) 
     
     
         6 . The method of  claim 1 , wherein the antigen is a therapeutic protein, an autoantigen or an allergen, or is associated with an inflammatory disease, an autoimmune disease, organ or tissue rejection or graft versus host disease. 
     
     
         7 . (canceled) 
     
     
         8 . The method of  claim 1 , wherein the subject has or is at risk of having an inflammatory disease, an autoimmune disease, an allergy, organ or tissue rejection or graft versus host disease. 
     
     
         9 . The method of  claim 1 , wherein the subject has undergone or will undergo transplantation. 
     
     
         10 . The method of  claim 1 , wherein the subject has or is at risk of having an undesired immune response against a therapeutic protein that is being administered or will be administered to the subject. 
     
     
         11 . The method of  claim 1 , wherein the method further comprises administering a transplantable graft or therapeutic protein to the subject. 
     
     
         12 . (canceled) 
     
     
         13 . The method of  claim 1 , wherein the administering of the synthetic nanocarriers is by intravenous, intraperitoneal, transmucosal, oral, subcutaneous, pulmonary, intranasal, intradermal or intramuscular administration. 
     
     
         14 . (canceled) 
     
     
         15 . The method of  claim 11 , wherein the administering of the transplantable graft or therapeutic protein, when the therapeutic protein is provided as one or more cells, is by parenteral, intraarterial, intranasal or intravenous administration or by injection to lymph nodes or anterior chamber of the eye or by local administration to an organ or tissue of interest. 
     
     
         16 . (canceled) 
     
     
         17 . The method of  claim 1 , wherein the immunosuppressants comprise a statin, an mTOR inhibitor, a TGF-β signaling agent, a corticosteroid, an inhibitor of mitochondrial function, a P38 inhibitor, an NF-κβ inhibitor, an adenosine receptor agonist, a prostaglandin E2 agonist, a phosphodiesterase 4 inhibitor, an HDAC inhibitor or a proteasome inhibitor. 
     
     
         18 . (canceled) 
     
     
         19 . The method of  claim 1 , wherein the load of the immunosuppressants and/or epitopes on average across the first and/or second population of synthetic nanocarriers is between 0.0001% and 50% (weight/weight). 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 1 , wherein the synthetic nanocarriers of the first population and/or second population comprise lipid nanoparticles, polymeric nanoparticles, metallic nanoparticles, surfactant-based emulsions, dendrimers, buckyballs, nanowires, virus-like particles or peptide or protein particles. 
     
     
         22 - 31 . (canceled) 
     
     
         32 . The method of  claim 1 , wherein the mean of a particle size distribution obtained using dynamic light scattering of the synthetic nanocarriers of the first and/or second population is a diameter greater than 100 nm. 
     
     
         33 - 36 . (canceled) 
     
     
         37 . The method of  claim 1 , wherein the aspect ratio of the synthetic nanocarriers of the first population and/or second population is greater than 1:1, 1:1.2, 1:1.5, 1:2, 1:3, 1:5, 1:7 or 1:10. 
     
     
         38 - 40 . (canceled) 
     
     
         41 . A composition comprising isolated antigen-specific CD8+ regulatory T cells produced according to the method of  claim 1 . 
     
     
         42 - 43 . (canceled) 
     
     
         44 . A dosage form comprising the composition of  claim 41 . 
     
     
         45 . A method comprising:
 (i) producing a first population of synthetic nanocarriers coupled to immunosuppressants, and   (ii) producing a second population of synthetic nanocarriers coupled to MHC Class I-restricted and/or MHC Class II-restricted epitopes of an antigen.   
     
     
         46 - 51 . (canceled) 
     
     
         52 . A process for producing a composition or dosage form comprising the steps of:
 (i) coupling a first population of synthetic nanocarriers to immunosuppressants, and   (ii) coupling a second population of synthetic nanocarriers to MHC Class I-restricted and/or MHC Class II-restricted epitopes of an antigen.   
     
     
         53 - 55 . (canceled) 
     
     
         56 . A composition or dosage form obtainable by the method of  claim 45 . 
     
     
         57 - 68 . (canceled) 
     
     
         69 . A method comprising:
 (A) administering to a subject:
 (i) a population of synthetic nanocarriers coupled to immunosuppressants, and 
 (ii) MHC Class I-restricted and/or MHC Class II-restricted epitopes of an antigen, 
 in an amount effective to generate antigen-specific CD8+ regulatory T cells in the subject; or 
   (B) generating antigen-specific CD8+ regulatory T cells in a subject by administering:
 (i) a population of synthetic nanocarriers coupled to immunosuppressants, and 
 (ii) MHC Class I-restricted and/or MHC Class II-restricted of an antigen; or 
   (C) administering to a subject, according to a protocol that was previously shown to generate antigen-specific CD8+ regulatory T cells in one or more test subjects:
 (i) a population of synthetic nanocarriers coupled to immunosuppressants, and 
 (ii) MHC Class I-restricted and/or MHC Class II-restricted epitopes of an antigen.