Targeting the innate immune system to induce long-term tolerance and to resolve macrophage accumulation in atherosclerosis

Abstract

Methods and compositions for inducing long-term tolerance by hybrid nanoparticles are provided. Compositions and formulations comprising hybrid nanoparticles with inherent affinity for innate immune cells are provided.

1 . A method of inducing immune tolerance comprising administering to a patient an effective amount of (i) a composition comprising a high-density lipoprotein-derived nanoparticle (HDL) which comprises an mTOR inhibitor. 
     
     
         2 . The method of  claim 1 , wherein the mTOR inhibitor is rapamycin or a pharmaceutically acceptable salt, solvate, poly-morph, tautomer or prodrug thereof, formulated as rapamycin nanoparticle (mTOR-HDL). 
     
     
         3 . The method of  claim 1 , wherein the administration promotes Ly-6C lo  Mo/MΦ development. 
     
     
         4 . The method of  claim 1 , wherein the patient has an autoimmune condition selected from the group consisting of coeliac disease, type I diabetes, multiple sclerosis, thyroiditis, Grave's disease, systemic lupus erythematosus, scleroderma, psoriasis, arthritis, rheumatoid arthritis, alopecia greata, ankylosing spondylitis, Churg-Strauss Syndrome, autoimmune hemolytic anemia, autoimmune hepatitis, Behcet's disease, Crohn's disease, dermatomyositis, glomerulonephritis, Guillain-Barre syndrome, irritable bowel disease (IBD), lupus nephritis, myasthenia gravis, myocarditis, pemphigus/pemphigoid, pernicious anemia, polyarteritis nodosa, polymyositis, primary biliary cirrhosis, rheumatic fever, sarcoidosis, Sjogren's syndrome, ulcerative colitis, uveitis, vitiligo, and Wegener's granulomatosis. 
     
     
         5 .- 16 . (canceled) 
     
     
         17 . A method for prophylaxis of organ or tissue rejection, the method comprising the step of administering to a patient in need thereof an effective amount of a composition comprising a high-density lipoprotein-derived nanoparticle (HDL) which comprises an mTOR inhibitor. 
     
     
         18 . The method of  claim 17 , wherein the mTOR inhibitor is rapamycin or a pharmaceutically acceptable salt, solvate, poly-morph, tautomer or prodrug thereof, formulated as rapamycin nanoparticle (mTOR-HDL). 
     
     
         19 . The method of  claim 17 , wherein the HDL comprises 1,2-dimyristoyl-sn-glycero-3-phosphatidylcholine (DMPC) and 1-myristoyl-2-hydroxy-sn-glycero-phosphocholine (MHPC) and further comprises ApoA-1. 
     
     
         20 . The method of  claim 17 , wherein the patient has undergone an organ or tissue transplant and the transplanted tissue is lung tissue, heart tissue, kidney tissue, liver tissue, retinal tissue, corneal tissue, skin tissue, pancreatic tissue, intestinal tissue, genital tissue, ovary tissue, bone tissue, tendon tissue, bone marrow, or vascular tissue. 
     
     
         21 . The method of  claim 17 , wherein the composition is administered intravenously or intra-arterially. 
     
     
         22 . The method of  claim 17 , further comprising administering to the patient one or more immunosuppressant agents. 
     
     
         23 .- 25 . (canceled) 
     
     
         26 . A composition comprising a high-density lipoprotein-derived nanoparticle (HDL) which comprises an m-TOR inhibitor. 
     
     
         27 . The composition of  claim 26 , wherein the HDL comprises 1,2-dimyristoyl-sn-glycero-3-phosphatidylcholine (DMPC) and 1-myristoyl-2-hydroxy-sn-glycero-phosphocholine (MHPC) and further comprises ApoA-1. 
     
     
         28 . The composition of  claim 27 , wherein the weight ratio of DMPC to MHPC is about 3:1. 
     
     
         29 . The composition of  claim 26 , wherein the mTOR inhibitor is rapamycin or a pharmaceutically acceptable salt, solvate, poly-morph, tautomer or prodrug thereof, formulated as rapamycin nanoparticle (mTOR-HDL or rapamycin-HDL). 
     
     
         30 . A pharmaceutical composition comprising a) pharmaceutically effective amount of the composition of  claim 26  and b) a pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant. 
     
     
         31 . The pharmaceutical composition of  claim 30 , further comprising one or more immunosuppressive agents or anti-inflammatory agent. 
     
     
         32 . The pharmaceutical composition of  claim 31 , wherein the immunosuppressant agent is cyclosporine A or FK506. 
     
     
         33 .- 38 . (canceled) 
     
     
         39 . A kit comprising the composition of  claim 26 . 
     
     
         40 . The kit of  claim 39 , wherein said m-TOR inhibitor is rapamycin. 
     
     
         41 . The kit of  claim 39 , further comprising one or more immunosuppressive agents. 
     
     
         42 . The kit of  claim 41 , wherein the immunosuppressant agent is cyclosporine A, FK506 or rapamycin. 
     
     
         43 .- 59 . (canceled) 
     
     
         60 . A composition comprising a high-density lipoprotein-derived nanoparticle (HDL) which comprises rapamycin or a pharmaceutically acceptable salt, solvate, poly-morph, tautomer or prodrug thereof, formulated as rapamycin nanoparticle (rapamycin-HDL) and wherein the HDL comprises 1,2-dimyristoyl-sn-glycero-3-phosphatidylcholine (DMPC) and 1-myristoyl-2-hydroxy-sn-glycero-phosphocholine (MHPC), and wherein the weight ratio of DMPC to MHPC is about 3:1. 
     
     
         61 . The composition of  claim 60 , further comprising ApoA-1.