Activation and inhibition of the immune system

Abstract

Activation of the immune response by NF-kB inducers, induction of an anergic response by NF-kB inhibitors and the inhibition and activation of immune response by the administration of an activator or inhibitor of NF-kB is disclosed. Examples of NF-kB inhibitors include IkBα, PSI, a nucleotide sequence encoding IkBα anti-sense nucleic acid encoding an NF-kB sequence, such as Rel B, and anti-NF-kB antibodies. Examples of NF-kB inducers include NIK, MEKK, IKK2, TFRRF2, and Rel B. Also disclosed are vectors encoding inducers and inhibitors of NF-kB, for example adenoviral vectors.

1 . (canceled) 
     
     
         2 . A method of inhibiting antigen presentation or inducing an anergic response in a mammal, such as a human, comprising administering a pharmaceutically-effective dose of an NF-κB inhibitor, wherein the mammal, such as a human, is administered an antigenic molecule or polynucleotide encoding an antigenic molecule. 
     
     
         3 . (canceled) 
     
     
         4 . A method of treating an autoimmune disease comprising administering a pharmaceutically-effective dose of an NF-κB inhibitor to induce an anergic response in a mammal, wherein the mammal, such as a human, is administered an antigenic molecule or polynucleotide encoding an antigenic molecule. 
     
     
         5 . (canceled) 
     
     
         6 . A method of preventing transplant rejection in a mammal, such as a human, comprising administering a pharmaceutically-effective dose of an NF-κB inhibitor to induce an anergic response in a mammal, wherein the mammal, such as a human, is administered an antigenic molecule or polynucleotide encoding an antigenic molecule. 
     
     
         7 . A method according to  claim 2 , comprising administering a vector comprising a nucleic acid encoding an NF-κB inhibitor operatively linked to regulatory elements necessary for expression of said nucleic acid. 
     
     
         8 . A method according to  claim 7 , wherein the vector is an adenovirus or a lentivirus. 
     
     
         9 - 13 . (canceled) 
     
     
         14 . A method according to  claim 2 , wherein the inhibitor is IκBα or PSI or an IKK2 dominant negative mutant. 
     
     
         15 . A method according to  claim 2 , wherein the inhibitor is an anti-sense nucleic acid effective against at least a portion of an NF-κB. 
     
     
         16 . A method according to  claim 15 , wherein the anti-sense nucleic acid is effective against Rel B. 
     
     
         17 . A method according to  claim 2 , wherein the inhibitor is encoded by a nucleic acid in a vector, the vector additionally comprising regulatory elements operatively linked to said nucleic acid. 
     
     
         18 . A method according to  claim 17 , wherein the inhibitor is an Fv fragment of an antibody. 
     
     
         19 . A method according to  claim 2 , wherein the inhibitor is an antibody or an effective fragment thereof, or a cDNA encoding an antibody or an effective fragment thereof, capable of binding NF-κB or a fragment thereof. 
     
     
         20 . A method according to  claim 19 , wherein the antibody is an anti-Rel B antibody or an effective fragment thereof or a cDNA encoding Rel B or an effective fragment thereof. 
     
     
         21 . (canceled) 
     
     
         22 . A method of stimulating antigen presentation or of stimulating an immune response in a mammal, such as a human, comprising administering a pharmaceutically effective amount of an NF-κB inducer, wherein the mammal, such as a human, is administered an antigenic molecule or polynucleotide encoding an antigenic molecule. 
     
     
         23 . A method according to  claim 22  for treating an infectious disease or a cancer. 
     
     
         24 - 27 . (canceled) 
     
     
         28 . A method according to  claim 22 , wherein the inducer is selected from the group consisting of MEKK1, NIK, IKK2, TRAF2, TRAF5, TRAF6, TAK, a dominant negative mutant of Myd88, TP L-2, IRAK, IKK5, Toll receptors, Rel B, and fragments and muteins thereof which are capable of inducing NF-κB. 
     
     
         29 . A method according to  claim 22 , wherein the NF-κB inducer is encoded by a nucleic acid within a vector, the vector additionally comprising regulatory elements operatively linked to said nucleic acid and necessary for expression of said nucleic acid. 
     
     
         30 . A method according to  claim 29 , wherein the vector is an adenovirus or a lentivirus. 
     
     
         31 . A method according to  claim 22 , wherein the NF-κB inducer is in the form of a DNA vaccine. 
     
     
         32 . A method of inhibiting maturation and activation of APCs, such as dendritic cells in vivo or in vitro, comprising administering an effective amount of an inhibitor of NF-κB. 
     
     
         33 . A method of stimulating maturation and activation of APCs, such as dendritic cells in vivo or in vitro, comprising administering an effective amount of an inducer of NF-κB. 
     
     
         34 . (canceled) 
     
     
         35 . The method according to  claim 33 , wherein the inducer is targeted to APCs such as dendritic cells or precursors thereof. 
     
     
         36 . The method according to  claim 33 , wherein APCs, such as dendritic cells or precursors thereof are exposed to the inducer in vitro and introduced into a mammal. 
     
     
         37 - 40 . (canceled) 
     
     
         41 . A kit of parts or composition or a chimaeric molecule, comprising (1) a modulating portion comprising or encoding an NF-κB inhibitor or inducer and (2) an antigenic portion comprising or encoding an antigenic molecule. 
     
     
         42 . The kit of parts to of  claim 41 , wherein the antigenic molecule comprises an epitope present on transformed or cancerous cells or on a pathogenic organism, or on a cell infected by a pathogenic organism, or a polypeptide expressed in a pathologic condition such as Alzheimer's disease or a spongiform encephalopathy. 
     
     
         43 . A vaccine effective against cancer or tumour cells, or against a pathogenic organism or cell infected with a pathogenic organism, or a disease characterised by expression of a polypeptide in a pathologic condition such as Alzheimer's disease or a spongiform encephalopathy comprising an effective amount of an NF-κB inducer or polynucleotide encoding an NF-κB inducer and further comprising an antigen or polynucleotide encoding an antigen, having an epitope present on the cancer or tumour cells, or the pathogenic organism or cell infected with a pathogenic organism or present in a polypeptide associated with a pathologic condition. 
     
     
         44 . (canceled) 
     
     
         45 . The vaccine of  claim 43 , wherein the vaccine is a nucleic acid vaccine. 
     
     
         46 . A pharmaceutical composition comprising an NF-κB inhibitor as defined in  claim 16  and a pharmaceutically acceptable carrier. 
     
     
         47 - 49 . (canceled) 
     
     
         50 . A method of killing target cells which aberrantly express an epitope in a patient, the method comprising the steps of (1) obtaining APCs, such as dendritic cells, from said patient; (2) contacting said APCs, such as dendritic cells, with an NF-κB inducer ex vivo; (3) optionally contacting said cells with the said epitope or with a polynucleotide or expression vector encoding the said epitope and (4) reintroducing the so treated APCs, such as dendritic cells, into the patient. 
     
     
         51 . A method of killing target cells in a patient according to  claim 50 , wherein the target cells are cancer cells. 
     
     
         52 - 57 . (canceled) 
     
     
         58 . A method of treating an allergy in a mammal, such as a human, comprising administering a pharmaceutically-effective dose of an NF-κB inhibitor to induce an anergic response in a mammal wherein the mammal, such as a human, is administered an antigenic molecule or polynucleotide encoding an antigenic molecule. 
     
     
         59 . The method according to  claim 2 , wherein the inhibitor is targeted to APCs such as dendritic cells or precursors thereof. 
     
     
         60 . The method according to  claim 2 , wherein APCs, such as dendritic cells or precursors thereof are exposed to the inhibitor in vitro and introduced into the mammal. 
     
     
         61 . The method according to  claim 2 , wherein the antigenic molecule comprises an epitope present on transformed or cancerous cells or on a pathogenic organism, or on a cell infected by a pathogenic organism, or a polypeptide expressed in a pathologic condition such as Alzheimer's disease or a spongiform encephalopathy. 
     
     
         62 . The method according to  claim 22 , wherein the inducer is targeted to APCs such as dendritic cells or precursors thereof. 
     
     
         63 . The method according to  claim 22 , wherein APCs, such as dendritic cells or precursors thereof are exposed to the inducer in vitro and introduced into the mammal. 
     
     
         64 . The method according to  claim 22 , wherein the antigenic molecule comprises an epitope present on transformed or cancerous cells or on a pathogenic organism, or on a cell infected by a pathogenic organism, or a polypeptide expressed in a pathologic condition as such as Alzheimer's disease or a spongiform encephalopathy. 
     
     
         65 . The method according to  claim 32 , wherein the inhibitor is targeted to APCs such as dendritic cells or precursors thereof. 
     
     
         66 . The method according to  claim 32 , wherein APCs, such as dendritic cells or precursors thereof are exposed to the inhibitor in vitro and introduced into the mammal. 
     
     
         67 . The method according to  claim 32 , wherein the antigenic molecule comprises an epitope present on transformed or cancerous cells or on a pathogenic organism, or on a cell infected by a pathogenic organism, or a polypeptide expressed in a pathologic condition such as Alzheimer's disease or a spongiform encephalopathy. 
     
     
         68 . The method according to  claim 33 , wherein the antigenic molecule comprises an epitope present on transformed or cancerous cells or on a pathogenic organism, or on a cell infected by a pathogenic organism, or a polypeptide expressed in a pathologic condition such as Alzheimer's disease or a spongiform encephalopathy. 
     
     
         69 . A polynucleotide encoding an antigenic molecule and an NF-κB inhibitor. 
     
     
         70 . The polynucleotide of  claim 69 , wherein the antigenic molecule comprises an epitope present on transformed or cancerous cells or on a pathogenic organism, or on a cell infected by a pathogenic organism, or a polypeptide expressed in a pathologic condition such as Alzheimer's disease or a spongiform encephalopathy. 
     
     
         71 . A polynucleotide encoding an antigenic molecule and an NF-κB inducer. 
     
     
         72 . The polynucleotide of  claim 71 , wherein the antigenic molecule comprises an epitope present on transformed or cancerous cells or on a pathogenic organism, or on a cell infected by a pathogenic organism, or a polypeptide expressed in a pathologic condition such as Alzheimer's disease or a spongiform encephalopathy. 
     
     
         73 . The kit of parts, composition or chimaeric molecule of  claim 41 , wherein the modulating portion comprises or encodes an NF-κB inducer. 
     
     
         74 . The kit of parts or composition or chimaeric molecule of  claim 41 , wherein the modulating portion comprises or encodes an NF-κB inducer. 
     
     
         75 . A pharmaceutical composition comprising an NF-κB inhibitor as defined in  claim 20  and a pharmaceutically acceptable carrier. 
     
     
         76 . A pharmaceutical composition comprising an NF-κB inhibitor as defined in  claim 43  and a pharmaceutically acceptable carrier. 
     
     
         77 . A pharmaceutical composition comprising a vaccine of  claim 69  and a pharmaceutically acceptable carrier. 
     
     
         78 . A pharmaceutical composition comprising a polynucleotide of  claim 71  and a pharmaceutically acceptable carrier.