Methods of treating systemic graft- versus-host disease with extracellular vesicles

Abstract

The present invention relates to a method of treating acute or chronic systemic graft-versus-host disease (GVHD) with extracellular vesicles, e.g., exosomes obtained from human cardiospheres or cardiosphere-derived cells (CDCs), wherein systemic GVHD involves, e.g., at least two organs selected from the group consisting of the skin, mucosa, gastrointestinal tract, liver, lungs, joints and fascia, genitalia, and eyes. The present invention also provides a pharmaceutical formulation comprising extracellular vesicles, e.g., exosomes obtained from human cardiospheres or CDCs, for systemic administration, e.g., intravenous infusion, to a human subject in need of treatment of systemic GVHD.

1 . A method of modulating T cells, the method comprising contacting T cells with an effective amount of extracellular vesicles derived from cardiosphere-derived cells (CDCs). 
     
     
         2 . The method of  claim 1 , wherein proliferation of said contacted T cells is down regulated. 
     
     
         3 . The method of  claim 1 , wherein expression of CDC69 is down regulated in said contacted T cells. 
     
     
         4 . The method of  claim 1 , wherein expression of HLA-DR is down regulated in said contacted T cells. 
     
     
         5 . The method of  claim 1 , wherein expression of CDC69 and expression of HLA-DR are down regulated in said contacted T cells. 
     
     
         6 . The method of  claim 1 , wherein the T cells comprise CD3+ T cells. 
     
     
         7 . The method of  claim 1 , wherein the T cells comprise CD4+ or CD8+ T cells. 
     
     
         8 . The method of  claim 1 , wherein the extracellular vesicles express HLA class I molecules and do not express HLA II molecules. 
     
     
         9 . The method of  claim 1 , wherein the extracellular vesicles express CD86 and do not express CD80. 
     
     
         10 . The method of  claim 1 , wherein the extracellular vesicles express HLA class I and CD86 molecules and do not express HLA II and CD80 molecules. 
     
     
         11 . The method of  claim 1 , wherein the extracellular vesicles express PD-LI and do not express ICOS-L. 
     
     
         12 . The method of  claim 1 , wherein the extracellular vesicles express NK activating receptor ligands. 
     
     
         13 . The method of  claim 1 , wherein the extracellular vesicles express NK activating receptor ligands, PD-L1, CD86, and HLA class I molecules. 
     
     
         14 . The method of  claim 13 , wherein the extracellular vesicles do not express CD80, ICOS-L, and HLA II molecules. 
     
     
         15 . The method of  claim 1 , wherein the effective amount of the extracellular vesicles is 5×10 9  to 20×10 9  extracellular vesicle particles. 
     
     
         16 . The method of  claim 1 , wherein the T cells are in vivo and said contacting comprises administering said effective amount of extracellular vesicles to a subject. 
     
     
         17 . The method of  claim 16 , wherein the subject had received hematopoietic stem cell transplant (HSCT). 
     
     
         18 . The method of  claim 17 , wherein said effective amount of extracellular vesicles is administered one or more times after the subject had undergone HSCT. 
     
     
         19 . The method according to  claim 17 , wherein said effective amount of extracellular vesicles is administered 1, 2, 3, 4, 5, 6, 7, or 8 weeks after HSCT. 
     
     
         20 . The method according to  claim 17 , wherein said effective amount of extracellular vesicles is administered in multiple administrations made 7 days apart between successive administrations.