Methods for use of TSLP and agonists and antagonists thereof

Abstract

Methods are disclosed herein for specifically inducing proliferation of CD4 + T cells. The methods are of use in treating immunodeficiencies, such as an immunodeficiency produced by infection with an immunodeficiency virus, such as infection with a human immunodeficiency virus (HIV). The methods include contacting isolated mammalian CD4+ T cells with an effective amount of a thymic stromal derived lymphopoietin (TSLP) polypeptide or a therapeutically effective amount of nucleic acid encoding the TSLP polypeptide, thereby inducing proliferation of the T cells. Methods are also disclosed for treating an IgE mediated disorder, such as asthma. The methods include administering to a subject a therapeutically effective amount of a TSLP antagonist. Transgenic mice are also disclosed herein. The somatic and germ cells of these mice include a disrupted thymic stromal lymphopoietin receptor (TSLP) gene, the disruption being sufficient to inhibit the interaction of TSLP with its receptor, and a disrupted γ c gene, the disruption being sufficient to reduce signaling through the γ c . The mice exhibit diminished thymic cellularity. Methods of using these mice for drug screening are also disclosed.

1 . A method for inducing proliferation of CD4+ T cells, comprising contacting isolated CD4+ T cells with an effective amount of a thymic stromal derived lymphopoietin (TSLP) polypeptide or a therapeutically effective amount of nucleic acid encoding the TSLP polypeptide, thereby inducing proliferation of the T cells.  
     
     
         2 . The method of  claim 1 , wherein the method comprises contacting isolated mammalian CD4+ T cells with an effective amount of the TSLP polypeptide.  
     
     
         3 . The method of  claim 1 , wherein the TSLP polypeptide comprises an amino acid sequence set forth as one of SEQ ID NOs: 1-5, amino acids 29 to 159 of SEQ ID NO: 1, or amino acids 35 to 159 of SEQ ID NO: 1.  
     
     
         4 . A method of inducing or enhancing an immune response in a subject, comprising 
 contacting isolated CD4+ T cells with a therapeutically effective amount of a TSLP polypeptide;    and administering the CD4+ T cells contacted with the TSLP polypeptide to the subject    thereby treating the subject.    
     
     
         5 . The method of  claim 4 , wherein the subject has an immunodeficiency.  
     
     
         6 . The method of  claim 4 , wherein the TSLP polypeptide comprises a polypeptide set forth as one of SEQ ID NOs: 1-5, amino acids 29 to 159 of SEQ ID NO: 1, or amino acids 35 to 159 of SEQ ID NO: 1.  
     
     
         7 . The method of  claim 5 , wherein the immunodeficiency is the result of an infection with an immunodeficiency virus.  
     
     
         8 . The method of  claim 7 , wherein the subject is human, and wherein the immunodeficiency virus is a human immunodeficiency virus (HIV).  
     
     
         9 . The method of  claim 5 , the subject has an immunodeficiency as a result of a genetic disorder.  
     
     
         10 . The method of  claim 5 , wherein the immunodeficiency is a result of treatment with radiation, a chemotherapeutic agent, or a combination thereof.  
     
     
         11 . The method of  claim 4 , comprising contacting the CD4+ cells with at least one composition comprising an antigen.  
     
     
         12 . The method of  claim 11 , wherein the antigen comprises a viral antigen, a bacterial antigen, or an antigen from a parasite.  
     
     
         13 . A method of treating a subject with an immunodeficiency, comprising 
 administering to the subject with the immunodeficiency a therapeutically effective amount of thymic stromal derived lymphopoietin (TSLP) polypeptide, or a therapeutically effective amount of nucleic acid encoding the TSLP polypeptide, thereby treating the subject.    
     
     
         14 . The method of  claim 13 , wherein the subject is infected with an immunodeficiency virus.  
     
     
         15 . The method of  claim 14 , wherein the subject is a human and where the immunodeficiency virus is a human immunodeficiency virus (HIV).  
     
     
         16 . The method of  claim 13 , wherein the subject has an immunodeficiency as a result of a genetic disorder.  
     
     
         17 . The method of  claim 13 , wherein the immunodeficiency is a result of treatment with radiation, a chemotherapeutic agent, or a combination thereof.  
     
     
         18 . A method of treating a subject with an IgE-mediated disorder, comprising administering to the subject a therapeutically effective amount of a thymic stromal derived lymphopoietin (TSLP) antagonist, thereby treating the subject.  
     
     
         19 . The method of  claim 18 , wherein the IgE-mediated disorder is asthma.  
     
     
         20 . The method of  claim 18 , wherein the TSLP antagonist is an antibody that binds TSLP or the TSLP receptor.  
     
     
         21 . The method of  claim 20 , wherein the antibody is a humanized antibody.  
     
     
         22 . The method of  claim 18 , further comprising administering a therapeutically effective amount of an anti-infective agent, an anti-inflammatory agent, a bronchodilator, an enzyme, an expectorant, a leukotriene antagonist, a leukotriene formation inhibitor, or a mast cell stabilizer.  
     
     
         23 . The method of  claim 18 , wherein the TSLP antagonist is administered by inhalation.  
     
     
         24 . The method of  claim 18 , wherein the disorder is rhino-conjunctivitis or allergic dermatitis.