Treatment of autoimmune disease

Abstract

The present invention features a novel combination therapy useful in the treatment of autoimmune disease that increases or maintains the number of functional cells of a predetermined type in a mammal by killing or inactivating autoimmune cells and re-educating the host immune system.

1. A method of increasing or maintaining the number of functional cells of a predetermined type in a mammal, said method comprising the steps of:
 a) providing a sample of cells of said predetermined type,   b) treating said cells to modify the presentation of an antigen of said cells that is capable of causing an in vivo autoimmune cell-mediated rejection response,   c) introducing said treated cells into said mammal, and   d) prior to, after, or concurrently with step c), treating said mammal to kill or inactivate autoimmune cells of said mammal.   
     
     
       2. The method of  claim 1 , wherein said mammal is a human patient. 
     
     
       3. The method of  claim 2 , wherein said cells are insulin-producing islet cells. 
     
     
       4. The method of  claim 1 , wherein step b) comprises eliminating, reducing, or masking said antigen. 
     
     
       5. The method of  claim 1 , wherein step d) comprises administering to said mammal TNF-alpha or a TNF-alpha inducing substance. 
     
     
       6. The method of  claim 5 , wherein the TNF-alpha inducing substance is tissue plasminogen activator, LPS, interleukin-1, UV light, or an intracellular mediator of the TNF-alpha signaling pathway. 
     
     
       7. The method of  claim 1 , wherein said mammal has a mutation in the lmp2 gene or equivalent thereof. 
     
     
       8. A method of increasing the number of functional cells of a predetermined type in a mammal, said method comprising the steps of:
 a) treating said mammal with an agent that kills or inactivates autoimmune cells of said mammal;   b) periodically monitoring the cell death rate of said autoimmune cells; and   c) periodically adjusting the dosage of said agent administered to said mammal based on the monitoring of step b).   
     
     
       9. The method of  claim 8 , wherein said agent comprises TNF-alpha, a THF-alpha inducing substance, tissue plasminogen activator, LPS, interleukin-1, UV light, or an intracellular mediator of the TNF-alpha signaling pathway. 
     
     
       10. The method of  claim 5 , wherein step d) comprises administering to said mammal two agents that increase TNF-alpha. 
     
     
       11. The method of  claim 8 , wherein step a) comprises administering to said mammal two agents that increase TNF-alpha. 
     
     
       12. A method for diagnosing an autoimmune disease or the predisposition to said disease in a mammal, said method comprising the steps of:
 a) providing peripheral cells from a mammal,   b) treating said cells with a TNF-alpha treatment regimen, and   c) detecting cell death of said peripheral cells, wherein an increase in cell death, when compared with control cells, is indicative of said mammal having an autoimmune disease or a predisposition to said disease.   
     
     
       13. The method of  claim 12 , wherein said peripheral cells comprise splenocytes, T lymphocytes, B lymphocytes, or cells of bone marrow origin. 
     
     
       14. The method of  claim 12 , wherein said mammal is a human patient. 
     
     
       15. The method of  claim 12 , wherein said TNF-alpha treatment regimen comprises treating said peripheral cell with TNF-alpha. 
     
     
       16. A method of treating an autoimmune disease in a mammal comprising administering to said mammal a composition comprising Bacillus Calmette-Guérin (BCG) by percutaneous injection, wherein the autoimmune disease is selected from multiple sclerosis, scleroderma, Sjogren's disease, systemic lupus erythematosus, Grave's disease, hypothyroidism, Crohn's disease, colititis, an autoimmune skin disease, and rheumatoid arthritis. 
     
     
       17. The method of claim 16, wherein said autoimmune disease is Sjogren's disease. 
     
     
       18. The method of claim 16, wherein said autoimmune disease is multiple sclerosis. 
     
     
       19. The method of claim 16, wherein said autoimmune disease is rheumatoid arthritis. 
     
     
       20. The method of claim 16, wherein said autoimmune disease is systemic lupus erythematosus. 
     
     
       21. The method of claim 16, wherein said autoimmune disease is Crohn's disease. 
     
     
       22. The method of claim 16, wherein said autoimmune disease is an autoimmune skin disease. 
     
     
       23. The method of claim 16, wherein said mammal is a human. 
     
     
       24. The method of claim 16, wherein said method further comprises administering a substance selected from TNF-alpha, a TNF-alpha receptor agonist, complete Freund's adjuvant, LPS, fMet-Leu-Phe, CD28, CD40, Fas (CD95), p75TNF, lymphotoxin Beta-receptor, and an agonist of TNF-alpha converting enzyme. 
     
     
       25. The method of claim 24, wherein said substance is a TNF-alpha receptor agonist. 
     
     
       26. The method of claim 25, wherein said TNF-alpha receptor agonist is an antibody. 
     
     
       27. The method of claim 16, wherein said treating comprises killing or inactivating autoimmune cells. 
     
     
       28. The method of claim 27, wherein said autoimmune cells are autoreactive T-cells. 
     
     
       29. The method of claim 16, wherein said mammal is presenting symptoms of said autoimmune disease. 
     
     
       30. The method of claim 23, wherein said method comprises repeatedly administering said composition to said human.