Methods and compositions for enhancing the immunostimulatory effect of interleukin-12

Abstract

Methods for enhancing the therapeutic and adjuvant use of IL- 12 by reducing unwanted transient immunosuppression caused by IL- 12 or by high doses thereof involve co-administering IL- 12 with an effective amount of an agent that inhibits or neutralizes nitric oxide (NO) in vivo. Enhanced vaccine therapy involves co-administering the IL- 12 adjuvant, a selected vaccine antigen and the NO inhibiting/neutralizing agent. Additionally, the toxicity of IL- 12 treatment may be reduced by co-administering IL- 12 with an effective amount of the NO inhibiting or neutralizing agent. A therapeutic composition characterized by reduced toxicity in mammals contains IL- 12, preferably a low dose thereof, and an NO inhibiting or neutralizing agent in a pharmaceutically acceptable carrier. A vaccine composition contains an effective adjuvanting amount of IL- 12, an effective amount of an NO inhibiting or neutralizing agent, and an effective protective amount of a vaccine antigen in a pharmaceutically acceptable carrier.

What is claimed is:  
     
         1 . A method for reducing the immunosuppressive effects of IL- 12  treatment comprising: co-administering with said IL- 12 , an effective amount of a nitric oxide inhibiting and/or neutralizing agent.  
     
     
         2 . The method according to  claim 1  wherein said co-administration comprises simultaneously administering said agent with said IL- 12 .  
     
     
         3 . The method according to  claim 1  wherein said co-administration comprises sequentially administering said agent, and said IL- 12 .  
     
     
         4 . The method according to  claim 3  wherein said co-administration comprises administering said IL- 12  before said agent.  
     
     
         5 . The method according to  claim 1  wherein said agent is an inhibitor of nitric oxide generation is an inhibitor of nitric oxide synthase.  
     
     
         6 . The method according to  claim 5  wherein said agent is specific for inducible nitric oxide synthase.  
     
     
         7 . The method according to  claim 5  wherein said inhibitor is selected from the group consisting of L-N G  monomethyl arginine (L-NMMA), L-N G  nitroarginine (L-NORAG), L-N G  nitroarginine methylester (L-NAME), L-N G  nitroarginine p-nitroanilide (L-NAPNA), L-N G  aminoarginine (L-NAA), L-N G  cyclopropylarginine, L-N G  allylarginine, asymmetric L-N G N G  dimethylarginine (L-ADMA), L-N ω iminoethyl ornithine (L-NIO), 7-nitro indazole (7-NI), 2,7 dinitro indazole, 3-bromo 7-nitro indazole, aminoguanidine, N,N′-diaminoguanidine, dimethylguanidine, diphenyleneiodonium, iodoniumdiphenyl, di-2-thienyliodonium, chlorpromazine, trifluoperazine, pimozide, clozapine, calmidazolium, 2,4 diamino-6-hydroxypyrimidine, methotrexate, N-acetyl-5-hydroxytryptamine, miconazole, ketoconazole, clotrimazole, imidazole, 1-, 2- and 4-phenylimidazole, methylene blue, NO, carbon monoxide, ebselen, phencyclidine, and antineoplastic agents (doxorubicin, aclarubicin).  
     
     
         8 . The method according to  claim 7  wherein said agent is L-NAME.  
     
     
         9 . The method according to  claim 7  wherein said agent is L-NMMA.  
     
     
         10 . The method according to  claim 1  wherein said agent is a nitric oxide scavenger.  
     
     
         11 . The method according to  claim 10  wherein said scavenger is selected from the group consisting of N-acetyl cysteine, pyrrolidine dithiocarbamate, and hemoglobin.  
     
     
         12 . A method for reducing the toxicity of IL- 12  treatment comprising: co-administering with an effective dose of said IL- 12 , an effective amount of a nitric oxide inhibiting and reducing agent.  
     
     
         13 . The method according to  claim 12  wherein said co-administration comprises simultaneously administering said agent with said IL- 12 .  
     
     
         14 . The method according to  claim 12  wherein said co-administration comprises sequentially administering said agent, and said IL- 12 .  
     
     
         15 . The method according to  claim 12  wherein said co-administration comprises administering said IL- 12  before said agent.  
     
     
         16 . The method according to  claim 12  wherein said effective amount of IL- 12  is a low dose thereof.  
     
     
         17 . The method according to  claim 12  wherein said agent is an inhibitor of nitric oxide synthase.  
     
     
         18 . The method according to  claim 17  wherein said agent is specific for inducible nitric oxide synthase.  
     
     
         19 . The method according to  claim 17  wherein said inhibitor is selected from the group consisting of L-N G  monomethyl arginine (L-NMMA), L-N G  nitroarginine (L-NORAG), L-N G  nitroarginine methylester (L-NAME), L-N G  nitroarginine p-nitroanilide (L-NAPNA), L-N G  aminoarginine (L-NAA), L-N G  cyclopropylarginine, L-N G  allylarginine, asymmetric L-N G N G  dimethylarginine (L-ADMA), L-N ω iminoethyl ornithine (L-NIO), 7-nitro indazole (7-NI), 2,7 dinitro indazole, 3-bromo 7-nitro indazole, aminoguanidine, N,N′-diaminoguanidine, dimethylguanidine, diphenyleneiodonium, iodoniumdiphenyl, di-2-thienyliodonium, chlorpromazine, trifluoperazine, pimozide, clozapine, calmidazolium, 2,4 diamino-6-hydroxypyrimidine, methotrexate, N-acetyl-5-hydroxytryptamine, miconazole, ketoconazole, clotrimazole, imidazole, 1-, 2- and 4-phenylimidazole, methylene blue, NO, carbon monoxide, ebselen, phencyclidine, and antineoplastic agents (doxorubicin, aclarubicin).  
     
     
         20 . The method according to  claim 19  wherein said agent is L-NAME.  
     
     
         21 . The method according to  claim 19  wherein said agent is L-NMMA.  
     
     
         22 . The method according to  claim 12  wherein said agent is a nitric oxide scavenger.  
     
     
         23 . The method according to  claim 22  wherein said scavenger is selected from the group consisting of N-acetyl cysteine, pyrrolidine dithiocarbamate, and hemoglobin.  
     
     
         24 . A therapeutic composition comprising IL- 12 , characterized by reduced toxicity in mammals, said composition comprising an effective dose of said IL- 12  and an effective amount of a nitric acid inhibiting and/or neutralizing agent in a pharmaceutically acceptable carrier.