Treatment of immune disease by mucosal delivery of antigents using genetically modified lactobacillus

Abstract

The present invention relates to the treatment of autoimmune and allergic diseases by mucosal delivery by micro-organism, in particular Lactococcus lactis , of secreted immunodominant antigens.

1 . A micro-organism secreting an antigen for use in mucosal delivery to treat an immune response related disease in a patient, wherein said immune response related disease is chosen from the group consisting of allergic asthma, multiple sclerosis, type I diabetes, autoimmune uveitis, autoimmune thyroiditis, autoimmune myasthenia gravis, rheumatoid arthritis, food allergy or celiac disease. 
     
     
         2 . A composition for use in mucosal delivery to treat, prevent and/or alleviate an immune response related disease chosen from the group consisting of allergic asthma, multiple sclerosis, type I diabetes, autoimmune uveitis, autoimmune thyroiditis, autoimmune myasthenia gravis, rheumatoid arthritis, food allergy or celiac disease in a patient, characterized in that said composition comprises at least a micro-organism secreting an antigen. 
     
     
         3 . The composition of  claim 2 , wherein said micro-organism is lactic acid bacterium, yeast, or  Lactococcus lactis  (LL). 
     
     
         4 . The composition of  claim 2 , wherein said antigen is constitutively secreted. 
     
     
         5 . The composition of  claim 2 , wherein said micro-organism is administered daily. 
     
     
         6 . The composition of  claim 2 , wherein said antigen induces regulatory T-cells (Treg). 
     
     
         7 . The composition according to  claim 6 , wherein said Treg cells are Foxp3+ Treg cells. 
     
     
         8 . The composition of  claim 7 , wherein said antigen is an immuno-dominant deamidated antigen. 
     
     
         9 . The composition of  claim 8 , wherein said antigen is recognized in the context of HLA-DQ2 or -DQ8. 
     
     
         10 . The composition of  claim 9 , wherein said antigen is α-gliadin or hordein. 
     
     
         11 . The composition for use according to  claim 10 , wherein said antigen comprises or consists of SEQ ID NO: 2, 4, 6 or 8. 
     
     
         12 . The composition of  claim 2 , wherein said antigen reduces proliferation of spleen and inguinal lymph node cells. 
     
     
         13 . The composition or  claim 2 , wherein said antigen suppresses inflammatory antigen specific T cell response. 
     
     
         14 . The composition of  claim 2 , wherein said mucosal delivery is selected from the group consisting of rectal delivery, buccal delivery, pulmonary delivery, ocular delivery, nasal delivery, vaginal delivery and oral delivery. 
     
     
         15 . The composition of  claim 2 , wherein said micro-organism is delivered for at least 1 week, 1 month or 1 year. 
     
     
         16 . The composition of  claim 2 , wherein said micro-organism is delivered at least once or twice a day. 
     
     
         17 . The composition of  claim 2 , wherein said micro-organism is delivered in a dose of at least 10 femtogram to 100 mg per day. 
     
     
         18 . The composition of  claim 2 , wherein said micro-organism is delivered by spray, capsule, aerosol, lozenges, bolus, tablet, sachets, liquid, suspension, emulsion or troches. 
     
     
         19 . The composition of  claim 2 , wherein said composition is formulated as a medicament, medical food or nutraceutical. 
     
     
         20 . Method for treating, preventing and/or alleviating an immune response related disease in a patient, comprising the mucosal delivery of a composition comprising a micro-organism expressing an antigen, wherein said antigen is secreted, and wherein said composition is delivered daily. 
     
     
         21 . The method according to  claim 20 , wherein said micro-organism is lactic acid bacterium, yeast or  Lactococcus lactis  (LL). 
     
     
         22 . The method according to  claim 20 , wherein disease is selected from the group consisting of allergic asthma, multiple sclerosis, type I diabetes, autoimmune uveitis, autoimmune thyroiditis, autoimmune myasthenia gravis, rheumatoid arthritis, food allergy and celiac disease. 
     
     
         23 . The method according to  claim 20 , wherein said secretion is constitutive. 
     
     
         24 . The method according to  claim 20 , wherein said antigen induces regulatory T-cells (Treg). 
     
     
         25 . The method according to  claim 24 , wherein said Treg cells are Foxp3+ Treg cells. 
     
     
         26 . The method according to  claim 20 , wherein said antigen is an immuno dominant deamidated antigen. 
     
     
         27 . The method according to  claim 20 , wherein said antigen is recognized in the context of HLA-DQ2 or -DQ8. 
     
     
         28 . The method according to  claim 20 , wherein said antigen is α-gliadin or hordein. 
     
     
         29 . The method according to  claim 28 , wherein said antigen comprises or consists of SEQ ID NO: 2, 4, 6 or 8. 
     
     
         30 . The method according to  claim 20 , wherein said antigen reduces proliferation of spleen and inguinal lymph node cells. 
     
     
         31 . The method according to  claim 20 , wherein said antigen suppresses inflammatory antigen specific T cell response. 
     
     
         32 . The method according to  claim 20 , wherein said mucosal delivery is chosen from the group consisting of rectal delivery, buccal delivery, pulmonary delivery, ocular delivery, nasal delivery, vaginal delivery and oral delivery. 
     
     
         33 . The method according to  claim 20 , wherein said micro-organism is delivered for at least 1 week, 1 month or 1 year. 
     
     
         34 . The method according to  claim 20 , wherein said micro-organism is delivered at least once or twice a day. 
     
     
         35 . The method according to  claim 20 , wherein said micro-organism is delivered in a dose of at least 10 femtogram to 100 mg per day. 
     
     
         36 . The method according to  claim 20 , wherein said micro-organism is delivered by spray, capsule, aerosol, lozenges, bolus, tablet, sachets, liquid, suspension, emulsion or troches. 
     
     
         37 . Composition comprising a micro-organism, wherein said micro-organism constitutively secretes an antigen, which is involved in the induction of allergic asthma, multiple sclerosis, type I diabetes, autoimmune uveitis, autoimmune thyroiditis, autoimmune myasthenia gravis, rheumatoid arthritis, food allergy or celiac disease. 
     
     
         38 . The composition according to  claim 37 , wherein said micro-organism is lactic acid bacterium or yeast or  Lactococcus lactis  (LL). 
     
     
         39 . The composition of  claim 37 , wherein said micro-organism is present in a dose of at least 10 femtogram to 100 mg, such as 100 fg to 10 mg, or 1 pg to 1 mg, or 10 pg to 100 μg, or 100 pg to 10 μg, or 1 ng to 1 μg, or 10 ng to 100 mg. 
     
     
         40 . Product comprising the composition of  claim 37 . 
     
     
         41 . The product of  claim 40 , wherein said product is selected from the group consisting of sprays, capsules, aerosols, lozenges, bolus, tablets, sachets, liquids, suspensions, emulsions and troches. 
     
     
         42 . Medicament, nutraceutical or medical food for treating, preventing and/or alleviating a disease or disorder involving an immune response related disease comprising at least a micro organism, wherein said micro-organism constitutively secretes an antigen, which is involved in the induction of allergic asthma, multiple sclerosis, type I diabetes, autoimmune uveitis, autoimmune thyroiditis, autoimmune myasthenia gravis, rheumatoid arthritis, food allergy or celiac disease. 
     
     
         43 . Medicament, nutraceutical or medical food according to  claim 42 , wherein said micro organism is lactic acid bacterium or yeast or  Lactococcus lactis  (LL). 
     
     
         44 . The composition of  claim 2 , wherein said antigen is prepared for the continued presence in said patient.