Methods for the treatment and prevention of inflammatory diseases

Abstract

The inventors demonstrate that treatment of young, suckling mice with a glycolipid derived from Helicobacter pylori activates NKT cells in a CD1d-restricted fashion, and is protective against AHR in a model of allergen-induced asthma. The inventors further found that this protective effect can be transferred by NKT cells exposed to the glycolipid, and is associated with the expansion of a suppressive double-negative NKT cells and Foxp3 + T Reg cells. The inventors also demonstrate herein that pretreatment of adult mice with a glycolipid derived from Helicobacter pylori partially suppresses airway hyperreactivity and inhibits BAL inflammation in an ozone-exposure model. Accordingly, provided herein are compositions and methods for the treatment and prevention of inflammatory diseases, such as asthma or autoimmune diseases, in a subject in need thereof.

1 . A method for the treatment or prevention of an inflammatory disease in a subject in need thereof, the method comprising administering to a subject having an inflammatory disease an effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is OR 3 , NH 2 , or NHC(O)-alkyl, or together with R 2  forms a second bond between the carbons they are attached to; 
         R 2  is OR 3  or together with R 1  forms a second bond between the carbons they are attached to; 
         R 3  and R 4  are independently H, alkyl, alkenyl, alkynyl, acyl, PO 3   2− , each of which may be optionally substituted; 
       
       
         
           
           
               
               
           
         
         R 5  is alkyl, alkenyl, alkynyl, or acyl, each of which may be optionally substituted; 
         R 6  and R 7  are both H or both alkyl; 
         R 8  is H or together with R 9  forms a second bond between the carbons to which they are attached; 
         R 9  is H, OR 3 , or together with R 8  forms a second bond between the carbons to which they are attached; 
         R 10  is H, OH, alkyl, or O-alkyl, each of which may be optionally substituted; 
         R 11  is alkyl, alkenyl, or alkynyl, each of which may be optionally substituted; 
         X is O, or NH; 
         Y is CH 2 , C(O), or CHOR 3 ; and 
         pharmaceutically acceptable salts thereof. 
       
     
     
         2 . The method of  claim 1 , further comprising administering an effective amount of antigen presenting cells. 
     
     
         3 . A method for the treatment or prevention of an inflammatory disease in a subject in need thereof, the method comprising administering to a subject having an inflammatory disease an NKT cell population contacted with an effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is OR 3 , NH 2 , or NHC(O)-alkyl, or together with R 2  forms a second bond between the carbons they are attached to; 
         R 2  is OR 3  or together with R 1  forms a second bond between the carbons they are attached to; 
         R 3  and R 4  are independently H, alkyl, alkenyl, alkynyl, acyl, PO 3   2− , each of which may be optionally substituted; 
       
       
         
           
           
               
               
           
         
         R 5  is alkyl, alkenyl, alkynyl, or acyl, each of which may be optionally substituted; 
         R 6  and R 7  are both H or both alkyl; 
         R 8  is H or together with R 9  forms a second bond between the carbons to which they are attached; 
         R 9  is H, OR 3 , or together with R 8  forms a second bond between the carbons to which they are attached; 
         R 10  is H, OH, alkyl, or O-alkyl, each of which may be optionally substituted; 
         R 11  is alkyl, alkenyl, or alkynyl, each of which may be optionally substituted; 
         X is O, or NH; 
         Y is CH 2 , C(O), or CHOR 3 ; and 
         pharmaceutically acceptable salts thereof. 
       
     
     
         4 . The method of  claim 3 , wherein the contacting of the NKT cell population with the compound of formula (I) occurs in vitro, ex vivo, or in vivo. 
     
     
         5 . The method of  claim 3 , wherein the contacting of the NKT cell population with the compound of formula (I) occurs in the presence of one or more antigen-presenting cells. 
     
     
         6 . The method of  claim 3 , wherein the NKT cells are allogeneic NKT cells obtained from one or more donors. 
     
     
         7 . The method of  claim 3 , wherein the NKT cells are autologous NKT cells. 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . A method for the treatment of an inflammatory disease in a subject in need thereof, the method comprising:
 a. administering to a first subject an effective amount of a compound of formula (I):   
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is OR 3 , NH 2 , or NHC(O)-alkyl, or together with R 2  forms a second bond between the carbons they are attached to; 
         R 2  is OR 3  or together with R 1  forms a second bond between the carbons they are attached to; 
         R 3  and R 4  are independently H, alkyl, alkenyl, alkynyl, acyl, PO 3   2− , each of which may he optionally substituted; 
       
       
         
           
           
               
               
           
         
         R 5  is alkyl, alkenyl, alkynyl, or acyl, each of which may be optionally substituted; 
         R 6  and R 7  are both H or both alkyl; 
         R 8  is H or together with R 9  forms a second bond between the carbons to which they are attached; 
         R 9  is H, OR 3 , or together with R 8  forms a second bond between the carbons to which they are attached; 
         R 10  is H, OH, alkyl, or O-alkyl, each of which may be optionally substituted; 
         R 11  is alkyl, alkenyl, or alkynyl, each of which may be optionally substituted; 
         X is O, or NH; 
         Y is CH 2 , C(O), or CHOR 3 ; and 
         pharmaceutically acceptable salts thereof; and 
         b. isolating a plurality of immune cells from the first subject, wherein the immune cells comprise an NKT population; 
         c. administering to a second subject an effective amount of the plurality of immune cells isolated from the first subject contacted with a compound of formula (I), wherein said second subject has an inflammatory disease. 
       
     
     
         11 . The method of  claim 10 , wherein the first and second subject are the same subject. 
     
     
         12 . The method of  claim 10 , wherein the first subject is a young subject or an infant subject. 
     
     
         13 . The method of  claim 10 , wherein the first subject is less than 10 years of age. 
     
     
         14 . The method of  claim 10 , wherein the plurality of immune cells further comprise antigen-presenting cells. 
     
     
         15 . The method of  claim 10 , wherein the plurality of immune cells are isolated from the peripheral blood, bone marrow, thymus, or spleen of the first subject. 
     
     
         16 . The method of  claim 10 , further comprising purifying an NKT cell population from the plurality of immune cells prior to the administration of the plurality of immune cells to the second subject. 
     
     
         17 . The method of  claim 16 , wherein the purified NKT cell population has a CD4-CD8-phenotype. 
     
     
         18 . The method of  claim 10 , wherein the compound of formula (I) is selected from cholesteryl-α-D-alloside; cholesteryl-α-D-glucoside; cholesteryl-α-D-mannoside; cholesteryl-α-D-guloside; cholesteryl-α-D-galactoside; cholesteryl-α-D-taloside; cholesteryl-α-D-glucosamine; cholesteryl-6-O-tetradecanoyl-α-D-alloside; cholesteryl-6-O-tetradecanoyl-α-D-glucoside; cholesteryl-6-O-tetradecanoyl-α-D-mannoside; cholesteryl-6-O-tetradecanoyl-α-D-guloside; cholesteryl-6-O-tetradecanoyl-α-D-galactoside; cholesteryl-6-O-tetradecanoyl-α-D-taloside ; cholesteryl-6-O-tetradecanoyl-α-D-glucosamine; cholesteryl-6-phosphate-α-D-alloside ; cholesteryl-6-phosphate-α-D-glucoside; cholesteryl-6-phosphate-α-D-mannoside; cholesteryl-6-phosphate-α-D-guloside; cholesteryl-6-phosphate-α-D-galactoside; cholesteryl-6-phosphate-α-D-taloside; cholesteryl-6-phosphate-α-D-glucosamine; cholesteryl-1,6-bisphosphate-α-D-alloside; cholesteryl-1,6-bisphosphate-α-D-glucoside; cholesteryl-1,6-bisphosphate-α-D-mannoside; cholesteryl-1,6-bisphosphate-α-D-guloside; cholesteryl-1,6-bisphosphate-α-D-galactoside; cholesteryl-1,6-bisphosphate-α-D-taloside; 7-beta-hydroxycholesteryl-α-D-alloside; 7-beta-hydroxycholesteryl-α-D-glucoside; 7-beta-hydroxycholesteryl-α-D-mannoside; 7-beta-hydroxycholesteryl-α-D-guloside; 7-beta-hydroxycholesteryl-α-D-galactoside; 7-beta-hydroxycholesteryl-α-D-taloside; 7-beta-hydroxycholesteryl-α-D-glucosamine; 7-beta-hydroxycholesteryl-6-O-tetradecanoyl-α-D-alloside; 7-beta-hydroxycholesteryl-6-O-tetradecanoyl-α-D-glucoside; 7-beta-hydroxycholesteryl-6-O-tetradecanoyl-α-D-mannoside; 7-beta-hydroxycholesteryl-6-O-tetradecanoyl-α-D-guloside; 7-beta-hydroxycholesteryl-6-O-tetradecanoyl-α-D-galactoside; 7-beta-hydroxycholesteryl-6-O-tetradecanoyl-α-D-taloside; 7-beta-hydroxycholesteryl-6-O-tetradecanoyl-α-D-glucosamine; 7-beta-hydroxycholesteryl-6-phosphate-α-D-alloside; 7-beta-hydroxycholesteryl-6-phosphate-α-D-glucoside; 7-beta-hydroxycholesteryl-6-phosphate-α-D-mannoside; 7-beta-hydroxycholesteryl-6-phosphate-α-D-guloside; 7-beta-hydroxycholesteryl-6-phosphate-α-D-galactoside; 7-beta-hydroxycholesteryl-6-phosphate-α-D-taloside; 7-beta-hydroxycholesteryl-6-phosphate-α-D-glucosamine; 7-beta-hydroxycholesteryl-1,6-bisphosphate-α-D-alloside; 7-beta-hydroxycholesteryl-1,6-bisphosphate-α-D-glucoside; 7-beta-hydroxycholesteryl-1,6-bisphosphate-α-D-mannoside; 7-beta-hydroxycholesteryl-1,6-bisphosphate-α-D-guloside; 7-beta-hydroxycholesteryl-1,6-bisphosphate-α-D-galactoside; 7-beta-hydroxycholesteryl-1,6-bisphosphate-α-D-taloside; 7-keto-cholesteryl-α-D-alloside; 7-keto-cholesteryl-α-D-glucoside; 7-keto-cholesteryl-α-D-mannoside; 7-keto-cholesteryl-α-D-guloside; 7-keto-cholesteryl-α-D-galactoside; 7 -keto-cholesteryl-α-D-taloside; 7-keto-cholesteryl-α-D-glucosamine; 7-keto-cholesteryl-6-O-tetradecanoyl-α-D-alloside; 7-keto-cholesteryl-6-O-tetradecanoyl-α-D-glucoside; 7-keto-cholesteryl-6-O tetradecanoyl-α-D-mannoside; 7-keto-cholesteryl-6-O-tetradecanoyl-α-D-guloside; 7-keto-cholesteryl-6-O-tetradecanoyl-α-D-galactoside; 7-keto-cholesteryl-6-O-tetradecanoyl-α-D-taloside; 7-keto-cholesteryl-6-O-tetradecanoyl-α-D-glucosamine; 7-keto-cholesteryl-6-phosphate-α-D-alloside; 7-keto-cholesteryl-6-phosphate-α-D-glucoside; 7-keto-cholesteryl-6-phosphate-α-D-mannoside; 7-keto-cholesteryl-6-phosphate-α-D-guloside; 7-keto-cholesteryl-6-phosphate-α-D-galactoside; 7-keto-cholesteryl-6-phosphate-α-D-taloside; 7-keto-cholesteryl-6-phosphate-α-D-glucosamine; 7-keto-cholesteryl-1,6-bisphosphate-α-D-alloside; 7-keto-cholesteryl-1,6-bisphosphate-α-D-glucoside; 7-keto-cholesteryl-1,6-bisphosphate-α-D-mannoside; 7-keto-cholesteryl-1,6-bisphosphate-α-D-guloside; 7-keto-cholesteryl-1,6-bisphosphate-α-D-galactoside; 7-keto-cholesteryl-1,6-bisphosphate-α-D-taloside; 6,7-dihydroxycholesteryl-α-D-alloside; 6,7-dihydroxycholesteryl-α-D-glucoside; 6,7-dihydroxycholesteryl-α-D-mannoside; 6,7-dihydroxycholesteryl-α-D-guloside; 6,7-dihydroxycholesteryl-α-D-galactoside; 6,7-dihydroxycholesteryl-α-D-taloside; 6,7-dihydroxycholesteryl-α-D-glucosamine; 6,7-dihydroxycholesteryl-6-O-tetradecanoyl-α-D-alloside; 6,7-dihydroxycholesteryl-6-O-tetradecanoyl-α-D-glucoside; 6,7-dihydroxycholesteryl-6-O-tetradecanoyl-α-D-mannoside; 6,7-dihydroxycholesteryl-6-O-tetradecanoyl-α-D-guloside; 6,7-dihydroxycholesteryl-6-O-tetradecanoyl-α-D-galactoside; 6,7-dihydroxycholesteryl-6-O-tetradecanoyl-α-D-taloside; 6,7-dihydroxycholesteryl-6-O-tetradecanoyl-α-D-glucosamine; 6,7-dihydroxycholesteryl-6-phosphate-α-D-alloside; 6,7-dihydroxycholesteryl-6-phosphate-α-D-glucoside; 6,7-dihydroxycholesteryl-6-phosphate-α-D-mannoside; 6,7-dihydroxycholesteryl-6-phosphate-α-D-guloside; 6,7-dihydroxycholesteryl-6-phosphate-α-D-galactoside; 6,7-dihydroxycholesteryl-6-phosphate-α-D-taloside; 6,7-dihydroxycholesteryl-6-phosphate-α-D-glucosamine; 6,7-dihydroxycholesteryl-1,6-bisphosphate-α-D-alloside; 6,7-dihydroxycholesteryl-1,6-bisphosphate-α-D-glucoside; 6,7-dihydroxycholesteryl-1,6-bisphosphate-α-D-mannoside; 6,7-dihydroxycholesteryl-1,6-bisphosphate-α-D-guloside; 6,7-dihydroxycholesteryl-1,6-bisphosphate-α-D-galactoside; and 6,7-dihydroxycholesteryl-1,6-bisphosphate-α-D-taloside. 
     
     
         19 . The method of  claim 10 , wherein the compound of formula (I) is cholesteryl 6-O-tetradecanoyl-α-D-glucopyranoside. 
     
     
         20 . The method of  claim 10 , wherein the inflammatory disease is a respiratory disease or an autoimmune disease. 
     
     
         21 . The method of  claim 20 , wherein the respiratory disease is selected from the group consisting of asthma, airway hyperreactivity, lung inflammation, chronic obstructive pulmonary disease, pneumonia, hypersensitivity pneumonitis, pulmonary infiltrate with eosinophilia, environmental lung disease, bronchiectasis, cystic fibrosis, interstitial lung disease, primary pulmonary hypertension, pulmonary thromboembolism, disorders of the pleura, acute respiratory distress syndrome, mesothelioma, allergic rhinitis, allergy, asbestosis, aspergilloma, aspergillosis, bronchiectasis, chronic bronchitis, emphysema, eosinophilic pneumonia, idiopathic pulmonary fibrosis, invasive pneumococcal disease, influenza, nontuberculous mycobacteria, pleural effusion, pneumoconiosis, pneumocytosis, pneumonia, pulmonary actinomycosis, pulmonary alveolar proteinosis, pulmonary anthrax, pulmonary edema, pulmonary embolus, pulmonary inflammation, pulmonary histiocytosis X, pulmonary hypertension, pulmonary nocardiosis, pulmonary tuberculosis, pulmonary veno-occlusive disease, rheumatoid lung disease, sarcoidosis, and Wegener's granulomatosis. 
     
     
         22 . The method of  claim 21 , wherein the asthma is allergic or non-allergic asthma. 
     
     
         23 . The method of  claim 20 , wherein the autoimmune disease is selected from the group consisting of type-I diabetes, multiple sclerosis, Hashinoto's thyroiditis, Crohn's disease, rheumatoid arthritis, systemic lupus erythromatosus, gastritis, autoimmune hepatitis, hemolytic anemia, autoimmune hemophilia, autoimmune lymphoproliferative syndrome (ALPS), autoimmune uveoretinitis, glomerulonephritis, Guillain-Barre syndrome, psoriasis and myasthenia gravis. 
     
     
         24 . A compound of formula (I) for use in treating or preventing an inflammatory disease in a subject in need thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is OR 3 , NH 2 , or NHC(O)-alkyl, or together with R 2  forms a second bond between the carbons 
         they are attached to; 
         R 2  is OR 3  or together with R 1  forms a second bond between the carbons they are attached to; 
         R 3  and R 4  are independently H, alkyl, alkenyl, alkynyl, acyl, PO 3   2− , each of which may be optionally substituted; 
       
       
         
           
           
               
               
           
         
         R 5  is alkyl, alkenyl, alkynyl, or acyl, each of which may be optionally substituted; 
         R 6  and R 7  are both H or both alkyl; 
         R 8  is H or together with R 9  forms a second bond between the carbons to which they are attached; 
         R 9  is H, OR 3 , or together with R 8  forms a second bond between the carbons to which they are attached; 
         R 10  is H, OH, alkyl, or O-alkyl, each of which may be optionally substituted; 
         R 11  is alkyl, alkenyl, or alkynyl, each of which may be optionally substituted; 
         X is O, or NH; 
         Y is CH 2 , C(O), or CHOR 3 ; and 
         pharmaceutically acceptable salts thereof. 
       
     
     
         25 .- 36 . (canceled) 
     
     
         37 . A method for the treatment or prevention of an inflammatory disease in a subject in need thereof, the method comprising administering to a subject having an inflammatory disease an effective amount of a compound of formula (VI): 
       
         
           
           
               
               
           
         
         wherein: 
         R 61  is OR 63 , NH 2 , or NHC(O)-alkyl, or together with R 62  forms a second bond between the carbons they are attached to; 
         R 62  is OR 63  or together with R 61  forms a second bond between the carbons they are attached to; 
         R 63  and R 64  are independently H, alkyl, alkenyl, alkynyl, acyl, PO 3   2− , each of which may be optionally substituted; 
         R 65  is alkyl, alkenyl, alkynyl, acyl, fatty acid, or lipid each of which may be optionally substituted; 
         X is O, or NH; 
         Y is absent, or a linker; and 
         pharmaceutically acceptable salts thereof. 
       
     
     
         38 . (canceled) 
     
     
         39 . A compound of formula (VI) for treating or preventing an inflammatory disease in a subject in need thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 61  is OR 63 , NH2, or NHC(O)-alkyl, or together with R 62  forms a second bond between the carbons they are attached to; 
         R 62  is OR 63  or together with R 61  forms a second bond between the carbons they are attached to; 
         R 63  and R 64  are independently H, alkyl, alkenyl, alkynyl, acyl, PO 3   2− , each of which may be optionally substituted; 
         R 65  is alkyl, alkenyl, alkynyl, acyl, fatty acid, or lipid each of which may be optionally substituted; 
         X is O, or NH; 
         Y is absent, or a linker; and 
         pharmaceutically acceptable salts thereof.