STRATEGIES TO PREVENT AND/OR TREAT IMMUNIE RESPONSES TO SOLUBLE ALLOFACTORS
The present invention relates to the use of immunogenic peptides comprising a T-cell epitope derived from a soluble allofactor and a redox motif such as C-(X)2-[CST] or [CST]-(X)2-C in the prevention and/or suppression of immune responses to said soluble allofactor and in the manufacture of medicaments therefore.
1 . A method of manufacturing a medicament comprising formulating a medicament comprising at least one isolated immunogenic peptide said medicament preventing or suppressing, in a subject expected to receive, receiving or having received a soluble allofactor, the immune responses to said soluble allofactor, the immunogenic peptide comprising (i) a T-cell epitope derived from the soluble allofactor and (ii) a C-(X)2-[CST] or [CST]-(X)2-C motif.
2 . The method of claim 1 , said medicament preventing, in a subject to receive, receiving or having received said soluble allofactor, activation of CD4+ effector T-cells by said soluble allofactor.
3 . The method of claim 1 , said medicament inducing, in a subject to receive, receiving or having received said soluble allofactor, CD4+ regulatory T cells which are cytotoxic to cells presenting said soluble allofactor.
4 . The method according to claim 1 wherein said soluble allofactor is used in replacement therapy.
5 . The method according to claim 1 wherein said soluble allofactor is a coagulation or fibrinolytic factor.
6 . The method according to claim 1 wherein said soluble allofactor is a hormone.
7 . The method according to claim 1 wherein said soluble allofactor is a cytokine or a growth factor.
8 . The method according to claim 1 wherein said soluble allofactor is an antibody used for therapeutic purpose.
9 . The method according to claim 1 wherein said C-(X)2-[CST] or [CST]-(X)2-C motif is adjacent to said T-cell epitope, or is separated from said T-cell epitope by a linker.
10 . The method according to claim 9 wherein said linker consists of at most 7 amino acids.
11 . The method according to claim 1 wherein said C-(X)2-[CST] or [CST]-(X)2-C motif does not naturally occur within a region of 11 amino acids N- or C-terminally adjacent to the T-cell epitope in said soluble allofactor.
12 . The method according to claim 1 wherein said immunogenic peptide further comprises an endosomal targeting sequence.
13 . The method according to claim 1 4 - 2 wherein said C-(X)2-[CST] or [CST]-(X)2-C motif is positioned N-terminally of the T-cell epitope.
14 . The method according to claim 1 wherein at least one X in said C-(X)2-[CST] or [CST]-(X)2-C motif is Gly, Ala, Ser or Thr.
15 . The method according to claim 1 wherein at least one X in said C-(X)2-[CST] or [CST]-(X)2-C motif is His or Pro.
16 . The method according to claim 1 wherein at least one C in said C-(X)24CST] or [CST]-(X)2-C motif is methylated.
17 . The method according to claim 1 wherein said immunogenic peptide is produced by chemical synthesis or by recombinant expression.
18 . A method for obtaining a population of soluble allofactor-specific regulatory T cells with cytotoxic properties, the method comprising the steps of:
providing peripheral blood cells;
contacting said cells in vitro with an immunogenic peptide comprising (i) a T-cell epitope derived from a soluble allofactor and (ii) a C-(X)2-[CST] or [CST]-(X)2-C motif; and
expanding said cells in the presence of IL-2.
19 . A method for obtaining a population of soluble allofactor-specific regulatory T cells with cytotoxic properties, the method comprising the steps of:
providing an immunogenic peptide comprising (i) a T-cell epitope derived from a soluble allofactor and (ii) a C-(X)2-[CST] or [CST]-(X)2-C motif;
administering said immunogenic peptide to a subject; and
obtaining said population of soluble allofactor-specific regulatory T cells from said subject.
20 . A population of soluble allofactor-specific regulatory T cells with cytotoxic properties obtainable by the method according to claim 18 .
21 . A method of manufacturing a medicament comprising formulating a medicament comprising the population of soluble allofactor-specific regulatory T cells according to claim 20 for preventing or suppressing, in a subject to receive, receiving or having received said soluble allofactor, the immune responses to said soluble allofactor.
22 . An isolated immunogenic peptide comprising a T-cell epitope from a soluble allofactor and, adjacent to said T-cell epitope or separated from said T-cell epitope by a linker, a C-(X)2-[CST] or [CST]-(X)2-C motif.
23 . A method of manufacturing a medicament comprising formulating a medicament comprising at least one isolated immunogenic peptide comprising (i) a T-cell epitope derived from an anti-allofactor antibody idiotype and (ii) a C-(X)2-[CST] or [CST]-(X)2-C motif, for eliminating allofactor-specific B cells in a subject having received said allofactor.