Immunotherapy targeting intracellular pathogens
The present invention relates to the use of immunogenic peptides comprising a T-cell epitope derived from an intracellular pathogen-associated antigen and a redox motif such as C-(X)2-[CST] or [CST]-(X)2-C in the prevention and/or treatment of infection with an intracellular pathogen and in the manufacture of medicaments therefore.
1. An isolated immunogenic peptide having a length of between 12 and 50 amino acids, comprising an MHC class II T-cell epitope from a viral intracellular pathogen-associated antigen and, separated from said MHC class II T-cell epitope by a linker of at most 7 amino acids, a C-(X)2-C(SEQ ID NO: 20) motif; wherein the intracellular pathogen-associated antigen does not comprise within its native natural sequence a C-(X)2-[CST] (SEQ ID NO: 26) or [CST]-(X)2-C(SEQ ID NO: 27) motif with redox properties within a sequence of 11 amino acids N- or C-terminally adjacent to the T-cell epitope.
2. The peptide according to claim 1 , wherein the linker has a length of at most 4 amino acids.
3. The peptide according to claim 1 , wherein the linker has a length of at most 2 amino acids.
4. The peptide according to claim 1 , wherein the peptide has a length of between 12 and 30 amino acids.
5. The peptide according to claim 1 , wherein X in the motif is His or Pro.
6. The peptide according to claim 1 , wherein X is not Cys.
7. The peptide according to claim 1 , wherein the virus is an RNA virus.
8. The peptide according to claim 1 , wherein the virus is a single stranded virus.
9. The peptide according to claim 1 , wherein the virus is selected from the group consisting of Herpesviridae, Flaviviridae and Picornaviridae.
10. A method for obtaining a peptide comprising the steps of:
identifying a MHC class II T-cell epitope in an antigen of a viral intracellular pathogen; and
producing the immunogenic peptide of claim 1 by chemical synthesis or recombinant expression.
11. A method for inducing apoptosis of virus infected cells that express MHC class II determinants in a human subject, comprising the step of administering to said subject an effective amount of the immunogenic peptide of claim 1 .
12. The method according to claim 11 , wherein said immunogenic peptide further comprises an endosomal targeting sequence.
13. The method according to claim 11 , wherein said motif is positioned N-terminally of the MHC class II T-cell epitope.
14. The method according to claim 11 , wherein at least one X in said motif is Gly, Ala, Ser or Thr, and/or at least one C is optionally methylated.
15. The method according to claim 11 , wherein at least one X in said motif is His or Pro, and/or at least one C is optionally methylated.
16. The method according to claim 11 , wherein said immunogenic peptide is produced by chemical synthesis or by recombinant expression.
17. An in vitro method for obtaining a population of viral intracellular pathogen-associated antigen-specific regulatory human T cells with cytotoxic properties, the method comprising the steps of:
providing human peripheral blood cells;
contacting said cells in vitro with an effective amount of the immunogenic peptide of claim 1 ; and
expanding said cells in the presence of Interleukin 2 (IL-2).
18. A method for obtaining a population of viral intracellular pathogen-associated antigen-specific regulatory human T cells with cytotoxic properties, the method comprising the steps of:
administering an effective amount of the immunogenic peptide of claim 1 to a human subject; and
obtaining said population of viral intracellular pathogen-associated antigen-specific regulatory T cells from a peripheral blood cell population of said subject.