US2007060519A1PendingUtilityA1

Hsp therapy in conjunction with a low antigenicity diet

Assignee: ROZING JOHANNESPriority: Jan 28, 2004Filed: Jul 27, 2006Published: Mar 15, 2007
Est. expiryJan 28, 2024(expired)· nominal 20-yr term from priority
A61K 38/018A61K 38/164A61K 38/1709A61P 3/10
50
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Claims

Abstract

The present invention fragments and analogs of heat shock proteins in combination with a low antigenicity diet for suppression, prevention and treatment of diabetes. The invention is exemplified using DiaPep277™, an analog of residues 437-460 of human Hsp60 in combination with a hydrolyzed casein diet. The invention further relates to orally active pharmaceutical compositions comprising Hsp60 fragments and analogs, such as DiaPep277, useful for suppression, prevention or treatment of diabetes and to a regimen for delaying the onset of type 1 diabetes and for inhibition of insulitis.

Claims

exact text as granted — not AI-modified
1 . A method for suppression, prevention or treatment of diabetes, comprising administering to an individual in need thereof a fragment of Hsp60 or analog thereof in conjunction with a low antigenicity diet.  
     
     
         2 . The method according to  claim 1  wherein a diabetogenic protein is omitted from the diet or replaced with hydrolyzed or denatured form.  
     
     
         3 . The method according to  claim 2  wherein the diabetogenic protein is selected from the group consisting of: casein, lactoglobulin, albumin, (pro)insulin, wheat gluten, soy bean proteins, and heat shock proteins.  
     
     
         4 . The method according to  claim 1  wherein the diet comprises hydrolyzed or denatured protein.  
     
     
         5 . The method according to  claim 4  wherein the hydrolyzed protein is selected from the group consisting of: casein hydrolysate, whey hydrolysate, soy hydrolysate, or a mixture thereof.  
     
     
         6 . The method according to  claim 4  wherein the hydrolyzed protein is hydrolyzed casein.  
     
     
         7 . The method according to  claim 1  wherein the protein source of the diet is replaced with free amino acids, short-chain peptides, or mixtures thereof.  
     
     
         8 . The method according to  claim 1  wherein the diabetes is type 1 diabetes.  
     
     
         9 . The method according to  claim 1  wherein the diabetes is latent autoimmune diabetes in adults (LADA).  
     
     
         10 . The method of  claim 1  wherein the hsp60 fragment comprises residues 437-460 having the sequence Val-Leu-Gly-Gly-Gly-Cys-Ala-Leu-Leu-Arg-Cys-Ile-Pro-Ala-Leu-Asp-Ser-Leu-Thr-Pro-Ala-Asn-Glu-Asp (SEQ ID NO:1), or a salt or functional derivative thereof.  
     
     
         11 . The method of  claim 1  wherein the analog of hsp60 comprises DiaPep277 having the sequence: Val-Leu-Gly-Gly-Gly-Val-Ala-Leu-Leu-Arg-Val-Ile-Pro-Ala-Leu-Asp-Ser-Leu-Thr-Pro-Ala-Asn-Glu-Asp (SEQ ID NO:2), or a salt or functional derivative thereof.  
     
     
         12 . The method of  claim 1  wherein the hsp60 fragment or analog comprises a sequence selected from the group consisting of: 
 residues 31-50 of human Hsp60: Lys-Phe-Gly-Ala-Asp-Ala-Arg-Ala-Leu-Met-Leu-Gln-Gly-Val-Asp-Leu-Leu-Ala-Asp-Ala (SEQ ID NO:3);  
 residues 136-155 of human Hsp60: Asn-Pro-Val-Glu-Ile-Arg-Arg-Gly-Val-Met-Leu-Ala-Val-Asp-Ala-Val-Ile-Ala-Glu-Leu (SEQ ID NO:4);  
 residues 151-170 of human Hsp60: Val-Ile-Ala-Glu-Leu-Lys-Lys-Gln-Ser-Lys-Pro-Val-Thr-Thr-Pro-Glu-Glu-Ile-Ala-Gln (SEQ ID NO:5);  
 residues 166-185 of human Hsp60: Glu-Glu-Ile-Ala-Gln-Val-Ala-Thr-Ile-Ser-Ala-Asn-Gly-Asp-Lys-Glu-Ile-Gly-Asn-Ile (SEQ ID NO:6);  
 residues 195-214 of human Hsp60: Arg-Lys-Gly-Val-Ile-Thr-Val-Lys-Asp-Gly-Lys-Thr-Leu-Asn-Asp-Glu-Leu-Glu-Ile-Ile (SEQ ID NO:7);  
 residues 255-274 of human Hsp60: Gln-Ser-Ile-Val-Pro-Ala-Leu-Glu-Ile-Ala-Asn-Ala-His-Arg-Lys-Pro-Leu-Val-Ile-Ile (SEQ ID NO:8);  
 residues 286-305 of human Hsp60: Leu-Val-Leu-Asn-Arg-Leu-Lys-Val-Gly-Leu-Gln-Val-Val-Ala-Val-Lys-Ala-Pro-Gly-Phe (SEQ ID NO:9);  
 residues 346-365 of human Hsp60: Gly-Glu-Val-Ile-Val-Thr-Lys-Asp-Asp-Ala-Met-Leu-Leu-Lys-Gly-Lys-Gly-Asp-Lys-Ala (SEQ ID NO:10);  
 residues 421-440 of human Hsp60: Val-Thr-Asp-Ala-Leu-Asn-Ala-Thr-Arg-Ala-Ala-Val-Glu-Glu-Gly-Ile-Val-Leu-Gly-Gly (SEQ ID NO:11);  
 residues 436-455 of human Hsp60: Ile-Val-Leu-Gly-Gly-Gly-Cys-Ala-Leu-Leu-Arg-Cys-Ile-Pro-Ala-Leu-Asp-Ser-Leu-Thr (SEQ ID NO:12);  
 residues 466-485 of human Hsp60: Glu-Ile-Ile-Lys-Arg-Thr-Leu-Lys-Ile-Pro-Ala-Met-Thr-Ile-Ala-Lys-Asn-Ala-Gly-Val (SEQ ID NO:13);  
 residues 511-530 of human Hsp60: Val-Asn-Met-Val-Glu-Lys-Gly-Ile-Ile-Asp-Pro-Thr-Lys-Val-Val-Arg-Thr-Ala-Leu-Leu (SEQ ID NO:14);  
 residues 343-366 of human Hsp60: Gly-Lys-Val-Gly-Glu-Val-Ile-Val-Thr-Lys-Asp-Asp-Ala-Met (SEQ ID NO:15);  
 or a salt or functional derivative thereof.  
 
     
     
         13 . The method of  claim 1  wherein the Hsp60 fragment or analog is administered by a route of administration selected from oral, nasal, bronchial, topical, transdermal and systemic administration.  
     
     
         14 . The method of  claim 1  wherein the Hsp60 fragment or analog is administered orally.  
     
     
         15 . The method according to  claim 14  wherein the Hsp60 fragment or analog is administered in a dosage ranging from about 0.02 mg/kg to about 10 mg/kg.  
     
     
         16 . The use according to  claim 15  wherein the Hsp60 fragment or analog is administered in a dosage ranging from about 0.05 mg/kg to about 2 mg/kg.  
     
     
         17 . The method of  claim 1  wherein the Hsp60 fragment or analog is formulated for oral administration.  
     
     
         18 . A method for delaying the onset of type 1 diabetes and for inhibition of insulitis, comprising: 
 i. administering a fragment of Hsp60 or analog thereof; and    ii. maintaining a hydrolyzed casein diet.    
     
     
         19 . The method of  claim 18  wherein the Hsp60 fragment or analog comprises residues 437-460 having the sequence Val-Leu-Gly-Gly-Gly-Cys-Ala-Leu-Leu-Arg-Cys-Ile-Pro-Ala-Leu-Asp-Ser-Leu-Thr-Pro-Ala-Asn-Glu-Asp (SEQ ID NO:1).  
     
     
         20 . The method of  claim 18  wherein the Hsp60 fragment or analog comprises DiaPep277 having the sequence: Val-Leu-Gly-Gly-Gly-Val-Ala-Leu-Leu-Arg-Val-Ile-Pro-Ala-Leu-Asp-Ser-Leu-Thr-Pro-Ala-Asn-Glu-Asp (SEQ ID NO:2).  
     
     
         21 . The method of  claim 18  wherein the Hsp60 fragment or analog comprises a sequence selected from the group consisting of:  
       
         
           
                 
                 
                 
               
                     
                 
                   residues 31-50 of human Hsp60: 
                     
                     
                 
                   Lys-Phe-Gly-Ala-Asp-Ala-Arg-Ala-Leu- 
                   (SEQ ID NO:3) 
                 
                     
                 
                   Met-Leu-Gln-Gly-Val-Asp-Leu-Leu-Ala- 
                 
                     
                 
                   Asp-Ala; 
                 
                     
                 
                   residues 136-155 of human Hsp60: 
                 
                   Asn-Pro-Val-Glu-Ile-Arg-Arg-Gly-Val- 
                   (SEQ ID NO:4) 
                 
                     
                 
                   Met-Leu-Ala-Val-Asp-Ala-Val-Ile-Ala- 
                 
                     
                 
                   Glu-Leu; 
                 
                     
                 
                   residues 151-170 of human Hsp60: 
                 
                   Val-Ile-Ala-Glu-Leu-Lys-Lys-Gln-Ser- 
                   (SEQ ID NO:5) 
                 
                     
                 
                   Lys-Pro-Val-Thr-Thr-Pro-Glu-Glu-Ile- 
                 
                     
                 
                   Ala-Gln; 
                 
                     
                 
                   residues 166-185 of human Hsp60: 
                 
                   Glu-Glu-Ile-Ala-Gln-Val-Ala-Thr-Ile- 
                   (SEQ ID NO:6) 
                 
                     
                 
                   Ser-Ala-Asn-Gly-Asp-Lys-Glu-Ile-Gly- 
                 
                     
                 
                   Asn-Ile; 
                 
                     
                 
                   residues 195-214 of human Hsp60: 
                 
                   Arg-Lys-Gly-Val-Ile-Thr-Val-Lys-Asp- 
                   (SEQ ID NO:7) 
                 
                     
                 
                   Gly-Lys-Thr-Leu-Asn-Asp-Glu-Leu-Glu- 
                 
                     
                 
                   Ile-Ile; 
                 
                     
                 
                   residues 255-274 of human Hsp60: 
                 
                   Gln-Ser-Ile-Val-Pro-Ala-Leu-Glu-Ile- 
                   (SEQ ID NO:8) 
                 
                     
                 
                   Ala-Asn-Ala-His-Arg-Lys-Pro-Leu-Val- 
                 
                     
                 
                   Ile-Ile; 
                 
                     
                 
                   residues 286-305 of human Hsp60: 
                 
                   Leu-Val-Leu-Asn-Arg-Leu-Lys-Val-Gly- 
                   (SEQ ID NO:9) 
                 
                     
                 
                   Leu-Gln-Val-Val-Ala-Val-Lys-Ala-Pro- 
                 
                     
                 
                   Gly-Phe; 
                 
                     
                 
                   residues 346-365 of human Hsp60: 
                 
                   Gly-Glu-Val-Ile-Val-Thr-Lys-Asp-Asp- 
                   (SEQ ID NO:10) 
                 
                     
                 
                   Ala-Met-Leu-Leu-Lys-Gly-Lys-Gly-Asp- 
                 
                     
                 
                   Lys-Ala; 
                 
                     
                 
                   residues 421-440 of human Hsp60: 
                 
                   Val-Thr-Asp-Ala-Leu-Asn-Ala-Thr-Arg- 
                   (SEQ ID NO:11) 
                 
                     
                 
                   Ala-Ala-Val-Glu-Glu-Gly-Ile-Val-Leu- 
                 
                     
                 
                   Gly-Gly; 
                 
                     
                 
                   residues 436-455 of human Hsp60: 
                 
                   Ile-Val-Leu-Gly-Gly-Gly-Cys-Ala-Leu- 
                   (SEQ ID NO:12) 
                 
                     
                 
                   Leu-Arg-Cys-Ile-Pro-Ala-Leu-Asp-Ser- 
                 
                     
                 
                   Leu-Thr; 
                 
                     
                 
                   residues 466-485 of human Hsp60: 
                 
                   Glu-Ile-Ile-Lys-Arg-Thr-Leu-Lys-Ile- 
                   (SEQ ID NO:13) 
                 
                     
                 
                   Pro-Ala-Met-Thr-Ile-Ala-Lys-Asn-Ala- 
                 
                     
                 
                   Gly-Val; 
                 
                     
                 
                   residues 511-530 of human Hsp60: 
                 
                   Val-Asn-Met-Val-Glu-Lys-Gly-Ile-Ile- 
                   (SEQ ID NO:14) 
                 
                     
                 
                   Asp-Pro-Thr-Lys-Val-Val-Arg-Thr-Ala- 
                 
                     
                 
                   Leu-Leu; 
                 
                     
                 
                   residues 343-366 of human Hsp60: 
                 
                   Gly-Lys-Val-Gly-Glu-Val-Ile-Val-Thr- 
                   (SEQ ID NO:15) 
                 
                     
                 
                   Lys-Asp-Asp-Ala-Met; 
                 
                     
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
       or a salt or functional derivative thereof.  
     
     
         22 . The method of  claim 18  wherein the Hsp60 fragment or analog is administered orally.  
     
     
         23 . The method of  claim 22  wherein the Hsp60 fragment or analog is administered in a dosage ranging from about 0.02 mg/kg to about 10 mg/kg.  
     
     
         24 . The method of  claim 18  wherein the Hsp60 fragment or analog is administered in a dosage ranging from about 0.05 mg/kg to about 2 mg/kg.  
     
     
         25 . A pharmaceutical composition for oral administration comprising an Hsp60 fragment or analog.  
     
     
         26 . The pharmaceutical composition of  claim 25  wherein said Hsp60 fragment or analog comprises residues 437-460 having the sequence Val-Leu-Gly-Gly-Gly-Cys-Ala-Leu-Leu-Arg-Cys-Ile-Pro-Ala-Leu-Asp-Ser-Leu-Thr-Pro-Ala-Asn-Glu-Asp (SEQ ID NO:1).  
     
     
         27 . The pharmaceutical composition of  claim 25  wherein said Hsp60 fragment or analog comprises DiaPep277 having the sequence: Val-Leu-Gly-Gly-Gly-Val-Ala-Leu-Leu-Arg-Val-Ile-Pro-Ala-Leu-Asp-Ser-Leu-Thr-Pro-Ala-Asn-Glu-Asp (SEQ ID NO:2).  
     
     
         28 . The pharmaceutical composition of  claim 25  wherein said Hsp60 fragment is selected from a sequence consisting of:  
       
         
           
                 
                 
                 
               
                     
                 
                   residues 31-50 of human Hsp60: 
                     
                     
                 
                   Lys-Phe-Gly-Ala-Asp-Ala-Arg-Ala-Leu- 
                   (SEQ ID NO:3) 
                 
                     
                 
                   Met-Leu-Gln-Gly-Val-Asp-Leu-Leu-Ala- 
                 
                     
                 
                   Asp-Ala; 
                 
                     
                 
                   residues 136-155 of human Hsp60: 
                 
                   Asn-Pro-Val-Glu-Ile-Arg-Arg-Gly-Val- 
                   (SEQ ID NO:4) 
                 
                     
                 
                   Met-Leu-Ala-Val-Asp-Ala-Val-Ile-Ala- 
                 
                     
                 
                   Glu-Leu; 
                 
                     
                 
                   residues 151-170 of human Hsp60: 
                 
                   Val-Ile-Ala-Glu-Leu-Lys-Lys-Gln-Ser- 
                   (SEQ ID NO:5) 
                 
                     
                 
                   Lys-Pro-Val-Thr-Thr-Pro-Glu-Glu-Ile- 
                 
                     
                 
                   Ala-Gln; 
                 
                     
                 
                   residues 166-185 of human Hsp60: 
                 
                   Glu-Glu-Ile-Ala-Gln-Val-Ala-Thr-Ile- 
                   (SEQ ID NO:6) 
                 
                     
                 
                   Ser-Ala-Asn-Gly-Asp-Lys-Glu-Ile-Gly- 
                 
                     
                 
                   Asn-Ile; 
                 
                     
                 
                   residues 195-214 of human Hsp60: 
                 
                   Arg-Lys-Gly-Val-Ile-Thr-Val-Lys-Asp- 
                   (SEQ ID NO:7) 
                 
                     
                 
                   Gly-Lys-Thr-Leu-Asn-Asp-Glu-Leu-Glu- 
                 
                     
                 
                   Ile-Ile; 
                 
                     
                 
                   residues 255-274 of human Hsp60: 
                 
                   Gln-Ser-Ile-Val-Pro-Ala-Leu-Glu-Ile- 
                   (SEQ ID NO:8) 
                 
                     
                 
                   Ala-Asn-Ala-His-Arg-Lys-Pro-Leu-Val- 
                 
                     
                 
                   Ile-Ile; 
                 
                     
                 
                   residues 286-305 of human Hsp60: 
                 
                   Leu-Val-Leu-Asn-Arg-Leu-Lys-Val-Gly- 
                   (SEQ ID NO:9) 
                 
                     
                 
                   Leu-Gln-Val-Val-Ala-Val-Lys-Ala-Pro- 
                 
                     
                 
                   Gly-Phe; 
                 
                     
                 
                   residues 346-365 of human Hsp60: 
                 
                   Gly-Glu-Val-Ile-Val-Thr-Lys-Asp-Asp- 
                   (SEQ ID NO:10) 
                 
                     
                 
                   Ala-Met-Leu-Leu-Lys-Gly-Lys-Gly-Asp- 
                 
                     
                 
                   Lys-Ala; 
                 
                     
                 
                   residues 421-440 of human Hsp60: 
                 
                   Val-Thr-Asp-Ala-Leu-Asn-Ala-Thr-Arg- 
                   (SEQ ID NO:11) 
                 
                     
                 
                   Ala-Ala-Val-Glu-Glu-Gly-Ile-Val-Leu- 
                 
                     
                 
                   Gly-Gly; 
                 
                     
                 
                   residues 436-455 of human Hsp60: 
                 
                   Ile-Val-Leu-Gly-Gly-Gly-Cys-Ala-Leu- 
                   (SEQ ID NO:12) 
                 
                     
                 
                   Leu-Arg-Cys-Ile-Pro-Ala-Leu-Asp-Ser- 
                 
                     
                 
                   Leu-Thr; 
                 
                     
                 
                   residues 466-485 of human Hsp60: 
                 
                   Glu-Ile-Ile-Lys-Arg-Thr-Leu-Lys-Ile- 
                   (SEQ ID NO:13) 
                 
                     
                 
                   Pro-Ala-Met-Thr-Ile-Ala-Lys-Asn-Ala- 
                 
                     
                 
                   Gly-Val; 
                 
                     
                 
                   residues 511-530 of human Hsp60: 
                 
                   Val-Asn-Met-Val-Glu-Lys-Gly-Ile-Ile- 
                   (SEQ ID NO:14) 
                 
                     
                 
                   Asp-Pro-Thr-Lys-Val-Val-Arg-Thr-Ala- 
                 
                     
                 
                   Leu-Leu; 
                 
                     
                 
                   residues 343-366 of human Hsp60: 
                 
                   Gly-Lys-Val-Gly-Glu-Val-Ile-Val-Thr- 
                   (SEQ ID NO:15) 
                 
                     
                 
                   Lys-Asp-Asp-Ala-Met; 
                 
                     
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
       or a salt or functional derivative thereof.  
     
     
         29 . The pharmaceutical composition according to  claim 25  wherein the Hsp60 fragment or analog is administered in a dosage ranging from about 0.02 mg/kg to about 10 mg/kg.  
     
     
         30 . A method of treating an individual in need thereof by administering a pharmaceutical composition comprising a fragment or an analog of a heat shock protein in conjunction with maintenance of a low antigenicity diet.  
     
     
         31 . The method of  claim 30  wherein the heat shock protein is Hsp60.  
     
     
         32 . The method of  claim 30  wherein the fragment of the heat shock protein comprises residues 437-460 having the sequence Val-Leu-Gly-Gly-Gly-Cys-Ala-Leu-Leu-Arg-Cys-Ile-Pro-Ala-Leu-Asp-Ser-Leu-Thr-Pro-Ala-Asn-Glu-Asp (SEQ ID NO:1).  
     
     
         33 . The method of  claim 30  wherein the fragment or the analog of the heat shock protein comprises DiaPep277 having the sequence: Val-Leu-Gly-Gly-Gly-Val-Ala-Leu-Leu-Arg-Val-Ile-Pro-Ala-Leu-Asp-Ser-Leu-Thr-Pro-Ala-Asn-Glu-Asp (SEQ ID NO:2), and the diet comprises a hydrolyzed casein diet.  
     
     
         34 . The method of  claim 30  wherein the fragment of the heat shock protein is selected from a sequence consisting of:  
       
         
           
                 
                 
                 
               
                     
                 
                   residues 31-50 of human Hsp60: 
                     
                     
                 
                   Lys-Phe-Gly-Ala-Asp-Ala-Arg-Ala-Leu- 
                   (SEQ ID NO:3) 
                 
                     
                 
                   Met-Leu-Gln-Gly-Val-Asp-Leu-Leu-Ala- 
                 
                     
                 
                   Asp-Ala; 
                 
                     
                 
                   residues 136-155 of human Hsp60: 
                 
                   Asn-Pro-Val-Glu-Ile-Arg-Arg-Gly-Val- 
                   (SEQ ID NO:4) 
                 
                     
                 
                   Met-Leu-Ala-Val-Asp-Ala-Val-Ile-Ala- 
                 
                     
                 
                   Glu-Leu; 
                 
                     
                 
                   residues 151-170 of human Hsp60: 
                 
                   Val-Ile-Ala-Glu-Leu-Lys-Lys-Gln-Ser- 
                   (SEQ ID NO:5) 
                 
                     
                 
                   Lys-Pro-Val-Thr-Thr-Pro-Glu-Glu-Ile- 
                 
                     
                 
                   Ala-Gln; 
                 
                     
                 
                   residues 166-185 of human Hsp60: 
                 
                   Glu-Glu-Ile-Ala-Gln-Val-Ala-Thr-Ile- 
                   (SEQ ID NO:6) 
                 
                     
                 
                   Ser-Ala-Asn-Gly-Asp-Lys-Glu-Ile-Gly- 
                 
                     
                 
                   Asn-Ile; 
                 
                     
                 
                   residues 195-214 of human Hsp60: 
                 
                   Arg-Lys-Gly-Val-Ile-Thr-Val-Lys-Asp- 
                   (SEQ ID NO:7) 
                 
                     
                 
                   Gly-Lys-Thr-Leu-Asn-Asp-Glu-Leu-Glu- 
                 
                     
                 
                   Ile-Ile; 
                 
                     
                 
                   residues 255-274 of human Hsp60: 
                 
                   Gln-Ser-Ile-Val-Pro-Ala-Leu-Glu-Ile- 
                   (SEQ ID NO:8) 
                 
                     
                 
                   Ala-Asn-Ala-His-Arg-Lys-Pro-Leu-Val- 
                 
                     
                 
                   Ile-Ile; 
                 
                     
                 
                   residues 286-305 of human Hsp60: 
                 
                   Leu-Val-Leu-Asn-Arg-Leu-Lys-Val-Gly- 
                   (SEQ ID NO:9) 
                 
                     
                 
                   Leu-Gln-Val-Val-Ala-Val-Lys-Ala-Pro- 
                 
                     
                 
                   Gly-Phe; 
                 
                     
                 
                   residues 346-365 of human Hsp60: 
                 
                   Gly-Glu-Val-Ile-Val-Thr-Lys-Asp-Asp- 
                   (SEQ ID NO:10) 
                 
                     
                 
                   Ala-Met-Leu-Leu-Lys-Gly-Lys-Gly-Asp- 
                 
                     
                 
                   Lys-Ala; 
                 
                     
                 
                   residues 421-440 of human Hsp60: 
                 
                   Val-Thr-Asp-Ala-Leu-Asn-Ala-Thr-Arg- 
                   (SEQ ID NO:11) 
                 
                     
                 
                   Ala-Ala-Val-Glu-Glu-Gly-Ile-Val-Leu- 
                 
                     
                 
                   Gly-Gly; 
                 
                     
                 
                   residues 436-455 of human Hsp60: 
                 
                   Ile-Val-Leu-Gly-Gly-Gly-Cys-Ala-Leu- 
                   (SEQ ID NO:12) 
                 
                     
                 
                   Leu-Arg-Cys-Ile-Pro-Ala-Leu-Asp-Ser- 
                 
                     
                 
                   Leu-Thr; 
                 
                     
                 
                   residues 466-485 of human Hsp60: 
                 
                   Glu-Ile-Ile-Lys-Arg-Thr-Leu-Lys-Ile- 
                   (SEQ ID NO:13) 
                 
                     
                 
                   Pro-Ala-Met-Thr-Ile-Ala-Lys-Asn-Ala- 
                 
                     
                 
                   Gly-Val; 
                 
                     
                 
                   residues 511-530 of human Hsp60: 
                 
                   Val-Asn-Met-Val-Glu-Lys-Gly-Ile-Ile- 
                   (SEQ ID NO:14) 
                 
                     
                 
                   Asp-Pro-Thr-Lys-Val-Val-Arg-Thr-Ala- 
                 
                     
                 
                   Leu-Leu; 
                 
                     
                 
                   residues 343-366 of human Hsp60: 
                 
                   Gly-Lys-Val-Gly-Glu-Val-Ile-Val-Thr- 
                   (SEQ ID NO:15) 
                 
                     
                 
                   Lys-Asp-Asp-Ala-Met; 
                 
                     
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
       or a salt or functional derivative thereof.  
     
     
         35 . The method of  claim 30  wherein the Hsp60 fragment or analog is administered orally.  
     
     
         36 . The method according to  claim 35  wherein the Hsp60 fragment or analog is administered in a dosage ranging from about 0.02 mg/kg to about 10 mg/kg.  
     
     
         37 . A pharmaceutical composition for improvement of the protective effect of a low antigenicity diet comprising as an active ingredient a fragment of hsp60 or an analog thereof.  
     
     
         38 . The pharmaceutical composition of  claim 37  wherein a diabetogenic protein is omitted from the diet or replaced with hydrolyzed or denatured form.  
     
     
         39 . The pharmaceutical composition of  claim 38  wherein the diabetogenic protein is selected from the group consisting of: casein, lactoglobulin, albumin, (pro)insulin, wheat gluten, soy bean proteins, and heat shock proteins.  
     
     
         40 . The pharmaceutical composition of  claim 37  wherein the diet comprises hydrolyzed or denatured protein.  
     
     
         41 . The pharmaceutical composition of  claim 40  wherein the hydrolyzed protein is selected from the group consisting of: casein hydrolysate, whey hydrolysate, soy hydrolysate, or a mixture thereof.  
     
     
         42 . The pharmaceutical composition of  claim 40  wherein the hydrolyzed protein is hydrolyzed casein.  
     
     
         43 . The pharmaceutical composition of  claim 37  wherein the protein source of the diet is replaced with free amino acids, short-chain peptides, or mixtures thereof.  
     
     
         44 . The pharmaceutical composition of  claim 37  wherein the diabetes is type 1 diabetes.  
     
     
         45 . The pharmaceutical composition of  claim 37  wherein the diabetes is latent autoimmune diabetes in adults (LADA).  
     
     
         46 . The pharmaceutical composition of  claim 37  wherein the Hsp60 fragment or analog comprises residues 437-460 having the sequence Val-Leu-Gly-Gly-Gly-Cys-Ala-Leu-Leu-Arg-Cys-Ile-Pro-Ala-Leu-Asp-Ser-Leu-Thr-Pro-Ala-Asn-Glu-Asp (SEQ ID NO:1).  
     
     
         47 . The pharmaceutical composition of  claim 37  wherein the Hsp60 fragment or analog comprises DiaPep277 having the sequence: Val-Leu-Gly-Gly-Gly-Val-Ala-Leu-Leu-Arg-Val-Ile-Pro-Ala-Leu-Asp-Ser-Leu-Thr-Pro-Ala-Asn-Glu-Asp (SEQ ID NO:2).  
     
     
         48 . The pharmaceutical composition of  claim 37  wherein the Hsp60 fragment is selected from a sequence consisting of:  
       
         
           
                 
                 
                 
               
                     
                 
                   residues 31-50 of human Hsp60: 
                     
                     
                 
                   Lys-Phe-Gly-Ala-Asp-Ala-Arg-Ala-Leu- 
                   (SEQ ID NO:3) 
                 
                     
                 
                   Met-Leu-Gln-Gly-Val-Asp-Leu-Leu-Ala- 
                 
                     
                 
                   Asp-Ala; 
                 
                     
                 
                   residues 136-155 of human Hsp60: 
                 
                   Asn-Pro-Val-Glu-Ile-Arg-Arg-Gly-Val- 
                   (SEQ ID NO:4) 
                 
                     
                 
                   Met-Leu-Ala-Val-Asp-Ala-Val-Ile-Ala- 
                 
                     
                 
                   Glu-Leu; 
                 
                     
                 
                   residues 151-170 of human Hsp60: 
                 
                   Val-Ile-Ala-Glu-Leu-Lys-Lys-Gln-Ser- 
                   (SEQ ID NO:5) 
                 
                     
                 
                   Lys-Pro-Val-Thr-Thr-Pro-Glu-Glu-Ile- 
                 
                     
                 
                   Ala-Gln; 
                 
                     
                 
                   residues 166-185 of human Hsp60: 
                 
                   Glu-Glu-Ile-Ala-Gln-Val-Ala-Thr-Ile- 
                   (SEQ ID NO:6) 
                 
                     
                 
                   Ser-Ala-Asn-Gly-Asp-Lys-Glu-Ile-Gly- 
                 
                     
                 
                   Asn-Ile; 
                 
                     
                 
                   residues 195-214 of human Hsp60: 
                 
                   Arg-Lys-Gly-Val-Ile-Thr-Val-Lys-Asp- 
                   (SEQ ID NO:7) 
                 
                     
                 
                   Gly-Lys-Thr-Leu-Asn-Asp-Glu-Leu-Glu- 
                 
                     
                 
                   Ile-Ile; 
                 
                     
                 
                   residues 255-274 of human Hsp60: 
                 
                   Gln-Ser-Ile-Val-Pro-Ala-Leu-Glu-Ile- 
                   (SEQ ID NO:8) 
                 
                     
                 
                   Ala-Asn-Ala-His-Arg-Lys-Pro-Leu-Val- 
                 
                     
                 
                   Ile-Ile; 
                 
                     
                 
                   residues 286-305 of human Hsp60: 
                 
                   Leu-Val-Leu-Asn-Arg-Leu-Lys-Val-Gly- 
                   (SEQ ID NO:9) 
                 
                     
                 
                   Leu-Gln-Val-Val-Ala-Val-Lys-Ala-Pro- 
                 
                     
                 
                   Gly-Phe; 
                 
                     
                 
                   residues 346-365 of human Hsp60: 
                 
                   Gly-Glu-Val-Ile-Val-Thr-Lys-Asp-Asp- 
                   (SEQ ID NO:10) 
                 
                     
                 
                   Ala-Met-Leu-Leu-Lys-Gly-Lys-Gly-Asp- 
                 
                     
                 
                   Lys-Ala; 
                 
                     
                 
                   residues 421-440 of human Hsp60: 
                 
                   Val-Thr-Asp-Ala-Leu-Asn-Ala-Thr-Arg- 
                   (SEQ ID NO:11) 
                 
                     
                 
                   Ala-Ala-Val-Glu-Glu-Gly-Ile-Val-Leu- 
                 
                     
                 
                   Gly-Gly; 
                 
                     
                 
                   residues 436-455 of human Hsp60: 
                 
                   Ile-Val-Leu-Gly-Gly-Gly-Cys-Ala-Leu- 
                   (SEQ ID NO:12) 
                 
                     
                 
                   Leu-Arg-Cys-Ile-Pro-Ala-Leu-Asp-Ser- 
                 
                     
                 
                   Leu-Thr; 
                 
                     
                 
                   residues 466-485 of human Hsp60: 
                 
                   Glu-Ile-Ile-Lys-Arg-Thr-Leu-Lys-Ile- 
                   (SEQ ID NO:13) 
                 
                     
                 
                   Pro-Ala-Met-Thr-Ile-Ala-Lys-Asn-Ala- 
                 
                     
                 
                   Gly-Val; 
                 
                     
                 
                   residues 511-530 of human Hsp60: 
                 
                   Val-Asn-Met-Val-Glu-Lys-Gly-Ile-Ile- 
                   (SEQ ID NO:14) 
                 
                     
                 
                   Asp-Pro-Thr-Lys-Val-Val-Arg-Thr-Ala- 
                 
                     
                 
                   Leu-Leu; 
                 
                     
                 
                   residues 343-366 of human Hsp60: 
                 
                   Gly-Lys-Val-Gly-Glu-Val-Ile-Val-Thr- 
                   (SEQ ID NO:15) 
                 
                     
                 
                   Lys-Asp-Asp-Ala-Met; 
                 
                     
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
       or a salt or functional derivative thereof.  
     
     
         49 . The pharmaceutical composition of  claim 37  wherein the Hsp60 fragment or analog is administered orally.  
     
     
         50 . The pharmaceutical composition according to  claim 49  wherein the Hsp60 fragment or analog is administered in a dosage ranging from about 0.02 mg/kg to about 10 mg/kg.

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