Low dose histone peptide treatment for autoimmune disorders

Abstract

The present invention provides low dose compositions comprising peptides and methods of using the same to treat autoimmune disorders, such as lupus. In particular, the present invention provides low dose compositions comprising nucleosomal histone peptide autoepitopes comprising MHC class I and II binding motifs and methods of using the same to suppress IFN-gamma and/or autoantibody production. In certain embodiments, the compositions contain the histone peptides at subnanomolor concentrations, such as 0.1 nM to 0.9 nM. In other embodiments, the compositions are adminstered in a low dose, such as 5-75 ug of histone peptides per kilogram of patient. In certain embodiments, the present invention provides related diagonstics employing histone peptides.

1 . A method of treating an animal having systemic lupus erythematosus (SLE) and a SLE-associated manifestation of nephritis, autoantibodies, and inflammation associated with autoantibodies, said method comprising administering to said animal an isolated peptide comprising a portion of a nucleosome histone protein, wherein said isolated peptide is capable of specifically binding with a T cell receptor present on a cell, and further wherein said isolated peptide is capable of promoting immunological tolerance in an animal, thereby treating said SLE and said SLE-associated manifestation, wherein said isolated peptide is administered at a concentration between 5 ug and 75 ug per kilogram of said animal or at a concentration of between at least 0.1 nM and no more than 0.9 nM.  
     
     
         2 . The method of  claim 1 , wherein said isolated peptide is administered in an amount which is from at least about 25 micrograms per kilogram of animal to about 50 micrograms per kilogram of said animal.  
     
     
         3 . The method of  claim 1 , wherein said peptide comprises the amino acid sequence shown in SEQ ID NO:3. or SEQ ID NO:1  
     
     
         4 . The method of  claim 1 , wherein said peptide is administered at a concentration of between at least 0.1 nM and no more than 0.9 nM.  
     
     
         5 . The method of  claim 1 , wherein said peptide comprises a MHC class I binding motif.  
     
     
         6 . The method of  claim 1 , wherein said administration is conducted once about every two weeks.  
     
     
         7 . The method of  claim 1 , wherein said administration is subcutaneous administration.  
     
     
         8 . The composition of  claim 1 , wherein said isolated peptides comprise an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-5, 7, 9-10, 14, 18-19, and 22-26.  
     
     
         9 . An isolated composition comprising isolated peptides comprising a portion of a nucleosome histone protein, wherein said isolated peptides are present in said composition at a concentration of at least 0.1 nM and no more than 0.9 nM.  
     
     
         10 . The composition of  claim 9 , wherein said nucleosome histone protein comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-5, 7, 9-10, 14, 18-19, and 22-26.  
     
     
         11 . The composition of  claim 9 , wherein said nucleosomal histone peptide comprises SEQ ID NO:3.  
     
     
         12 . The composition of  claim 9 , wherien said nucleosomal histone peptide comprises SEQ ID NO:1.  
     
     
         13 . The composition of  claim 9 , wherein said isolated peptide is capable of specifically binding with a T cell receptor present on a cell, and further wherein the isolated peptide is capable of promoting immunological tolerance in an animal.  
     
     
         14 . A system comprising; 
 a) a composition comprising isolated peptides comprising a portion of a nucleosome histone protein, wherein said isolated peptides are present in said composition at a concentration of at least 0.1 nM and no more than 0.9 nM; and    b) a container, wherein said composition is in said container.    
     
     
         15 . The system of  claim 14 , wherein said container is a syringe bottle configured to allow a needle to withdraw at least a portion of said composition in a sterile manner.  
     
     
         16 . The system of  claim 14 , wherein said nucleosome histone protein comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-5, 7, 9-10, 14, 18-19, and 22-26.  
     
     
         17 . The system of  claim 14 , wherien said nucleosomal histone peptide comprises SEQ ID NO:3.  
     
     
         18 . The system of  claim 14 , wherien said nucleosomal histone peptide comprises SEQ ID NO:1.  
     
     
         19 . The system of  claim 14 , wherein the isolated peptide is capable of specifically binding with a T cell receptor present on a cell, and further wherein the isolated peptide is capable of promoting immunological tolerance in an animal.  
     
     
         20 . A method comprising: 
 (a) contacting a sample from an animal with a composition comprising an isolated histone peptide complex, wherein said histone peptide complex comprises: 
 i) a histone peptide portion, said histone peptide portion comprising no more than 27 contiguous amino acids and having an amino acid sequence corresponding to a portion of a nucleosome histone protein;  
 ii) a fused portion having an amino acid sequence which corresponds to a portion of a protein selected from the group consisting of a major histocompatibility class molecule and an immunoglobin; and  
 iii) an indicator portion, wherein said indicator portion is a molecule which is capable of producing a detectable chemical signal; and wherein each of said histone peptide portion, said fused portion, and said indication portion is covalently linked to at least one other component of said histone peptide complex; and  
   (b) identifying in said animal the signal produced by said indicator portion, whereby the identification of said signal in said animal is an indication that said animal has systemic lupus erythematosus, thereby diagnosing systemic lupus erythematosus in said animal.    
     
     
         21 . The method of  claim 20  wherein said indicator portion is selected from the group consisting of a flourophore, a chromophore, a light reactive moiety and a biotin moiety