Inhibitors of serine protease activity and their use in methods and compositions for treatment of graft rejection and promotion of graft survival

Abstract

Embodiments of the present invention illustrate methods of treating and preventing transplantation and side effects associated with transplantation. In particular, the present invention relates to compositions and methods for inhibition of graft rejection and promotion of graft survival. Thus, the invention relates to modulation of cellular activities, including graft rejection, promotion of graft survival, graft versus host rejection and conditions commonly associated with graft rejection. More particularly, the present invention relates to the inhibitory compounds comprising naturally occurring and man-made inhibitors of serine protease and inducers of other alpha1-antitrypsin activities.

1 . A method for reducing the risk of a transplant rejection or a side-effect of a transplant rejection in a subject, said method comprising administering to the subject a composition comprising a compound that is capable of significantly reducing serine protease activity. 
     
     
         2 . The method of  claim 1 , wherein the composition is administered to the subject before transplantation, during transplantation, after transplantation or combination thereof. 
     
     
         3 . The method of  claim 1 , wherein the composition further comprises one or more anti-transplant rejection agent, anti-inflammatory agent, immunosuppressive agent, immunomodulatory agent, anti-microbial agent, or a combination thereof. 
     
     
         4 . The method of  claim 1 , wherein the compound comprises alpha1-antitrypsin, an analog thereof or a combination thereof. 
     
     
         5 . The method of  claim 1 , wherein the transplant is selected from an organ or non-organ transplant. 
     
     
         6 . The method of  claim 5 , wherein the organ transplant is selected from the group consisting of lung, kidney, heart, liver, soft tissue, skin, pancreas, intestine and a combination thereof. 
     
     
         7 . The method of  claim 5 , wherein the non-organ transplant is selected from the group consisting of cornea, bone marrow, stem cell, pancreatic islet, and a combination thereof. 
     
     
         8 . A method for treating a subject in need of immunotolerance therapy, said method comprising administering to the subject a composition comprising a compound that is capable of significantly reducing serine protease activity, activating the SEC (Serpine-Enzyme-Complex) receptor, induces other alpha-1-antitrypsin-like activity or combination thereof. 
     
     
         9 . The method of  claim 8 , wherein the compound comprises alpha-1-antitrypsin, an analog thereof or a combination thereof. 
     
     
         10 . The method of  claim 8 , wherein the composition significantly reduces the need for immunosuppressive therapy. 
     
     
         11 . The method of  claim 8 , wherein the composition further comprises one or more anti-inflammatory agent, immunosuppressive agent, immunomodulatory agent, anti-microbial agent, or a combination thereof. 
     
     
         12 . The method of  claim 8 , wherein the immunotolerance therapy is selected from the group consisting of reducers of apoptosis production, reducers of cytokine production, reducers of nitric oxide production and a combination thereof. 
     
     
         13 . The method of  claim 12 , wherein inhibition of cytokine production is selected from the group consisting of inhibition of TNFα (tumor necrosis factor alpha), IL-1 (interleukin-1), IL-12 (interleukin-12), IL-18 (interleukin-18), IFNγ (interferon gamma) and a combination thereof. 
     
     
         14 . A method for reducing the risk of a graft rejection or a side-effect of a graft rejection in a subject, said method comprising administering to the subject a composition comprising a compound that is capable of significantly reducing serine protease activity. 
     
     
         15 . The method of  claim 14 , wherein the compound comprises alpha1-antitrypsin, an analog thereof or a combination thereof. 
     
     
         16 . The method of  claim 14 , wherein graft rejection comprises graft versus host disease (GVHD). 
     
     
         17 . The method of  claim 14 , wherein the substance exhibiting serine protease inhibitor activity targets the following proteases selected from the group consisting of proteinase-3, cathepsin G, chymotrypsin, elastase, elafin, eglin C, tryptase clara, trypsin and a combination thereof. 
     
     
         18 . The method of  claim 14 , further comprising one or more anti-rejection agent, anti-inflammatory agent, immunosuppressive agent, immunomodulatory agent, anti-microbial agent, anti-viral or combination thereof. 
     
     
         19 . A method for preserving an explanted organ or non-organ, said method comprising administering to the organ or non-organ, a composition comprising a compound that is capable of alpha1-antitrypsin-like activity, inhibiting serine protease activity or combination thereof. 
     
     
         20 . The method of  claim 19 , wherein preserving the explant comprises preserving the explant any time prior to implanting the organ or non-organ into a recipient. 
     
     
         21 . The method of  claim 19 , wherein preserving an explant is selected from the group consisting of reducing apoptosis in the explant, reducing cytokine production in the explant, reducing nitric oxide production in the explant and a combination thereof.