Methods and compositions for treatment of graft rejection and promotion of graft survival

Abstract

Embodiments herein illustrate methods of treating, reducing or preventing transplantation rejection and/or side effects associated with transplantation. Some embodiments relate to compositions and methods for inhibition of graft rejection and promotion of graft survival. Other embodiments relate to modulation of cellular activities, including graft rejection, promotion of graft survival, graft versus host rejection and conditions commonly associated with graft rejection. Yet other embodiments relate to the inhibitory compounds comprising naturally occurring and man-made inhibitors of serine protease, derivatives and fragments of the carboxy-terminus of alpha1-antitrypsin and inducers of other alpha1-antitrypsin activities and uses thereof.

1 . A method for preventing or reducing the risk of developing an organ or cellular transplant rejection in a subject having had or undergoing a cellular transplant, the method comprising administering to the subject a composition comprising alpha-1 antitrypsin (AAT), alpha-1 antitrypsin-like compound or combination thereof. 
     
     
         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 composition comprises a carboxy-terminal peptide corresponding to AAT, an analog thereof, any derivative of AAT carboxy terminus that binds to serpin-enzyme complex (SEC) receptor or a combination thereof. 
     
     
         5 . The method of  claim 1 , wherein the cellular transplant is selected from the group consisting of cornea, bone marrow, liver, stem cell, pancreatic islet, pancreas, kidney, lung, intestine, and a combination thereof. 
     
     
         6 . The method of  claim 5 , wherein the cellular transplant is pancreatic islet cell transplant. 
     
     
         7 . The method of  claim 3 , wherein the immunosuppressive agent is chosen from inhibitors of apoptosis, serine protease inhibitors, reducers of lymphocyte numbers, reducers of cytokine production, reducers of cytokine activities, monoclonal antibodies, reducers of cytokine receptors, reducers of nitric oxide production and a combination thereof. 
     
     
         8 . The method of  claim 7 , wherein reducers of cytokine production, reducers of cytokine activities, reducers of cytokine receptors is an inhibitor of one or more of TNFα (tumor necrosis factor alpha), IL-1 (interleukin-1), IL-12 (interleukin-12), IL-18 (interleukin-18), IL-17 (interleukin-17), IL-23 (interleukin-23), IL-32 (interleukin-32), IFNγ (interferon gamma) or a combination thereof. 
     
     
         9 . A method for treating organ or cellular transplant rejection in a subject in need of such a treatment comprising:
 identifying a subject having or in need of a cellular or organ transplant;   performing cellular or organ transplantation on the subject; and   administering a therapeutically effective amount of a composition comprising AAT, AAT-like compound, AAT analog, AAT derivative, serine protease inhibitor, one or more carboxy-terminal peptides derived from AAT, any derivative of AAT carboxy terminus that binds to serpin-enzyme complex (SEC) receptor or combination thereof to the subject.   
     
     
         10 . The method of  claim 9 , wherein administration comprises administering the composition to the organ or cells to be transplanted before transplant, administering the composition to the subject before transplant, administering the composition to the subject during transplantation, administering the composition to the subject after transplantation or a combination thereof. 
     
     
         11 . The method of  claim 9 , wherein treating the subject with the composition reduces the risk of transplantation rejection by at least 10% compared to a subject not treated with the composition. 
     
     
         12 . The method of  claim 9 , wherein the cellular transplant is selected from the group consisting of cornea, bone marrow, liver, stem cell, pancreatic islet, pancreas, kidney, lung, intestine, skin and a combination thereof. 
     
     
         13 . The method of  claim 9 , 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. 
     
     
         14 . A method for treating diabetes in a subject in need of such a treatment comprising:
 identifying a subject having or at risk of developing diabetes;   performing pancreatic islet cell transplantation on the subject; and   administering a therapeutically effective amount of a composition comprising AAT, AAT-like compound, AAT analog, AAT derivative, a serine protease inhibitor, one or more carboxy-terminal peptides derived from AAT, any derivative or fragment of AAT carboxy terminus that binds to serpin-enzyme complex (SEC) receptor or combination thereof to the subject.   
     
     
         15 . The method of  claim 14 , wherein administration comprises administering the composition to the organ or cells to be transplanted before transplant, administering the composition to the subject before transplant, administering the composition to the subject during transplantation, administering the composition to the subject after transplantation or a combination thereof. 
     
     
         16 . The method of  claim 14 , wherein the subject has or is at risk of developing Type 1 diabetes. 
     
     
         17 . The method of  claim 14 , wherein the subject is in early phase type 1 diabetes. 
     
     
         18 . The method of  claim 14 , wherein the subject has or is at risk of developing Type 2 diabetes. 
     
     
         19 . The method of  claim 14 , wherein treating the subject with the composition decreases the risk of transplantation rejection by at least 10% compared to a subject not treated with the composition. 
     
     
         20 . The method of  claim 14 , wherein the compound comprises one or more carboxy-terminal peptides derived from AAT, an analog thereof, any derivative or fragment of AAT carboxy terminus that binds to serpin-enzyme complex (SEC) receptor or a combination thereof. 
     
     
         21 . A method for reducing a side-effect of cellular transplant rejection in a subject, the method comprising administering to the subject a composition comprising alpha-1 antitrypsin (AAT), one or more carboxy-terminal peptides derived from AAT, or alpha-1 antitrypsin-like compound. 
     
     
         22 . The method of  claim 21 , wherein administration comprises administering the composition to the organ or cells to be transplanted before transplant, administering the composition to the subject before transplant, administering the composition to the subject during transplantation, administering the composition to the subject after transplantation or a combination thereof. 
     
     
         23 . The method of  claim 21 , 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. 
     
     
         24 . The method of  claim 21 , wherein the compound comprises a carboxy-terminal peptide corresponding to AAT, an analog thereof, any derivative or fragment of AAT carboxy terminus that binds to serpin-enzyme complex (SEC) receptor or a combination thereof. 
     
     
         25 . The method of  claim 21 , wherein the cellular transplant is selected from the group consisting of cornea, bone marrow, liver, stem cell, pancreatic islet, pancreas, kidney, lung, intestine, and a combination thereof. 
     
     
         26 . The method of  claim 21 , wherein the cellular transplant is pancreatic islet cell transplant. 
     
     
         27 . The method of  claim 21 , wherein the side effects of cellular or organ transplant are selected from the group consisting essentially of production of pro-inflammatory cytokines, infiltration of immunocompetent cells, infiltration of inflammatory cells, infiltration of cytotoxic T-cells, infiltration of mature dendritic cells, infiltration of monocytes, production of nitric oxide, production of prostaglandins, production of reactive oxygen species, production of super oxide radicals, infiltration of natural killer cells, infiltration of natural killer T-cells and a combination thereof. 
     
     
         28 . The method of  claim 23 , wherein the immunosuppressive agent is chosen from inhibitors of apoptosis, reducers of cytokine production, reducers of cytokine activities, reducers of nitric oxide production and a combination thereof. 
     
     
         29 . The method of  claim 21 , wherein the composition inhibits the production of TNFα (tumor necrosis factor alpha), IL-1 (interleukin-1), IL-12 (interleukin-12), IL-18 (interleukin-18), IFNγ (interferon gamma), nitric oxide (NO) or a combination thereof. 
     
     
         30 . A method for preventing or reducing the risk of developing pancreatic islet cell transplant rejection in a subject having had or undergoing a pancreatic islet cell transplant, the method comprising administering to the subject a composition comprising alpha-1 antitrypsin (AAT), one or more carboxy-terminal peptides derived from AAT, engager of the SEC receptor, alpha-1 antitrypsin-like compound, serine protease inhibitor or combination thereof. 
     
     
         31 . The method of  claim 30 , wherein administration comprises administering the composition to the organ or cells to be transplanted before transplant, administering the composition to the subject before transplant, administering the composition to the subject during transplantation, administering the composition to the subject after transplantation or a combination thereof. 
     
     
         32 . The method of  claim 30 , 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. 
     
     
         33 . The method of  claim 30 , wherein the composition comprises a carboxy-terminal peptide corresponding to AAT, an analog thereof, any derivative or fragment of AAT carboxy terminus that binds to serpin-enzyme complex (SEC) receptor or a combination thereof. 
     
     
         34 . The method of  claim 30 , wherein the subject has juvenile or late onset type 1 diabetes. 
     
     
         35 . The method of  claim 30 , wherein the subject has type 2 diabetes. 
     
     
         36 . The method of  claim 30 , wherein reducing the risk of developing pancreatic islet cell transplant rejection in a subject comprises reducing the risk by at least 10 percent in the subject compared to a second subject not treated with the composition. 
     
     
         37 . The method of  claim 30 , wherein the subject is a human. 
     
     
         38 . The method of  claim 30 , wherein the subject is a domesticated animal or livestock. 
     
     
         39 . A pharmaceutical composition comprising, AAT, AAT-like compound, serine protease inhibitor, AAT analog, AAT derivative, one or more carboxy-terminal peptides derived from AAT, any derivative or fragment of AAT carboxy terminus that binds to serpin-enzyme complex (SEC) receptor or combination thereof and at least one of an anti-transplant rejection agent, an anti-inflammatory agent, an immunosuppressive agent, an immunomodulatory agent, and an anti-microbial agent. 
     
     
         40 . The pharmaceutical composition of  claim 39 , wherein the compositions is AAT, serine protease inhibitor, AAT-like compound, AAT analog, AAT derivative, carboxy-terminal peptide corresponding to AAT, any derivative or fragment of AAT carboxy terminus that binds to serpin-enzyme complex (SEC) receptor or combination thereof and one or more anti-transplant rejection agents. 
     
     
         41 . A method for inducing immunological tolerance in a subject undergoing a cellular or organ transplant comprising: the method comprising administering to the subject a composition comprising alpha-1 antitrypsin (AAT), alpha-1 antitrypsin-like compound or combination thereof. 
     
     
         42 . The method of  claim 41 , wherein the subject is undergoing islet cell transplant. 
     
     
         43 . The method of  claim 41  , 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. 
     
     
         44 . The method of  claim 41 , wherein the composition comprises one or more carboxy-terminal peptides corresponding to AAT, an analog thereof, any derivative or fragment of AAT carboxy terminus that binds to serpin-enzyme complex (SEC) receptor or a combination thereof. 
     
     
         45 . The method of  claim 41 , wherein the cellular transplant is selected from the group consisting of cornea, bone marrow, stem cell, pancreatic islet, kidney, lung, intestine, skin and a combination thereof. 
     
     
         46 . The method of  claim 41 , wherein the cellular transplant is pancreatic islet cell transplant. 
     
     
         47 . The method of  claim 46 , wherein the immunosuppressive agent is chosen from inhibitors of apoptosis, reducers of cytokine production, reducers of cytokine activities, reducers of nitric oxide production and a combination thereof. 
     
     
         48 . A method comprising, at least one of increasing numbers of or increasing effectiveness and/or of sustaining T-regulatory cells in a subject by administering an AAT or AAT derivative composition to the subject. 
     
     
         49 . A method comprising, increasing immune tolerance in a subject in need thereof by administering an AAT or AAT derivative composition to the subject in need thereof. 
     
     
         50 . The method of  claim 49 , further comprising inhibiting dendridic cell maturation. 
     
     
         51 . The method of  claim 49 , wherein the subject is having, undergoing or previously having had a transplant. 
     
     
         52 . A method comprising, reducing antigen presentation by dendritic cells by administering an AAT or AAT derivative composition to the cells. 
     
     
         53 . The method of  claim 52 , wherein the cells are cells of a human subject and administration is to the subject in need of reducing antigen presentation. 
     
     
         54 . A method comprising, inhibiting maturation of dendritic cells by administering an AAT, any derivative or fragment of AAT carboxy terminus that binds to serpin-enzyme complex (SEC) receptor or AAT derivative composition to a subject having, undergoing or previously having had a transplant.