Altered Peptide Ligands in MS immunotherapy: role of citrullination
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The document discusses the role of citrullination in multiple sclerosis and describes research synthesizing altered peptide ligands of myelin basic protein to modulate the immune response. Studies showed that citrullinated peptides induced cytokine secretion from MS patient immune cells. Additional experiments conjugating myelin peptide analogs to mannan were able to divert the immune response from a Th1 to a Th2 profile, demonstrating the immunomodulatory potential of altered peptide ligands.
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Altered Peptide Ligands in MS immunotherapy: role of citrullination
- 1. Altered Peptide Ligands in the immunotherapy of Multiple Sclerosis: the role of citrullination Deraos Georgios MSc, PhD ELDRUG S.A. Patras, Greece
- 3. Epidemiology of MS Age onset 20 – 50 years old Women are 2 times more likely to develop MS 500,000 cases in US Over 2.5 million people around the world More prevalent whites of northern European ancestry Genetic Influences
- 4. • Vision problems • Numbness • Difficulty walking • Fatigue, Depression • Coordination and Balance problems, • Pain • Spasticity Symptoms of MS
- 5. http://www.chumsweb.org/types.htm MS Types Relapsing-remitting MS (RRMS) Attacks followed by partial or complete recovery Symptoms may be inactive for months or years •Secondary-progressive MS (SPMS) Occasional relapses but symptoms remain constant, no remission Progressive disability late in disease course Primary-progressive MS (PPMS) Affects approximately 10% of MS population. Slow onset but continuous worsening condition Benign MS. small attacks followed by complete recovery.
- 7. Immunodominant epitopes in MS MBP 83-99 ENPVVHFFKNIVTPRTP MOG 35-55 MEVGWYRSPFSRVVHLYRNGK PLP 139-151 HCLGKWLGHPDKF
- 8. HLA-DR2 – PEPTIDE COCMPLEX Val 87 Phe 90 Lys 91 Crystal Structure of HLA-DR2 (DRA*0101, DRB1*1501) Complexed with a Peptide from Human Myelin Basic Protein kathine J. Smith, Jason Pyrdol, Laurent Gauthier, Don C Wiley, Kai W. Wucherpfenning.
- 9. Citrullination in Multiple Sclerosis
- 10. Medications and MS Therapies Administration Class Avonex IM 1x a week Interferon beta-1a Betaseron SC, every other day Interferon beta-1b Copaxone SC 1x a day Glatiramer acetate Rebif SC 3x a week Interferon beta-1a Gilenya Oral capsule 1x day Fingolimod Tysabri IV Monthly at Center Natalizumab
- 11. 1 Myelin Peptide Analogues 2 MBP83-99(Tyr91) 3 MBP83-99(Phe91) 4 MBP83-99(Glu91) 5 Cyclo(83-99)MBP83-99(Ala91, 96) 6 MBP87-99(Cit91, 97) 7 CycloMBP87-99(Cit91, 97) 8 MBP87-99(Arg91Ala96) 9 CycloMBP87-99(Arg91Ala96) 10 MBP87-99(Ala91,96) 11 CycloMBP87-99(Ala91,96) 12 MOG35-55 rat mouse 13 MOG35-55 Human 14 CyclicMOG35-55 rat mouse 15 CyclicMOG35-55 human
- 12. Synthesis of peptide analogues Solid Phase peptide Synthesis
- 13. Conversion of the citrullinated analogues
- 14. HPLC analysis of the citrullinated analogues
- 15. Biological evaluation Citrullinated analogues MBP87-99(Cit91,97) cycloMBP87-99(Cit91,97) PBMCs of MS patients Cytokine secretion Mannan conjugated peptides • MBP83-99(Tyr91) • MBP83-99(Phe91) • MBP83-99(Arg91) • MBP83-99(Glu91) EAE experiment In SJL/J mice Cytokine secretion Cross reaction antibodies assays Department of Medical school, University of Patras, Burnet Institute, Australia
- 16. Deraos et al. J. Med. Chem. 2008 Dec 25;51(24):7834-42. . Citrullinated peptides in PBMCs from MS patients
- 17. Katsara et al , Mol Immiunol2008 Aug;45(13):3661-70. Manosylated Peptide analogs IFN-γ IL-4 IL-10 Proliferation Abs Cross reaction MBP MBP83-99 ++ -- +++ +++ MBP83-99(A91) -- ++ + + MBP83-99(E91) -- ++ +++ + MBP83-99(F91) ++ ++ ++ +++ +/- - MBP83-99(Y91) -- ++ ++ +/- +++ - MBP83-99(R91,A96) -- ++ +++ +++ Manosylation of MBP83-99 peptide analogues
- 18. Katsara et al , Mol Immiunol2008 Aug;45(13):3661-70. Manosylated Peptide analogs IFN-γ IL-4 IL-10 Proliferation Abs Cross reaction MBP MBP83-99 ++ -- +++ +++ MBP83-99(A91) -- ++ + + MBP83-99(E91) -- ++ +++ + MBP83-99(F91) ++ ++ ++ +++ +/- - MBP83-99(Y91) -- ++ ++ +/- +++ - MBP83-99(R91,A96) -- ++ +++ +++ Manosylation of MBP83-99 peptide analogues
- 19. Katsara et al , Mol Immiunol2008 Aug;45(13):3661-70. Manosylated Peptide analogs IFN-γ IL-4 IL-10 Proliferation Abs Cross reaction MBP MBP83-99 ++ -- +++ +++ MBP83-99(A91) -- ++ + + MBP83-99(E91) -- ++ +++ + MBP83-99(F91) ++ ++ ++ +++ +/- - MBP83-99(Y91) -- ++ ++ +/- +++ - MBP83-99(R91,A96) -- ++ +++ +++ Manosylation of MBP83-99 peptide analogues
- 20. Katsara et al , Mol Immiunol2008 Aug;45(13):3661-70. Manosylated Peptide analogs IFN-γ IL-4 IL-10 Proliferation Abs Cross reaction MBP MBP83-99 ++ -- +++ +++ MBP83-99(A91) -- ++ + + MBP83-99(E91) -- ++ +++ + MBP83-99(F91) ++ ++ ++ +++ +/- - MBP83-99(Y91) -- ++ ++ +/- +++ - MBP83-99(R91,A96) -- ++ +++ +++ Manosylation of MBP83-99 peptide analogues
- 21. Katsara et al , Mol Immiunol2008 Aug;45(13):3661-70. Manosylated Peptide analogs IFN-γ IL-4 IL-10 Proliferation Abs Cross reaction MBP MBP83-99 ++ -- +++ +++ MBP83-99(A91) -- ++ + + MBP83-99(E91) -- ++ +++ + MBP83-99(F91) ++ ++ ++ +++ +/- - MBP83-99(Y91) -- ++ ++ +/- +++ - MBP83-99(R91,A96) -- ++ +++ +++ Manosylation of MBP83-99 peptide analogues
- 22. Katsara et al , Mol Immiunol2008 Aug;45(13):3661-70. Manosylated Peptide analogs IFN-γ IL-4 IL-10 Proliferation Abs Cross reaction MBP MBP83-99 ++ -- +++ +++ MBP83-99(A91) -- ++ + + MBP83-99(E91) -- ++ +++ + MBP83-99(F91) ++ ++ ++ +++ +/- - MBP83-99(Y91) -- ++ ++ +/- +++ - MBP83-99(R91,A96) -- ++ +++ +++ Manosylation of MBP83-99 peptide analogues
- 23. Katsara et al , Mol Immiunol2008 Aug;45(13):3661-70. Manosylated Peptide analogs IFN-γ IL-4 IL-10 Proliferation Abs Cross reaction MBP MBP83-99 ++ -- +++ +++ MBP83-99(A91) -- ++ + + MBP83-99(E91) -- ++ +++ + MBP83-99(F91) ++ ++ ++ +++ +/- - MBP83-99(Y91) -- ++ ++ +/- +++ - MBP83-99(R91,A96) -- ++ +++ +++ Manosylation of MBP83-99 peptide analogues
- 24. Conclusions ➢Citrullination is essential for antigenic recognition of self epitopes by T cells and may be a new strategy of citrullinated inhibitors like drugs in the future ➢Mutations to the native MBP83–99 peptide were able to induce IL-4 responses, although IFN-γ responses were still present. ➢ However, conjugating MBP83–99 peptide analogs to mannan was able to further divert the immune response from Th1 to Th2, demonstrating the importance of mannan as conjugates. ➢ APLs linear or cyclic can be used as immunomodulator agents in the MS. Although linear peptides have the disadvantage of being degradated easily from proteolytic enzymes and can not be used as oral administered drugs.
- 26. PATRAS GREECE