Il-21 as a regulator of immunoglobin production

Abstract

A transgenic mouse is disclosed herein whose somatic and germ cells comprise a disrupted IL-21 receptor gene, the disruption being sufficient to inhibit the binding of IL-21 to an IL-21 receptor, and a disrupted IL-4 gene, the disruption being sufficient to inhibit the production of IL-4 or the binding of IL-4 to the IL-4 receptor. A mouse homozygous for the disrupted IL-21 receptor gene and homozygous for the disrupted IL-4 gene has diminished B cell function. A method is disclosed for altering a B cell activity. The method includes administering a therapeutically effective amount of an agent that interferes with the interaction of IL-21 with an IL-21 receptor, thereby altering the B cell activity. A method is also disclosed for of treating a subject with Job's disorder or atopic disease. A method is also disclosed for treating or preventing an allergic reaction in a subject. A method is also disclosed for treating a subject with an autoimmune or antibody mediated disorder.

1 . A transgenic mouse whose somatic and germ cells comprise a disrupted IL-21 receptor gene, the disruption being sufficient to inhibit the binding of IL-21 to an IL-21 receptor, and a disrupted IL-4 gene, the disruption being sufficient to inhibit the production of IL-4 or the binding of IL-4 to the IL-4 receptor, the disrupted IL-21 receptor and IL-4 genes being introduced into the mouse or an ancestor of the mouse at an embryonic stage, wherein a mouse homozygous for the disrupted IL-21 receptor gene and homozygous for the disrupted IL-4 gene has diminished B cell function. 
     
     
         2 . The transgenic mouse of  claim 1 , wherein the mouse has pan-hypogammaglobulinemia. 
     
     
         3 . The transgenic mouse of  claim 1 , wherein the mouse is deficient in the production of an immunoglobulin. 
     
     
         4 . The transgenic mouse of  claim 3 , wherein the immunoglobulin is an IgG1, IgG2a, IgG2b, or IgG3. 
     
     
         5 . The transgenic mouse of  claim 3 , wherein the immunoglobulin is IgE. 
     
     
         6 . The transgenic mouse of  claim 1 , wherein the genome of the transgenic mouse is heterozygous for an engineered disruption in an IL-21 receptor gene and heterozygous for an engineered disruption in an IL-4 gene, wherein the engineered IL-21 receptor gene and the engineered IL-4 gene in a homozygous state inhibits production of a functional IL-21 receptor and a functional IL-4. 
     
     
         7 . The transgenic mouse of  claim 6 , wherein the immunoglobulin is an IgG. 
     
     
         8 . The transgenic mouse of  claim 6 , wherein the immunoglobulin is an IgE. 
     
     
         9 . A method of altering a B cell activity, comprising
 contacting a B cell with an effective amount of an agent that interferes with at least one of (i) an interaction of IL-21 with an IL-21 receptor and (ii) activity of an IL-21 induced signaling pathway, thereby altering the B cell activity.   
     
     
         10 . The method of  claim 9 , wherein the B cell activity is production of an immunoglobulin. 
     
     
         11 . The method of  claim 10 , wherein the immunoglobulin is an IgG, an IgA, an IgM or an IgE. 
     
     
         12 . The method of  claim 11 , wherein the IgG is an IgG1, an IgG2a, an IgG2b or an IgG3. 
     
     
         13 . The method of  claim 11 , wherein the IgG is an IgG1, an IgG2, and IgG3 or an IgG4. 
     
     
         14 . The method of  claim 9 , wherein the agent is selected from the group consisting of an antagonist of IL-21, an antagonist of the IL-21 receptor and an antagonist of an IL-21 induced signaling pathway. 
     
     
         15 . The method of  claim 9 , wherein the agent is:
 (a) an antagonist of IL-21 or the IL-21 receptor;   (b) a soluble IL21 receptor;   (c) a peptide that binds the IL-21 receptor;   (d) a small molecule that binds the IL-21 receptor;   (e) an antibody that specifically binds IL-21 or the IL-21 receptor and inhibits the interaction of IL-21 with its receptor; or,   (f) an antisense nucleic acid, a small inhibitory RNA, or a ribozyme that specifically binds a nucleic acid encoding IL-21, the IL-21 receptor or a protein required for IL-21 induced signaling.   
     
     
         16 . The method of  claim 9 , further comprising contacting the cell with an effective amount of an agent that interferes with the interaction of IL-4 with an IL-4 receptor or with IL-4 induced signaling. 
     
     
         17 . The method of  claim 16 , wherein the agent is:
 (a) an antagonist of IL-4 or the IL-4 receptor;   (b) a soluble IL-4 receptor;   (c) a peptide that binds the IL-4 receptor;   (d) a small molecule that binds the IL-4 receptor;   (e) an antibody that specifically binds IL-4 or the IL-4 receptor and inhibits the interaction of IL-4 with its receptor; or,   (f) an antisense nucleic acid, a small inhibitory RNA, or a ribozyme that specifically binds a nucleic acid encoding IL-4, the IL-4 receptor or a protein required for IL-4 induced signaling.   
     
     
         18 . The method of  claim 9 , wherein the B cell is in vitro. 
     
     
         19 . The method of  claim 9 , wherein the B cell is in a subject. 
     
     
         20 . The method of  claim 19 , wherein the subject is a human subject. 
     
     
         21 . The method of  claim 19 , wherein the subject has:
 (a) an autoimmune disorder;   (b) an antibody mediated disorder;   (c) an allergic disorder; or,   (d) an atopic disorder.   
     
     
         22 . The method of  claim 21 , wherein the subject has systemic lupus erythematosus, rheumatoid arthritis, myasthenia gravis, insulin-dependent diabetes mellitus, Hashimoto's thyroiditis, Graves disease, idiopathic thrombocytopenia purpura, hypertrophic cardiomyopathy, pernicious anemia, Goodpasture's syndrome, IgA nephropathy, autoimmune hepatitis, chronic active hepatitis, primary biliary cirrhosis, pemphigus, vitiligo, dermatitis herpetiformis, vitiligo, autoimmune astritis, autoimmune bowel disease, Addison's disease, Sjogren's syndrome, uveitis, or multiple sclerosis. 
     
     
         23 . A method of treating a subject with Job's disorder or atopic disease, comprising administering to the subject a therapeutically effective amount of IL-21 or an agonist thereof, thereby ameliorating a sign or a symptom of Job's disorder or atopic disease. 
     
     
         24 . The method of  claim 23 , wherein the agonist is a small molecule that binds to IL-21 or the IL-21 receptor. 
     
     
         25 . A method of treating or preventing an allergic reaction in a subject, comprising administering to the subject a therapeutically effective amount of an agent that inhibits the interaction of IL-21 with its receptor or inhibits IL-21 induced signaling, thereby treating or preventing the allergic reaction. 
     
     
         26 . The method of  claim 25 , wherein the agent is:
 (a) an antagonist of IL-21 or the IL-21 receptor;   (b) a soluble IL-21 receptor;   (c) a peptide that binds the IL-21 receptor;   (d) a small molecule that binds the IL-21 receptor;   (e) an antibody that specifically binds IL-21 or the IL-21 receptor and inhibits the interaction of IL-21 with its receptor; or,   (f) an antisense nucleic acid, a small inhibitory RNA, or a ribozyme that specifically binds a nucleic acid encoding IL-21, the IL-21 receptor or a protein required for IL-21 induced signaling.   
     
     
         27 . The method of  claim 25 , further comprising administering to the subject a therapeutically effective amount of an agent that inhibits the interaction of IL-4 with its receptor or inhibits an IL-4 induced signaling pathway. 
     
     
         28 . The method of  claim 27 , wherein the agent is:
 (a) an antagonist of IL-4 or the IL-4 receptor;   (b) a soluble IL-4 receptor;   (c) a peptide that binds the IL-4 receptor;   (d) a small molecule that binds the IL-4 receptor;   (e) an antibody that specifically binds IL-4 or the IL-4 receptor and inhibits the interaction of IL-4 with its receptor; or,   (f) an antisense nucleic acid, a small inhibitory RNA, or a ribozyme that 10 specifically binds a nucleic acid encoding IL-4, the IL-4 receptor or a protein required for IL-4 induced signaling.   
     
     
         29 . A method of treating an IL-4 mediated disorder in a subject, comprising administering to the subject a therapeutically effective amount of IL-21 or an agonist thereof. 
     
     
         30 . The method of  claim 29 , wherein the IL-4 mediated disorder is an allergic disorder or an atopic disorder. 
     
     
         31 . The method of  claim 30 , wherein the IL-4 mediated disorder is selected from the group consisting of allergic inflammation, allergic rhinitis, allergic conjunctivitis, respiratory allergy, atopic dermatitis, eczema and asthma.