Compositions and methods for preventing and treating graft versus host disease

Abstract

ILC2 cells play a role in the pathogenesis of graft versus host disease (GvHD) and idiopathic pneumonia syndrome (IPS), both conditions associated with allogeneic stem cell transplantation. Infusion of IL-33 activated ILC2 cells into patients with ongoing GvHD or IPS, or prior to onset of GvHD or IPS in susceptible patients, substantially ameliorates the disease and improves survival.

1 . A pharmaceutical composition for treating graft versus host disease (GvHD) or idiopathic pneumonia syndrome (IPS), the composition comprising:
 a therapeutically effective amount of a cell preparation of IL-33 activated type 2 innate immune cells (ILC2); and   a pharmaceutically acceptable carrier.   
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the ILC2 cells have the following properties:
 test positive for expression of lymphoid marker CD90;   test positive for expression of lymphoid marker ICOS; and   test negative for expression of lympohoid marker lin.   
     
     
         3 . The pharmaceutical composition of  claim 2 , wherein the ILC2 cells test positive for expression of CD127, ST2, Sca-1, CD25, CD90, and ICOS, and test negative for expression of lin. 
     
     
         4 . The pharmaceutical composition of  claim 3 , wherein the ILC2 cells are activated by cytokines IL-33, IL-25, IL-7 and/or combinations thereof. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the ILC2 cells are derived from human cord blood cells. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition is substantially free of MPP2 cells. 
     
     
         7 . An in vitro method for generating activated ILC2 cells, comprising:
 collecting human cord blood from a subject;   isolating c-Kit positive cells from the cord blood; and   culturing the c-Kit positive cells in the presence of an IL-33 cytokine, whereby IL-33 activated ILC2 cells are generated.   
     
     
         8 . The method of  claim 7 , wherein the ILC2 cells are activated by exposing the c-Kit positive cells in culture to cytokines IL-33, IL-25, IL-7 and/or combinations thereof. 
     
     
         9 . The method of  claim 7 , further comprising analyzing the generated ILC2 cells by measuring expression of ST2 and CD127 in the ILC2 cells, whereby expression of ST2 and CD127 is indicative of the phenotype of ILC2 cells. 
     
     
         10 . The method of  claim 7 , wherein the ILC2 cells are substantially free of MPP2 cells. 
     
     
         11 . The method of  claim 7 , wherein the subject is a human patient or donor. 
     
     
         12 . A composition comprising activated ILC2 cells produced by the method of  claim 7 . 
     
     
         13 . A method for treating graft versus host disease (GvHD) or idiopathic pneumonia syndrome (IPS) in a subject, comprising:
 providing a subject in need of treatment for GvHD and/or IPS; and   administering to the subject a therapeutically effective amount of a cell preparation of IL-33 activated ILC2 cells.   
     
     
         14 . The method of  claim 13 , wherein the ILC2 cells have the following properties:
 test positive for expression of lymphoid marker CD90;   test positive for expression of lymphoid marker ICOS; and   test negative for expression of lympohoid marker lin.   
     
     
         15 . The method of  claim 14 , wherein the ILC2 cells test positive for expression of CD127, ST2, Sca-1, CD25, CD90, and ICOS, and test negative for expression of lin. 
     
     
         16 . The method of  claim 13 , wherein the subject is a human subject receiving an allogeneic stem cell transplant (allo-SCT) or allogeneic bone marrow transplant (allo-BMT). 
     
     
         17 . The method of  claim 13 , wherein the cell preparation of IL-33 activated ILC2 cells is administerd to the subject within 1 to 30 days after receiving the allo-SCT or allo-BMT. 
     
     
         18 . The method of  claim 13 , wherein the risk and/or severity of acute GVHD associated with allo-SCT or allo-BMT is reduced. 
     
     
         19 . The method of  claim 13 , wherein the cell preparation of IL-33 activated ILC2 cells is administered as a co-infusion with the allo-SCT or allo-BMT. 
     
     
         20 . The method of  claim 13 , wherein production of Th2 cytokines in the subject is increased, and/or production of Th1 and/or Th17 cytokines in the subject is decreased. 
     
     
         21 . A method for preventing GvHD or IPS in a subject, comprising:
 providing a subject receiving allo-SCT or allo-BMT; and   administering to the subject a therapeutically effective amount of a cell preparation of IL-33 activated ILC2 cells.   
     
     
         22 . The method of  claim 21 , wherein the cell preparation of IL-33 activated ILC2 cells is administered as a co-infusion with the allo-SCT or allo-BMT. 
     
     
         23 . The method of  claim 22 , wherein the co-infusion of ILC2 cells with the allo-SCT or allo-BMT comprises infusion of the ILC2 cells at a time sufficiently proximate to the allo-SCT or allo-BMT to prevent or substantially prevent onset of GvHD or IPS. 
     
     
         24 . The method of  claim 21 , wherein the ILC2 cells have the following properties:
 test positive for expression of lymphoid marker CD90;   test positive for expression of lymphoid marker ICOS; and   test negative for expression of lympohoid marker lin.   
     
     
         25 . The method of  claim 24 , wherein the ILC2 cells test positive for expression of CD127, ST2, Sca-1, CD25, CD90, and ICOS, and test negative for expression of lin. 
     
     
         26 . The method of  claim 21 , wherein production of Th2 cytokines in the subject is increased, and/or production of Th1 and/or Th17 cytokines in the subject is decreased. 
     
     
         27 . A method of increasing production of Th2 cytokines in a subject, comprising:
 providing a subject in need of increased Th2 cytokine production; and   administering to the subject a therapeutically effective amount of a cell preparation of IL-33 activated ILC2 cells.   
     
     
         28 . The method of  claim 27 , wherein the subject comprises a human subject receiving allo-SCT or allo-BMT. 
     
     
         29 . The method of  claim 27 , wherein production of Th1 and/or Th17 cytokines is decreased in the subject. 
     
     
         30 . The method of  claim 27 , wherein the ILC2 cells have the following properties:
 test positive for expression of lymphoid marker CD90;   test positive for expression of lymphoid marker ICOS; and   test negative for expression of lympohoid marker lin.   
     
     
         31 . The method of  claim 30 , wherein the ILC2 cells test positive for expression of CD127, ST2, Sca-1, CD25, CD90, and ICOS, and test negative for expression of lin.