Methods of use of the TACI/TACI-L interaction

Abstract

The invention discloses a novel interaction between a TNF receptor (TACI) and its interacting ligand (TACI-L). Also disclosed are methods of screening candidate molecules to determine potential antagonists and agonists of the TACI/TACI-L interaction. The use of the antagonists and agonists as therapeutics to treat autoimmune diseases, inflammation, and to inhibit graft vs. host rejections is further disclosed.

What is claimed:  
     
         1 . A method of screening a candidate molecule to identify its ability to inhibit or prevent the dissociation of a TACI/TACI-L complex, said method comprising the steps of: 
 a. forming said TACI/TACI-L complex or a TACI/TACI-L fragment complex in the absence of said candidate molecule;    b. adding said candidate molecule to a medium containing said TACI/TACI-L complex or said TACI/TACI-L fragment complex;    c. changing the conditions of said medium so that, but for the presence of said candidate molecule, said TACI or TACI fragments, would be released from the complex;    d. measuring the concentration of free or bound said TACI, TACI-L or fragments thereof; and    e. determining the dissociation constant of said TACI/TACI-L complex or said TACI/TACI-L fragment complex and comparing said constant to a dissociation constant of a TACI/TACI-L complex or TACI/TACI-L fragment complex measured in a medium not containing the candidate molecule.    
     
     
         2 . A method of screening a candidate molecule to identify its ability to inhibit a TACI/TACI-L complex, said method comprising the steps of: 
 a. adding TACI to a medium containing TACI-L and said candidate molecule, wherein one of either said TACI or said TACI-L is labeled and the other is bound;    b. measuring the level of signal produced; and    c. comparing the level of signal produced in step (b) to the level of signal produced by a TACI/TACI-L complex or TACI/TACI-L fragment complex formed with said labeled TACI or TACI-L in the absence of said candidate molecule;    wherein diminished levels of signal produced in step (b) indicate that said candidate molecule inhibited said TACI/TACI-L complex.    
     
     
         3 . A method of screening a candidate molecule to identify its ability to mimic the biological activity of the TACI/TACI-L complex, said method comprising the steps of: 
 a. determining if said candidate molecule binds to TACI, TACI-L or fragments thereof;    b. adding said candidate molecule to a biological assay to determine its biological effects; and    c. comparing said biological effects of said candidate molecule with the biological effects of said TACI/TACI-L complex or a TACI/TACI-L fragment complex.    
     
     
         4 . A method of screening a candidate molecule to identify its ability to be useful in the treatment of diseases modulated by the TACI/TACI-L complex, said method comprising the steps of: 
 a. forming said TACI/TACI-L complex or a TACI/TACI-L fragment complex in the absence of said candidate molecule;    b. adding said candidate molecule to a medium containing said TACI/TACI-L complex or said TACI/TACI-L fragment complex;    c. changing the conditions of said medium so that, but for the presence of said candidate molecule, said TACI or TACI fragments, would be released from said TACI/TACI-L complex or said TACI/TACI-L fragment complex;    d. measuring the concentration of free or bound said TACI, TACI-L or fragments thereof; and    e. determining the dissociation constant of said TACI/TACI-L complex or said TACI/TACI-L fragment complex and comparing said constant to a dissociation constant of a TACI/TACI-L complex or TACI/TACI-L fragment complex measured in a medium not containing the candidate molecule.    
     
     
         5 . A method of screening a candidate molecule to identify its ability to be useful in the treatment of diseases modulated by the TACI/TACI-L complex, said method comprising the steps of: 
 a. adding TACI to a medium containing TACI-L and said candidate molecule, wherein one of either said TACI or said TACI-L is labeled and the other is bound;    b. measuring the level of signal produced; and    c. comparing the level of signal produced in step (b) to the level of signal produced by a TACI/TACI-L complex or TACI/TACI-L fragment complex formed with said labeled TACI or TACI-L in the absence of said candidate molecule.    
     
     
         6 . A method of screening a candidate molecule to identify its ability to be useful in the treatment of diseases modulated by the TACI/TACI-L complex, said method comprising the steps of: 
 a. determining if said candidate molecule binds to TACI or TACI-L;    b. adding said candidate molecule to a biological assay to determine its biological effects; and    c. comparing the biological effects of said candidate molecule with the biological effects of said TACI/TACI-L complex or a TACI/TACI-L fragment complex.    
     
     
         7 . The method of any one of claims  1  through  6  in which the candidate molecule is selected from a group consisting of a small molecule, antibody, or peptide.  
     
     
         8 . The method of claims  1 ,  3 ,  4  or  6 , in which either TACI or TACI-L, or fragments thereof, is labeled.  
     
     
         9 . The method of any one of claims  1  through  6 , in which at least one fragment of said TACI/TACI-L fragment complex is soluble.  
     
     
         10 . The method of any one of claims  1  through  6 , in which said TACI/TACI-L complex is comprised of the sequence of SEQ. ID. NO.:2 and the sequence of SEQ. ID. NO.:4.  
     
     
         11 . A method of screening a candidate molecule to identify its ability to inhibit (antagonize) or agonize a TACI/TACI-L complex, said method comprising the steps of: 
 (a) adding said candidate molecule to a medium which contains cells expressing TACI and cells expressing TACI-L;    (b) changing the conditions of said medium so that, but for the presence of said candidate molecule, said TACI/TACI-L complex and/or a TACI/TACI-L fragment complex would be formed;    (c) determining the level of biological activity of said TACI/TACI-L complex and/or said TACI/TACI-fragment complex formed in said medium; and    (d) comparing the level of biological activity of step (c) with the level of biological activity that occurs in said medium in the absence of said candidate molecule.    
     
     
         12 . An antagonist as identified by the method of  claim 11 .  
     
     
         13 . An agonist as identified by the method of  claim 11 .  
     
     
         14 . A method of modulating an intracellular signaling cascade mediated by the TACI/TACI-L complex in a mammal comprising administering to such a mammal an effective amount of an agonist or an antagonist of the TACI/TACI-L complex.