Methods For Treating Arthritis, Autoimmune Disease, and Ischemia-Reperfusion Injury

Abstract

The instant invention provides a method of treating an animal suffering a disease characterized by excessive apoptosis by administering a therapeutically effective amount of at least one serine protease inhibitor and thereafter monitoring a decrease in apoptosis. The inhibitor of the invention includes α 1 -antitrypsin or an α 1 -antitrypsin-like agent, including, but not limited to oxidation-resistant variants of α 1 -antitrypsin, and peptoids with antitrypsin activity. The diseases treatable by the invention include cancer, autoimmune disease, sepsis neurodegenerative disease, myocardial infarction, stroke, ischemia-reperfusion injury, toxin induced liver injury and AIDS. The method of the invention is also suitable for the prevention or amelioration of diseases characterized by excessive apoptosis.

1 - 28 . (canceled) 
     
     
         29 . A method of treating arthritis, autoimmune disease or ischemia-reperfusion injury in a subject in need of such a treatment, said method comprising administering a composition comprising a therapeutically effective amount of α 1 -antitrypsin (AAT), an oxidation-resistant α 1 -antitrypsin Met 358  variant, a free radical-resistant α 1 -antitrypsin M 358  variant, or a combination thereof to the subject. 
     
     
         30 . The method of  claim 29 , wherein the composition further comprises at least one free radical scavenger or inhibitor. 
     
     
         31 . The method of  claim 29 , wherein the therapeutically effective amount is sufficient to provide at least 10 μM and no greater than 2 mM of the inhibitor in a biological fluid of the subject. 
     
     
         32 . The method of  claim 29 , wherein the autoimmune disease comprises Ankylosing Spondylitis, Chagas disease, chronic obstructive pulmonary disease, Crohns Disease, Dermatomyositis, Endometriosis, Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome, Hashimoto's disease, Hidradenitis suppurativa, Kawasaki disease, IgA nephropathy, idiopathic thrombocytopenic purpura, interstitial cystitis, lupus erythematosus, mixed connective tissue disease, morphea, myasthenia gravis, narcolepsy, neuromyotonia, pemphigus vulgaris, pernicious anaemia, psoriasis, psoriatic Arthritis, polymyositis, primary biliary cirrhosis, relapsing polychondritis, rheumatoid arthritis, schizophrenia, scleroderma, Sjögren's syndrome, stiff person syndrome, temporal arteritis, ulcerative colitis, vasculitis, vitiligo, or Wegener's granulomatosis. 
     
     
         33 . The method of  claim 29 , wherein the ischemia-reperfusion injury comprises ischemia-reperfusion injury associated with thrombolytic therapy, organ transplantation, coronary angioplasty, aortic cross-clamping, or cardiopulmonary bypass surgery. 
     
     
         34 . The method of  claim 29 , in which the therapeutically effective amount is sufficient to provide at least 0.5 μM and no greater than 2000 μM in a biological fluid of the subject. 
     
     
         35 . The method of  claim 29 , wherein the composition is administered parenterally, orally, vaginally, rectally, nasally, buccally, intravenously, intramuscularly, subcutaneously, intrathecally, epidurally, transdermally, intracerebroventricularly, by osmotic pump, by inhalation, or combinations thereof. 
     
     
         36 . The method of  claim 29 , wherein the composition is administered orally. 
     
     
         37 . The method of  claim 29 , wherein the composition is administered at least once daily. 
     
     
         38 . The method of  claim 29 , wherein the composition comprises AAT. 
     
     
         39 . The method of  claim 38 , wherein the AAT is substantially purified from a wild type, mutant, or transgenic mammalian source. 
     
     
         40 . The method of  claim 38 , wherein the AAT is isolated from a culture of wild type, mutant, or transformed cells. 
     
     
         41 . The method of  claim 29 , wherein the composition further comprises a pharmaceutically acceptable carrier. 
     
     
         42 . The method of  claim 29 , wherein α 1 -antitrypsin, an oxidation-resistant α 1 -antitrypsin Met 358  variant, a free radical-resistant α 1 -antitrypsin M 358  variant, or a combination thereof are derivatized by esterification, acetylation, or amidation. 
     
     
         43 . A method for ameliorating ischemia in a donor organ during transport, transplant, or a combination thereof, said method comprising treating the donor organ with a composition comprising α 1 -antitrypsin (AAT), an oxidation-resistant α 1 -antitrypsin Met 358  variant, a free radical-resistant α 1 -antitrypsin M 358  variant, or a combination thereof upon removal of the donor organ from a subject. 
     
     
         44 . The method of  claim 43 , wherein the composition comprises AAT.