Combined therapy of alpha-1-antitrypsin and temporal t-cell depletion for preventing graft rejection

Abstract

The present invention provides compositions and methods for the prevention and treatment of aggressive immune processes to life-saving grafts, such as xenograft rejection, and for attenuating host responses in transplantation of tissues, cells and organs. More specifically, the compositions and methods of the present invention relate to combined therapies comprising treatment of alpha-1-antitrypsin (AAT) and temporary T-cell depletion including but not limited to anti-CD4 and anti-CD8 antibodies.

1 . A composition comprising: (a) alpha-1-antitrypsin (AAT); and (b) anti-CD4 antibody, anti-CD8 antibody, or their combination. 
     
     
         2 . A method of preventing or treating xenotransplant rejection in a subject in need thereof, the method comprising administering a therapeutically effective amount of alpha-1-antitrypsin (AAT) in combination with a therapeutically effective amount of at least one temporary T cell depleting agent. 
     
     
         3 . The method of  claim 2 , wherein the at least one temporary T cell depleting agent is selected from anti-CD4 and anti-CD8 antibodies or antigen binding fragments thereof. 
     
     
         4 . The method of  claim 2 , wherein the at least one temporary T cell depleting agent is anti-CD4 antibodies or antigen binding fragments thereof. 
     
     
         5 . The method of  claim 2 , wherein the at least one temporary T cell depleting agent is anti-CD8 antibodies or antigen binding fragments thereof. 
     
     
         6 . The method of  claim 2 , wherein the temporary T cell depleting agent is administered prior to transplantation. 
     
     
         7 . The method of  claim 2 , wherein said temporary T cell depleting agent is administered no more than 14 days prior to transplantation. 
     
     
         8 . The method of  claim 2 , wherein said anti-CD4 and anti-CD8 antibodies administration is concomitant. 
     
     
         9 . The method of  claim 2 , wherein said AAT consists of an amino acid sequence as set forth in SEQ ID NO: 1. 
     
     
         10 . The method of  claim 2 , wherein said AAT is a recombinant protein. 
     
     
         11 . The method of  claim 2 , wherein AAT is administered prior to transplantation, following transplantation or a combination thereof. 
     
     
         12 . The method of  claim 2 , wherein the subject is a human. 
     
     
         13 . The method of  claim 2 , wherein said xenotransplant is selected from cells, pancreatic islets, pancreas, heart, lung, kidney, liver or skin. 
     
     
         14 . A method of preventing or treating graft rejection in a recipient subject afflicted with graft dysfunction, the method comprises administering to the recipient a therapeutically effective amount of AAT in combination with a therapeutically effective amount of at least one temporary T cell depleting agent. 
     
     
         15 . The method of  claim 14 , wherein the at least one temporary T cell depleting agent is selected from anti-CD4 and anti-CD8 antibodies or antigen binding fragments thereof. 
     
     
         16 . The method of  claim 14 , wherein said graft is selected from the group consisting of pancreatic islets, cell, hematopoietic cells, stem cells, pancreas, heart, lung, kidney, liver or skin. 
     
     
         17 . The method of  claim 14 , wherein the graft is a xenograft.