T Cell Regulatory Genes And Methods Of Use Thereof

Abstract

A genetic locus and corresponding family of proteins associated with regulation of immune function and cell survival are provided. These genes encode cell surface molecules with conserved IgV and mucin domains. The locus comprising the TIM family is genetically associated with immune dysfunction, including asthma. Furthermore, the TIM gene family is located within a region of human chromosome 5 that is commonly deleted in malignancies and myelodysplastic syndrome. Polymorphisms in the gene sequences are associated with the development of airway hyperreactivity and allergic inflammation, and T cell production of IL-4 and IL-13. The proteins include the human hepatitis A cellular receptor, hHAVcr-1.

1 . An isolated nucleic acid molecule comprising a mammalian TIM gene sequence. 
     
     
         2 . An isolated nucleic acid molecule according to  claim 1 , wherein said mammalian TIM gene sequence is a human sequence selected from the group consisting of alleles 2, 3, 4, 5, and 6 of TIM-1, TIM-3, and TIM-4. 
     
     
         3 . An isolated nucleic acid according to  claim 1 , wherein said mammalian TIM gene sequence is a mouse sequence selected from the group consisting of TIM-1, TIM-2, TIM-3 and TIM-4. 
     
     
         4 . An isolated nucleic acid comprising at least 20 nucleotides of contiguous sequence as set forth in any one of SEQ ID NO:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34 or 36. 
     
     
         5 . An isolated nucleic acid comprising a sequence as set forth in any one of SEQ ID NO:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34 or 36. 
     
     
         6 . An isolated nucleic acid molecule according to  claim 1 , comprising a probe for detection of a TIM gene polymorphism. 
     
     
         7 . An array of oligonucleotides comprising:
 two or more probes according to  claim 6 .   
     
     
         8 . A cell comprising a nucleic acid composition according to  claim 1 . 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . An antibody specific for a mammalian TIM polypeptide. 
     
     
         12 . A method for detecting a predisposition to asthma in an individual, the method comprising:
 analyzing said individual for the presence of at least one predisposing TIM polymorphism; wherein the presence of said predisposing polymorphism is indicative of an increased susceptibility to asthma.   
     
     
         13 . The method according to  claim 12 , wherein said analyzing step comprises detection of specific binding between genomic DNA or mRNA of said individual with a probe or probes according to  claim 6 . 
     
     
         14 . The method according to  claim 12 , wherein said analyzing step comprises detection of specific binding between cells or protein from said individual and the antibody according to  claim 11 . 
     
     
         15 . A non-human transgenic animal model for TIM gene function comprising a knockout of a TIM gene. 
     
     
         16 . A method of screening for biologically active agents that modulate
 TIM function, the method comprising:   combining a candidate biologically active agent with any one of:   (a) a mammalian TIM polypeptide;   (b) a cell comprising a nucleic acid encoding a mammalian TIM polypeptide; or   (c) a non-human transgenic animal model for TIM gene function; and determining the effect of said agent on TIM function.   
     
     
         17 . The method according to  claim 16 , wherein said biologically active agent downregulates or upregulates TIM expression. 
     
     
         18 . The method according to  claim 16 , wherein said biologically active agent inhibits or increases activity of said TIM polypeptide. 
     
     
         19 . A method for the diagnosis or staging of immune dysfunction in an individual, the method comprising:
 analyzing said individual for the presence of at least one predisposing TIM polymorphism; wherein the presence of said predisposing polymorphism is indicative of an increased susceptibility to said immune dysfunction.   
     
     
         20 . A method for the diagnosis or staging of cancer in an individual, the method comprising:
 analyzing said individual for the presence of at least one predisposing TIM polymorphism; wherein the presence of said predisposing polymorphism is indicative of an increased resistance to cancer therapy.   
     
     
         21 . A method for the diagnosis or staging of cancer in an individual, the method comprising:
 analyzing said individual for the presence of at least one predisposing TIM-1 expression profile; wherein the expression profile of TIM-1 indicative of an increased resistance to cancer therapy.   
     
     
         22 . A method for the diagnosis or staging of cancer in an individual, the method comprising:
 analyzing said individual for the presence of at least one predisposing TIM-4 expression profile; wherein the expression profile of TIM-4 indicative of an increased resistance to cancer therapy.   
     
     
         23 . A method for the treatment of an immunological disorder in an individual, the method comprising:
 administering to said individual an agent that modulates function of a TIM polypeptide.   
     
     
         24 . The method according to  claim 23 , wherein said TIM polypeptide is TIM-1 or TIM-4. 
     
     
         25 . The method according to  claim 24 , wherein said agent is an antibody or antibody fragment specific for TIM-1. 
     
     
         26 . The method according to  claim 24 , wherein said agent is a compound that inhibits TIM-1 function. 
     
     
         27 . The method according to  claim 24 , wherein said immunological disorder is asthma. 
     
     
         28 . The method according to  claim 24 , wherein said immunological disorder is an allergy. 
     
     
         29 . The method according to  claim 24 , wherein said immunological disorder is eczema. 
     
     
         30 . The method according to  claim 24 , wherein said immunological disorder is an autoimmune disease. 
     
     
         31 . The method according to  claim 23 , wherein said agent is an antibody or antibody fragment specific for TIM-4. 
     
     
         32 . The method according to  claim 30 , wherein said agent is a compound that inhibits the function of TIM-4. 
     
     
         33 . A method for the treatment of malignancy in an individual, the method comprising: administering to said individual an agent that modulates function of a TIM polypeptide. 
     
     
         34 . The method according to  claim 33 , wherein said TIM polypeptide is TIM-1. 
     
     
         35 . The method according to  claim 34 , wherein said agent is an antibody or antibody fragment specific for TIM-1. 
     
     
         36 . The method according to  claim 35 , wherein said agent is a compound that inhibits the function of TIM-1 and potentiates the effect of chemotherapeutic agents or radiation therapy. 
     
     
         37 . The method according to  claim 33 , wherein said TIM polypeptide is TIM-4. 
     
     
         38 . The method according to  claim 37 , wherein said agent is an antibody or antibody fragment specific for TIM-4. 
     
     
         39 . The method according to  claim 38 , wherein said agent is a compound that inhibits the function of TIM-4 and potentiates the effect of chemotherapeutic agents or radiation therapy. 
     
     
         40 . (canceled)