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] (SEQ ID NO: 18) or [CST]-(X)2-C(SEQ ID NO: 19) in the prevention and/or treatment of allograft rejection and in the manufacture of medicaments therefore.
1 - 28 . (canceled)
29 . A method of preventing or treating in a recipient the rejection of a mammalian allograft, said method comprising administering a peptide comprising (i) a T-cell epitope derived from an alloantigenic protein of said allograft and comprising (ii) a C-XX-[CST] (SEQ ID NO: 18) or [CST]-XX-C(SEQ ID NO: 19) motif.
30 . The method according to claim 29 , wherein said allograft is a solid organ graft.
31 . The method according to claim 30 , wherein said solid organ graft is selected from the group consisting of: kidney, lung, heart, liver, pancreas, bone and skin.
32 . The method according to claim 29 , wherein said allograft is a cellular graft.
33 . The method according to claim 29 , wherein said allograft is a bone marrow graft.
34 . The method according to claim 32 , wherein said cellular graft is a cord blood cell graft, stem cell graft, or pancreatic islet cell graft.
35 . The method according to claim 29 , wherein said alloantigenic protein is selected from the group of minor histocompatibility antigens, major histocompatibility antigens or tissue-specific antigens.
36 . The method according to claim 29 , wherein said major histocompatibility antigen is an MEW class I-antigen or an MEW class II-antigen.
37 . The method according to claim 29 , wherein said C-XX-[CST] (SEQ ID NO: 18) or [CST]-XX-C(SEQ ID NO: 19) motif is adjacent to said T-cell epitope, or is separated from said T-cell epitope by a linker.
38 . The method according to claim 37 , wherein said linker consists of at most 7 amino acids.
39 . The method according to claim 29 , wherein said C-XX-[CST] (SEQ ID NO: 18) or [CST]-XX-C(SEQ ID NO: 19) motif does not naturally occur within a region of 11 amino acids N- or C-terminally adjacent to the T-cell epitope in said alloantigenic protein.
40 . The method according to claim 29 , wherein said immunogenic peptide further comprises an endosomal targeting sequence.
41 . The method according to claim 29 , wherein said C-XX-[CST] (SEQ ID NO: 18) or [CST]-XX-C(SEQ ID NO: 19) motif is positioned N-terminally of the T-cell epitope.
42 . A method for obtaining a population of allograft antigen-specific regulatory T cells with cytotoxic properties, the method comprising the steps of:
providing peripheral blood cells;
contacting said cells with an immunogenic peptide comprising (i) a T-cell epitope derived from an allograft antigenic protein and (ii) a C-(X)2-[CST] (SEQ ID NO: 18) or [CST]-(X)2-C(SEQ ID NO: 19) motif; and
expanding said cells in the presence of IL-2.
43 . 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, wherein said alloantigenic protein does not comprise C-XX-[CST] (SEQ ID NO: 18) or [CST]-XX-C(SEQ ID NO: 19) within 11 amino acids N- or C-terminally of said epitope in said alloantigenic protein, and
(ii) a redox motif, which is C-(X)2-[CST] (SEQ ID NO: 18) or [CST]-(X)2-C(SEQ ID NO: 19);
wherein said epitope and said motif are immediately adjacent to each other or are separated by at most 7 amino acids.
44 . The peptide according to claim 44 , wherein said alloantigenic protein does not comprise said motif.
45 . The peptide according to claim 44 , wherein said epitope and said motif are immediately adjacent to each other or are separated by at most 4 amino acids in said peptide.
46 . The peptide according to claim 44 , which has a length of between 12 and 50 amino acids.
47 . The peptide according to claim 44 , wherein said allograft is a solid organ graft or a cellular graft.
48 . The peptide according to claim 44 , wherein said immunogenic peptide further comprises an endosomal targeting sequence.