Immunogenic peptides and their use in transplantation

Abstract

The present invention relates to the use of immunogenic peptides comprising a T-cell epitope derived from an allograft antigen and a redox motif such as C-(X)2-[CST] or [CST]-(X)2-C in the prevention and/or treatment of allograft rejection and in the manufacture of medicaments therefore.

I claim: 
     
         1 . An isolated immunogenic peptide with a length of between 12 and 75 amino acids comprising:
 (i) an MHC class II T-cell epitope of an alloantigenic protein of an allograft, and   (ii) C-(X)2-[CST] or [CST]-(X)2-C redox motif,   
       wherein said epitope and said motif are immediately adjacent to each other or are separated by at most 7 amino acids. 
     
     
         2 . The peptide according to  claim 1 , wherein the sequence of said antigen does not comprise said redox motif within a region of 11 amino acids N- or C terminally of said MHC class II T-cell epitope in said alloantigenic protein. 
     
     
         3 . The peptide according to  claim 1 , wherein the sequence of said antigen does not comprise a C-(X)2-[CST] or [CST]-(X)2-C redox motif sequence within its sequence. 
     
     
         4 . The peptide according to  claim 1 , wherein said motif is C-X(2)-C. 
     
     
         5 . The peptide according to  claim 1 , wherein said epitope and said motif are immediately adjacent to each other or are separated by at most 4 amino acids. 
     
     
         6 . The peptide according to  claim 1 , which has a length of between 12 and 50 amino acids. 
     
     
         7 . The peptide according to  claim 1 , wherein said allograft is a solid organ graft. 
     
     
         8 . The peptide according to  claim 6 , wherein said solid organ graft is selected from the group consisting of kidney, lung, heart, liver, pancreas, bone and skin. 
     
     
         9 . The peptide according to  claim 1 , wherein said allograft is a cellular graft. 
     
     
         10 . The peptide according to  claim 9 , wherein said cellular graft is selected from the group consisting of a bone marrow graft, a cord blood cell graft, a stem cell graft, and a pancreatic islet cell graft. 
     
     
         11 . The peptide according to  claim 1 , wherein said alloantigenic protein is selected from the group of minor histocompatibility antigens, major histocompatibility antigens or tissue-specific antigens. 
     
     
         12 . The peptide according to  claim 11 , wherein said tissue specific antigen is the Dby antigen or wherein said major histocompatibility antigen is an MHC class I-antigen or an MHC class II-antigen. 
     
     
         13 . The peptide according to  claim 1 , wherein said immunogenic peptide further comprises an endosomal targeting sequence. 
     
     
         14 . The peptide according to  claim 1 , wherein at least one X in said motif is Gly, Ala, Ser or Thr or wherein at least one X in said motif is His or Pro, or wherein at least one C in said motif is methylated. 
     
     
         15 . A method for preparing an immunogenic peptide capable of eliciting a population of allograft antigen-specific cytolytic CD4+ T cells, the method comprising the steps of:
 a) identifying in an alloantigenic protein of an allograft an MHC class II T cell epitope, and   b) synthesising a peptide of between 12 and 75 amino acids comprising the se sequence of said identified MHC class II T cell epitope and comprising an C-(X)2-[CST] or [CST]-(X)2-C redox motif sequence whereby said epitope and said motif are immediately adjacent to each other or are separated by at most 7 amino acids.   
     
     
         16 . A method for obtaining a population of allograft antigen-specific cytolytic CD4+ T cells, the method comprising the steps of:
 providing peripheral blood cells;   contacting said cells with an immunogenic peptide of between 12 and 75 amino acids comprising (i) an MCH class II T-cell epitope of an allograft antigenic protein and (ii) a C-(X)2-[CST] or [CST]-(X)2-C redox motif wherein said epitope and said motif are immediately adjacent to each other or are separated by at most 7 amino acids; and   expanding said cells in the presence of IL-2.   
     
     
         17 . A method for obtaining a population of allograft antigen-specific cytolytic CD4+ T cells, the method comprising the steps of:
 providing an immunogenic peptide of between 12 and 75 amino acids comprising   (i) an MHC class II T-cell epitope of an allograft antigenic protein and   (ii) a C-(X)2-[CST] or [CST]-(X)2-C redox motif wherein said epitope and said motif are immediately adjacent to each other or are separated by at most 7 amino acids;   administering said immunogenic peptide to a subject; and   obtaining said population of allograft antigen-specific cytolytic CD4+ T cells from said subject.   
     
     
         18 . A population of allograft antigen-specific cytolytic CD4+ T cells obtainable by the method according to  claim 16   
     
     
         19 . A population of allograft antigen-specific cytolytic CD4+ T cells obtainable by the method according to  claim 17 . 
     
     
         20 . A method for preventing or treating in a mammalian recipient the rejection of an allograft comprising the steps of administering to said recipient, prior to or after introducing said allograft population of cells according to  claim 18 . 
     
     
         21 . A method for preventing or treating in a mammalian recipient the rejection of an allograft comprising the steps of administering to said recipient, prior to or after introducing said allograft population of cells according to  claim 19 . 
     
     
         22 . A method for preventing or treating in a mammalian recipient the rejection of an allograft comprising the steps of administering to said recipient, prior to or after introducing said allograft, at least one isolated immunogenic peptide with a length of between 12 and 75 amino acids comprising:
 (a) an MHC class II T-cell epitope of an alloantigenic protein of said allograft and   (b) a C-(X)2-[CST] or [CST]-(X)2-C redox motif, wherein said epitope and said motif are immediately adjacent to each other or are separated by at most 7 amino acids.