Methods and compositions relating to modulation of hepatocyte growth, plasma cell differentiation or T cell subset activity by modulation of XBP-1 activity

Abstract

The invention demonstrates that the transcription factor XBP-1 is a regulator of hepatocyte growth, plasma cell differentiation and T cell subset activity. Methods for identifying modulators of hepatocyte growth, plasma cell differentiation and/or T cell subset activity, using XBP-1-containing indicator compositions or XBP-1-deficient cells, are provided. Methods of modulating hepatocyte growth, plasma cell differentiation and/or T cell subset activity (e.g., Th2 cytokine production) using agents that modulate the activity of XBP-1 are also provided. Methods for diagnosing disorders associated with aberrant hepatocyte growth, plasma cell differentiation and/or T cell subset activity, by assessing a change in XBP-1 expression, are also provided. XBP-1 deficient cells, animals and embryos, as well as kits for the methods of the invention, are also provided by the invention.

1 . A method of identifying a compound that modulates hepatocyte growth or plasma cell differentiation or T cell subset activity comprising:
 a) contacting hepatocytes or B cells or T cells deficient in XBP-1 with a test compound; and   b) determining the effect of the test compound on the growth of the hepatocytes or differentiation of the B cells into plasma cells or Th2 cytokine production by the T cells, the test compound being identified as a modulator of hepatocyte growth or plasma cell differentiation or T cell subset activity based on the ability of the test compound to modulate the growth of the hepatocytes or differentiation of the B cells or Th2 cytokine production by the T cells deficient in XBP-1.   
     
     
         2 . The method of  claim 1 , wherein the cells deficient in XBP-1 are in a non-human XBP-1 deficient animal and the cells are contacted with the test compound by administering the test compound to the non-human XBP-1 deficient animal. 
     
     
         3 . The method of  claim 2 , wherein the non-human XBP-1 deficient animal is a mouse. 
     
     
         4 . The method of  claim 1 , wherein the cells deficient in XBP-1 are isolated from a non-human XBP-1 deficient animal, or embryo thereof, and the cells are contacted with the test compound by culturing the test compound with the isolated cells deficient in XBP-1. 
     
     
         5 . The method of  claim 1 , wherein the compound stimulates hepatocyte growth or plasma cell differentiation or Th2 cytokine production 
     
     
         6 . A method for modulating growth of hepatocytes or differentiation of plasma cells or T cell subset activity, comprising contacting hepatocytes or plasma cell precursors or T cells with a modulator of XBP-1 activity such that growth of the hepatocytes or differentiation of plasma cells or Th2 cytokine production by the T cells is modulated. 
     
     
         7 . The method of  claim 6 , wherein the modulator inhibits XBP-1 activity. 
     
     
         8 . The method of  claim 7 , wherein the modulator is an antisense oligonucleotide. 
     
     
         9 . The method of  claim 7 , wherein the modulator is an intracellular antibody. 
     
     
         10 . The method of  claim 6 , wherein the modulator stimulates XBP-1 activity. 
     
     
         11 . The method of  claim 6 , wherein the modulator is an expression vector encoding XBP-1. 
     
     
         12 . The method of  claim 6 , wherein the hepatocytes or plasma cell precursors or T cells are contacted with the modulator by culturing the hepatocytes or plasma cell precursors or T cells in vitro with the modulator. 
     
     
         13 . The method of  claim 12 , wherein the hepatocytes or plasma cell precursors or T cells are contacted with a modulator that stimulates XBP-1 activity such growth of the hepatocytes or differentiation of the plasma cell precursors into plasma cells or Th2 cytokine production by the T cells is stimulated, the method further comprising administering the hepatocytes or plasma cells or T cells to a subject after stimulation in vitro.