Immunogenic fragments of t-cell receptor constant domains and peptides derived therefrom

Abstract

The present invention is directed to an isolated T-Cell Receptor constant domain and to peptides derived therefrom and recombinant constructs encoding same, effective in therapy of T cell mediated inflammatory disease, autoimmunity and graft rejection. Therapeutic and prophylactic vaccine compositions and methods utilizing these proteins and peptides, DNA vaccines encoding same and T cell vaccines thereof are further provided.

1 - 71 . (canceled) 
     
     
         72 . A vaccine composition comprising:
 (a) at least one pharmaceutically acceptable carrier, adjuvant, excipient or diluent; and   (b) at least one peptide immunogen comprising an immunogenic fragment of the constant domain of a chain of a TCR,   wherein the immunogenic fragment of the constant domain of a chain of a TCR is at least 12 amino acid residues in length and exhibits at least one Major Histocompatibility Complex (MHC) Class II binding motif, and wherein said peptide immunogen elicits an immune response to the constant domain of the TCR chain as measured by an increased anti-ergotypic T cell activity.   
     
     
         73 . The composition of  claim 72 , wherein the chain of a TCR is selected from the group consisting of TCR alpha chains and the peptide immunogen comprises an amino acid sequence as set forth in any one of SEQ ID NOS: 1-27, conservative variations, and salts thereof. 
     
     
         74 . The composition of  claim 72 , wherein the chain a TCR is selected from the group consisting of TCR beta chains and the peptide immunogen has an amino acid sequence as set forth in any one of SEQ ID NOS: 28-64, conservative variations, and salts thereof. 
     
     
         75 . The composition of  claim 74 , wherein the peptide immunogen is a peptide of up to about 50 amino acids in length comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 47-52, 55, 59, 64 and 152, conservative variations, and salts thereof. 
     
     
         76 . The composition of  claim 74 , wherein the peptide comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 51, 59 and 152. 
     
     
         77 . The composition of  claim 72 , wherein the chain of a TCR is selected from the group consisting of TCR gamma chains and TCR delta chains and the peptide immunogen comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 65-92, 93-146 and 157-167, conservative variations, and salts thereof. 
     
     
         78 . The composition of  claim 72 , wherein said peptide immunogen is a fusion peptide comprising a plurality of peptide sequences derived from at least one TCR constant domain and a plurality of MHC-II binding motifs, wherein at least one peptide sequence derived from the at least one TCR constant domain comprises an amino acid sequence as set forth in any one of SEQ ID NOs:1-146. 
     
     
         79 . The composition of  claim 78 , wherein at least one of the plurality of peptide sequences derived from the at least one TCR constant domain has an amino acid sequence as set forth in any one of SEQ ID NOs: 47-52, 55, 64 and 152. 
     
     
         80 . The composition of  claim 72 , wherein the adjuvant is a metabolizable lipid emulsion. 
     
     
         81 . A DNA vaccine composition comprising (a) at least one pharmaceutically acceptable carrier; and (b) at least one recombinant construct comprising an isolated nucleic acid sequence encoding at least one immunogen selected from the group consisting of:
 (i) the constant domain of a chain of a human T Cell Receptor (TCR); and   (ii) a peptide comprising an immunogenic fragment of the constant domain of a chain of a TCR, wherein the immunogenic fragment of the constant domain of a chain of a TCR is at least 12 amino acid residues in length, exhibits at least one Major Histocompatibility Complex (MHC) Class II binding motif, and elicits an immune response to the constant domain of a TCR chain as measured by an increased anti-ergotypic T cell activity, said peptide having an amino acid sequence as set forth in any one of SEQ ID NOs: 1-146 and 157-167,   
       wherein the nucleic acid sequence is operatively linked to one or more transcription control sequences. 
     
     
         82 . A method of treating or preventing the development of a T-cell mediated inflammatory autoimmune disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a vaccine composition according to  claim 72 . 
     
     
         83 . The method of  claim 82 , wherein said T cell-mediated inflammatory disease is selected from the group consisting of: multiple sclerosis, rheumatoid arthritis, juvenile rheumatoid arthritis, autoimmune neuritis, systemic lupus erythematosus, psoriasis, Type I diabetes, Sjogren's disease, thyroid disease, myasthenia gravis, sarcoidosis, autoimmune uveitis, inflammatory bowel disease (Crohn's and ulcerative colitis), autoimmune hepatitis, graft rejection, and allergies. 
     
     
         84 . The method of  claim 82 , wherein said composition is administered to said subject prior to the appearance of disease symptoms. 
     
     
         85 . A method of treating or preventing the development of a T-cell mediated inflammatory disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of at least one DNA vaccine composition according to  claim 81 . 
     
     
         86 . A method of enhancing anti-ergotypic T cells activity in a subject in need thereof, the method comprising administering to a subject in need thereof a therapeutically effective amount of the vaccine composition of  claim 72 . 
     
     
         87 . A method of enhancing anti-ergotypic T cells activity in a subject in need thereof, the method comprising administering to a subject in need thereof a therapeutically effective amount of the DNA vaccine composition of  claim 81 . 
     
     
         88 . A method of diagnosing a condition associated with an immune response in a subject in need thereof, the method comprising:
 (i) obtaining an antibody-containing biological sample from a subject;   (iii) contacting the sample, under conditions such that an antigen-antibody complex may be formed, with an antigen probe comprising a peptide having an amino acid sequence as set forth in any one of SEQ ID NOs: 1-146 and 157-167, conservative variations, and salts thereof; and   (iii) determining the capacity of the antigen probe to specifically bind said antibody-containing biological sample, wherein the capacity is indicative of the condition.