Immunogenic peptides and their use in transplantation
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.
1. A method of suppressing an immune response against an allogeneic protein expressed by a mammalian solid organ allograft, comprising the steps of administering to a recipient, prior to or after introducing said allograft to said recipient, at least one isolated immunogenic peptide with a length of between 13 and 50 amino acids, said peptide comprising (i) an MHC class II restricted T-cell epitope of 9 amino acids of said allogeneic protein expressed by said allograft and comprising (ii) a C-(X)2-C redox motif, wherein X is not cysteine, and wherein said motif is adjacent to said T-cell epitope, or is separated from said T-cell epitope by a linker of at most 4 amino acids, wherein said administering generates a population of cytotoxic CD4+ T cells against antigen presenting cells presenting said allogeneic protein.
2. The method of claim 1 , said immunogenic peptide suppressing activation of CD4+ effector T-cells of said recipient by an alloantigenic protein of said allograft.
3. The method of claim 1 , said immunogenic peptide inducing in a recipient CD4+ regulatory T cells which are cytotoxic to cells presenting an alloantigenic protein of said allograft.
4. The method of claim 1 , said immunogenic peptide suppressing activation of CD8+ effector T-cells of the recipient by an alloantigenic protein of said allograft.
5. The method according to claim 1 wherein said solid organ graft is a kidney, lung, heart, liver, pancreas, bone or skin.
6. The method according to claim 1 , wherein said allogeneic protein is selected from the group of minor histocompatibility antigens, major histocompatibility antigens or tissue-specific antigens.
7. The method according to claim 1 wherein said motif does not naturally occur within a region of 11 amino acids N- or C-terminally adjacent to the T-cell epitope in said allogeneic protein.
8. The method according to claim 1 wherein said immunogenic peptide further comprises an endosomal targeting sequence.
9. The method according to claim 1 wherein said motif is positioned N-terminally of the T-cell epitope.
10. The method according to claim 1 wherein at least one X in said motif is Gly, Ala, Ser or Thr.
11. The method according to claim 1 wherein at least one X in said motif is His or Pro.
12. The method according to claim 1 wherein at least one C in said motif is methylated.
13. The method according to claim 1 wherein said immunogenic peptide is produced by chemical synthesis or by recombinant expression.
14. The method according to claim 1 wherein said allogeneic protein is the Dby antigen encoded by the H-Y chromosome.
15. The method according to claim 1 , wherein the recipient is a human and said solid organ allograft is a human solid organ.