Novel Approaches in the Immunotherapy of Multiple Sclerosis: History
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Subjects: Neurosciences
Contributor:
John Matsoukas

Multiple Sclerosis (MS) is a serious autoimmune disease. The patient in an advanced state of the disease has restrained mobility and remains handicapped. It is therefore understandable that there is a great need for novel drugs and vaccines for the treatment of MS. 

  • multiple sclerosis
  • peptide

1. Introduction

Multiple Sclerosis (MS) is a serious systemic demyelinating disease that leads to the partial paralysis of the patient who needs the assistance of medicare in order to survive with low quality of life. The need for an effective treatment in the form of medication or vaccine is more urgent than ever before [1][2][3][4][5]. This chronic inflammatory and neurodegenerative disease is initiated by autoreactive T helper (Th) cells and affects approximately 2.5 million people worldwide. Thus, there is an urgent need to develop effective treatments. Advances in the immunotherapy of MS have been recently reported in excellent reviews [6][7][8][9]. The pathogenesis of MS has been extensively studied over the last years, which shows a complex immunological involvement. Myelin epitopes have been identified as a target for autoimmune CD4+ T cells and antibodies, and much focus has been around the modulation of Th1 pro-inflammatory autoreactive CD4+ T cells against myelin epitopes, namely myelin basic protein (MBP), proteolipid protein (PLP), and myelin oligodendrocyte glycoprotein (MOG) [10][11][12][13][14][15][16][17][18].

2. Applied Strategies Utilized against MS

2.1. Linear Epitopes and Derivatives of Selective MBP Epitopes

Linear myelin epitopes MBP83–99, MBP82–98, MBP85–99, MBP87–99 (Figure 1 and Figure 2), MOG35–55, and PLP139–151 have been identified as agonist peptides inducing disease in humans and in animal models of MS. These peptides bind to MHC class II alleles, however, peptides binding to MHC class I have also been identified, primarily HLA-A*0301 (HLA-A3) in complex with a PLP45–53 peptide and the crystal structure known (Figure 3). Mutant analogs of linear agonist MHC class II peptides have been used to obtain information on the molecular basis of the disease. Data points out that mutant analogs of disease-associated epitopes can inhibit disease through two distinct mechanisms, one via the activation of antigen-specific regulatory T cells, or two, by activation and secretion of appropriate cytokines. The application of MBP83–99-based altered peptide ligands inhibits MBP-reactive T cell proliferation in vitro [19]; this is attributed to anti-inflammatory Th2 cytokine secretion by T cells, primarily IL-4 and IL-10. These obtained results point out that cytokine regulation is the major mechanism through which T-cell receptor (TCR)-specific CD4+ T cells regulate encephalitogenic and potentially other bystander Th1 cells. Thus, the modulation of cytokine secretion by auto-reactive T cells through peptide or non-peptide mimetics, even in longstanding autoimmune disease through cytokine therapy, might be beneficial therapeutically. This beneficial response is achieved by switching the function of myelin reactive T cells.
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Figure 1. (A) The X-ray structure (pdb: 1YMM) of a human autoimmune TCR bound to a myelin basic protein (MBP85–99) peptide and a MS-associated MHC class II molecule (HLA-DR2b), (B) close view of the docking site of (MBP85–99) peptide.
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Figure 2. (A) The X-ray structure (pdb: 1ZGL) of a human autoimmune TCR bound to a myelin basic protein self-peptide (MBP87–99) and a multiple sclerosis-associated MHC class II molecule (HLA-DR2a), (B) close view of the docking site of (MBP87–99) peptide.
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Figure 3. The X-ray crystal structure (pdb: 2XPG) of the human major histocompatibility (MHC) class I molecule HLA-A*0301 (HLA-A3) in complex with a PLP45–53 peptide.
One of the first human clinical studies for patients with secondary progressive MS (MAESTRO-01) used the agonist MBP82–98 peptide (dirucotide). Intravenous injection of MBP82–98 peptide delayed disease progression. However, this effort was suspended at phase III stage since it lacked efficacy and did not meet primary endpoints [20][21].
Two mutant peptides namely [R91, A96]MBP87–99 and [A91,A96]MBP87–99 derived from the immunodominant agonist identified in MS (MBP87–99) were synthesized. The chosen mutations occurred at amino acids K91 and P96 as they are critical TCR contact sites. Immunization of mice with these altered peptide ligands (ALPs) emulsified in complete Freund’s adjuvant induced both IFNγ and interleukin-4 (IL-4) responses while the native MBP87–99 peptide induced only IFNγ responses. The linear MBP72–85 peptide (EKSERSEDENPV) is well known to induce experimental autoimmune encephalitis (EAE), and D79 mutation with A79 resulted in an analog that suppressed the induction of EAE [22]. In addition, the immunodominant peptide from PLP, HSLGKWLGHPDKF, is a naturally processed epitope. A double mutation of the agonist PLP139–151, in which both of the TCR binding sites are replaced with Leu or Arg ([L144, R147]PLP139–151), is able to antagonize PLP-specific T cell clones in vitro [23]. The mutated analog inhibited EAE and prevented clinical disease progression when administrated in the early stage of EAE induction [23]. Antibodies against the minor protein MOG have been noted in inflammation areas of MS. This proves that antibodies do play a role in MS and cooperate with antigen-presenting cells in myelin destruction. Blocking the effects of these MOG antibodies with secondary antibodies or non-peptide mimetics might be an important avenue for future therapy.

2.2. Cyclization of Selective Linear Epitopes and Their Derivatives

Linear peptide are known to be sensitive to proteolytic enzymes, which results in their degradation. Cyclization of linear peptides increases their stability in vitro and in vivo [24]. In an attempt to develop non-peptide mimetics, cyclic peptides are an important intermediate step towards this. As such, cyclic counterparts of linear peptides have been synthesized in an effort to improve their biological properties and structural stability [25][26][22][27][28][29][30]. Cyclic MBP82–98 exerts strong binding to the HLA-DR2 allele but has lower affinity binding to the HLA-DR4 allele. Cyclic analogues of dirucotide proved to be promising leads, and it is proposed that they be evaluated for their ability to alter T cell responses for therapeutic benefit against MS [20][21].
Spectroscopic data combined with Molecular Dynamics (MD) calculations showed that the linear MBP72–85 peptide adopts a pseudo-cyclic conformation. Based on this information, the cyclic analogue QKSQRSQDQNPV-NH2 was rationally designed. The cyclization of this molecule was achieved by connecting the side-chain amino and carboxyl groups of Lys and Glu at positions 2 and 9. This cyclic analogue exerted similar biological activity to the linear peptide; however, in EAE experiments, the cyclic analogue completely suppressed EAE by co-injection with the agonist peptide in Lewis rats. The similar potencies propose that cyclization does not substantially affect the conformational properties of its linear analogue and provides support to its proposed pseudo-cyclic conformation. In addition, this study proposes that a pseudo cyclic conformation for the MBP72–85 epitope allows D81 and K78 binding to the trimolecular complex MHC-peptide-TCR, and as a consequence, it inhibits EAE [27].
A cyclic analogue, cyclo(87–99)MBP87–99 (Figure 4), of the human immunodominant MBP87–99 epitope, was synthesized based on the same rational as MBP72–85 epitope. This cyclic analogue in the same manner was shown to mimic the effects of the linear MBP87–99 epitope peptide, and thus to induce EAE, bind HLA-DR4, and increase CD4 T-cell line proliferation. The mutant cyclic peptides, cyclo(91–99)[A96]MBP87–99 and cyclo(87–99)[R91A96]MBP87–99, suppressed, to a varying degree, EAE, and possessed the following immunomodulatory properties: (i) they suppressed the proliferation of a CD4 T-cell line raised from a MS patient; (ii) they scored the best in vitro Th2/Th1 cytokine ratio in peripheral blood mononuclear cell (PBMC) cultures, inducing IL-10 selectively; (iii) they bound to HLA-DR4, first to be reported for cyclic MBP peptides; and (iv) they were found to be more stable to lysosomal enzymes and Cathepsin B, D, and H, compared to their linear counterparts. Such beneficial properties establish these synthetic peptides as putative immunotherapeutics for treating MS and potentially other Th1-mediated autoimmune diseases [27]. The mutations have been chosen as they identified the major TCR contact sites by X-ray crystallographic studies of human MHC and Molecular Dynamics (MD) studies using murine MHC.
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Figure 4. (A) cyclic-MBP87–99 (VHFFKNIVTPRTP), (B) cyclic-MOG35–55 (MEVGWYRSPFSRVVHLYRNGK), (C) cyclic-PLP139–151 (HSLGKWLGHPDKF).
The cyclic-MOG35–55 peptide, cyclized at the C- and N-terminal amino acids (cyclic-MOG35–55), altered the 3D conformation of the linear MOG35–55 peptide (Figure 4). Following the injection of cyclic-MOG35–55 during disease induction, EAE, demyelination, and chronic axonopathy in acute and chronic phases of disease were reduced. Molecular docking and spectroscopic data revealed milder interactions between the cycic-MOG35–55 and mouse or human MHC class II alleles (H2-IAb and HLA-DR2) [31]. Likewise, synthesis of cyclic PLP139–151 peptide and injection in SJL/J mice showed that cylic-PLP139–151 analog is minimally encephalitogenic when administered to induce EAE (Figure 4). In particular, cyclic-PLP139–151 analog showed low disease burden and minimal inflammatory, demyelinating, and axonopathic pathology compared to its linear counterpart. Proliferation assays confirmed the low stimulatory potential of the cyclic-PLP139–151 compared to linear PLP139–151 as well as the induction of lower antibody responses. Comparative molecular modeling studies between the two molecules may explain the biological data, as it was shown that different amino acids are involved in the TCR recognition [23]. It is clear that cyclic modification of linear peptide counterparts may provide novel approaches for future, immunomodulative treatments against MS.

2.3. Conjugation of Selective Epitopes with Mannan

Mannan, a poly-mannose isolated from the cell wall of yeasts, has been shown to exert immunomodulatory effects in the cancer settings in vitro [32][33][34][35][36][37], in vivo (inbred mice, transgenic mice, rats, rabbits, and chickens) [38][39][40][41][42][43][44][45][46][47][48][49], in rhesus macaques [50][51][52], and in human clinical trials [53][54][55][56][57][58][59][60][61][62]. Mannan targets antigens to the mannose receptor, antigens endocytosed for MHC class I or II presentation, and modulation of appropriate T cells [32][40][41][42][63][64][65][66][67][68]. In relation to autoimmune disorders, mannan conjugates (i) represent a new class of immunoregulators that directly and selectively target a population of immune cells that are implicated in the pathogenesis and progression of disease; (ii) provide first line treatment that selectively tolerates or inactivates disease-inducing cells in patients and also prevents progression of disease by stopping diversification of the autoimmune response to additional epitopes; (iii) allows easier formulation of newly discovered molecules within the mannan matrix platform; and (iv) can achieve block-buster status as a global vaccine drug for efficient treatment of MS [69][70][71][19].
Altered peptide ligands, where one to two amino acid mutations are made to those interacting with the TCR are able to alter an agonist peptide into an antagonist peptide by reduction of hydrogen bond interactions [72]. Cyclization of peptides allows for their stronger stability and protection against enzymatic and proteolytic degradation [24]. As such, a cyclic APL, cyclo(87–99)[A91,A96]MBP87–99] reduced Th1 responses, but when conjugated to reduced mannan, an additional significant reduction of Th1 responses and moderate Th2 responses was induced (Table 1) [69][19]. Likewise, APL of linear and cyclic MBP83–99 analogs, MBP83–99(A91,A96), conjugated to reduced mannan, resulted in diversion of Th1 response to Th2 [69]. The use of reduced mannan to further divert immune responses to Th2 when conjugated to MBP peptides constitutes a novel strategy for immunotherapy of the disease. The main advantages of mannan conjugates is their stability and non-toxicity. In addition, linear and cyclic peptide analogs based on MBP83–99 immunodominant epitope conjugated to reduced mannan via (KG)5 or keyhole limpet hemocyanin (KLH) linkers, were evaluated for their biological/immunological profiles in SJL/J mice. Of all the peptide analogs tested, linear MBP83–99(F91) and MBP83–99(Y91) conjugated to reduced mannan and cyclic MBP83–99(F91) conjugated to reduced mannan yielded the best immunological profile and constitute novel candidates for further immunotherapeutic studies against MS for translation into human clinical trials. Immune responses were diverted from Th1 to Th2 in SJL/J mice and generated antibodies that did not cross-react with native MBP protein. Molecular modeling was used to identify H-bonding and van der Waals interactions between peptides and MHC (I–As) [26]. Furthermore, MBP87–99(R91, A96) conjugated to reduced mannan induced 70% less IFNγ compared with the native MBP87–99 peptide. However, MBP87–99(A91,A96) conjugated to reduced mannan did not induce IFNγ-secreting T cells, elicited very high levels of IL-4, and antibodies generated did not cross-react with the native MBP87–99 peptide. It is clear that this double-mutant peptide analog conjugated to reduced mannan is able to divert immune responses from Th1 to Th2 and is a promising mutant peptide analogue for use in studies exploring potential treatments for MS [26].
Table 1. Biological effects of myelin-derived peptides (linear, cyclic, mannan conjugated).
Peptide Analog [Reference] Major Effects
MBP83–99 and PLP139–151 [10][11][12][13][14][15][16][17][18] These agonist peptides are involved in the pathophysiology of MS and also induce EAE in animal models.
MBP82–98 [20][21] Dirucotide in animal models inhibits disease and in early human clinical trials showed efficacy; however, the peptide did not meet primary endpoints in phase III-trials.
cyclic(87–99)[MBP87–99] [27] Stimulates Th2 cytokines and inhibits EAE in mice.
MBP87–99(R91,A96), MBP87–99(A91,A96) [26] Induces IL-4 and antagonizes IFNγ responses in mice.
MBP72–85 [22] These agonist peptides induce EAE in mice and Th1 responses in humans.
MBP72–85(A79) [22] Suppresses EAE in mice.
PLP139–151(L144, R147) [23] Antagonizes PLP-specific T-clones in vitro.
cyclic-MBP82–98 Exerts strong binding to the HLA-DR2 and lowers binding to the HLA-DR4 allele in vitro
cyclic-MBP87–99(A96) or (R91A96) [26][19] Suppresses proliferation of CD4+ T cells and exerts IL-10 selectivity in vitro. Binds to HLA-DR4 and is stable to lysosomal enzymes and cathepsins B, D, and H.
cyclic-MOG35–55 [31]
cyclic-PLP131–151 [23]
linear and cyclic-MBP83–99(A91,A96) [69]
Mannan-linear and cyclic-MBP83–99(A91,A96) [69]		 Reduces EAE, demyelination, and chronic axonopathy in acute and chronic phases of EAE in mice.
Low disease burden in regards to EAE in mice with minimal inflammatory, demyelinating, and axonopathic pathology compared to its linear counterpart.
Decreases IFNγ responses in mice.
Diverts the “bad” IFNγ to “good” IL-4 cytokine in mice.
Mannan-MOG35–55 [70] Protects mice against EAE in prophylactic and therapeutic protocols, with oxidized-conjugated peptides giving the best results.
Cyclo(87–99)MBP87-99(A91,A96) [69][19]
Mannan-cyclo(87–99)MBP87-99(A91,A96) [69][19]		 Decreases Th1 responses.
Shifts Th1 responses to Th2 responses.
MBP87–99[Cit91,A96,Cit97] [29]
cyclic-MBP87–99[Cit91,A96,Cit97] [29]		 Induces T-cell proliferation and IFNγ secretion in mice.
Activates T cells and increases IFNγ secretion in mice.

This entry is adapted from the peer-reviewed paper 10.3390/brainsci11121583

References

  1. Compston, A.; Coles, A. Multiple sclerosis. Lancet 2002, 359, 1221–1231.
  2. Steinman, M.D.L. Multiple Sclerosis: A Coordinated Immunological Attack against Myelin in the Central Nervous System. Cell 1996, 85, 299–302.
  3. Grytten, N.; Torkildsen, Ø.; Myhr, K.M. Time trends in the incidence and prevalence of multiple sclerosis in Norway during eight decades. Acta Neurol. Scand. 2015, 132, 29–36.
  4. Polman, C.H.; Reingold, S.C.; Banwell, B.; Clanet, M.; Cohen, J.A.; Filippi, M.; Fujihara, K.; Havrdova, E.; Hutchinson, M.; Kappos, L.; et al. Diagnostic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteria. Ann. Neurol. 2011, 69, 292–302.
  5. Eckstein, C.; Bhatti, M.T. Currently approved and emerging oral therapies in multiple sclerosis: An update for the ophthalmologist. Surv. Ophthalmol. 2016, 61, 318–332.
  6. Dargahi, N.; Katsara, M.; Tselios, T.; Androutsou, M.E.; de Courten, M.; Matsoukas, J.; Apostolopoulos, V. Multiple Sclerosis: Immunopathology and Treatment Update. Brain Sci. 2017, 7, 78.
  7. Florou, D.; Katsara, M.; Feehan, J.; Dardiotis, E.; Apostolopoulos, V. Anti-CD20 Agents for Multiple Sclerosis: Spotlight on Ocrelizumab and Ofatumumab. Brain Sci. 2020, 10, 758.
  8. Kammona, O.; Kiparissides, C. Recent Advances in Antigen-Specific Immunotherapies for the Treatment of Multiple Sclerosis. Brain Sci. 2020, 10, 333.
  9. Metaxakis, A.; Petratou, D.; Tavernarakis, N. Molecular Interventions towards Multiple Sclerosis Treatment. Brain Sci. 2020, 10, 299.
  10. Dai, H.; Ciric, B.; Zhang, G.-X.; Rostami, A. Interleukin-10 plays a crucial role in suppression of experimental autoimmune encephalomyelitis by Bowman–Birk inhibitor. J. Neuroimmunol. 2012, 245, 1–7.
  11. Rostami, A.; Gregorian, S.K. Peptide 53–78 of myelin P2 protein is a T cell epitope for the induction of experimental autoimmune neuritis. Cell. Immunol. 1991, 132, 433–441.
  12. Rostami, A.; Gregorian, S.K.; Brown, M.J.; Pleasure, D.E. Induction of severe experimental autoimmune neuritis with a synthetic peptide corresponding to the 53–78 amino acid sequence of the myelin P2 protein. J. Neuroimmunol. 1990, 30, 145–151.
  13. Martin, R.; McFarland, H.F.; McFarlin, D.E. Immunological Aspects of Demyelinating Diseases. Annu. Rev. Immunol. 1992, 10, 153–187.
  14. Hafler, D.A.; Weiner, H.L. Immunologic Mechanisms and Therapy in Multiple Sclerosis. Immunol. Rev. 1995, 144, 75–107.
  15. Kappos, L.; Comi, G.; Panitch, H.; Oger, J.; Antel, J.; Conlon, P.; Steinman, L.; Comi, G.; Kappos, L.; Oger, J.; et al. Induction of a non-encephalitogenic type 2 T helper-cell autoimmune response in multiple sclerosis after administration of an altered peptide ligand in a placebo-controlled, randomized phase II trial. Nat. Med. 2000, 6, 1176–1182.
  16. Bielekova, B.; Goodwin, B.; Richert, N.; Cortese, I.; Kondo, T.; Afshar, G.; Gran, B.; Eaton, J.; Antel, J.; Frank, J.A.; et al. Encephalitogenic potential of the myelin basic protein peptide (amino acids 83–99) in multiple sclerosis: Results of a phase II clinical trial with an altered peptide ligand. Nat. Med. 2000, 6, 1167–1175.
  17. Anagnostouli, M.; Artemiadis, A.; Gontika, M.; Skarlis, C.; Markoglou, N.; Katsavos, S.; Kilindireas, K.; Doxiadis, I.; Stefanis, L. HLA-DPB1*03 as Risk Allele and HLA-DPB1*04 as Protective Allele for Both Early- and Adult-Onset Multiple Sclerosis in a Hellenic Cohort. Brain Sci. 2020, 10, 374.
  18. Vergelli, M.; Hemmer, B.; Utz, U.; Vogt, A.; Kalbus, M.; Tranquill, L.; Conlon, P.; Ling, N.; Steinman, L.; McFarland, H.F.; et al. Differential activation of human autoreactive T cell clones by altered peptide ligands derived from myelin basic protein peptide (87–99). Eur. J. Immunol. 1996, 26, 2624–2634.
  19. Katsara, M.; Deraos, G.; Tselios, T.; Matsoukas, J.; Apostolopoulos, V. Design of Novel Cyclic Altered Peptide Ligands of Myelin Basic Protein MBP83−99That Modulate Immune Responses in SJL/J Mice. J. Med. Chem. 2008, 51, 3971–3978.
  20. Warren, K.G.; Catz, I.; Ferenczi, L.Z.; Krantz, M.J. Intravenous synthetic peptide MBP8298 delayed disease progression in an HLA Class II-defined cohort of patients with progressive multiple sclerosis: Results of a 24-month double-blind placebo-controlled clinical trial and 5 years of follow-up treatment. Eur. J. Neurol. 2006, 13, 887–895.
  21. Freedman, M.S.; Bar-Or, A.; Oger, J.; Traboulsee, A.; Patry, D.; Young, C.; Olsson, T.; Li, D.; Hartung, H.P.; Krantz, M.; et al. A phase III study evaluating the efficacy and safety of MBP8298 in secondary progressive MS. Neurology 2011, 77, 1551–1560.
  22. Tselios, T.; Probert, L.; Daliani, I.; Matsoukas, E.; Troganis, A.; Gerothanassis, I.P.; Mavromoustakos, T.; Moore, G.J.; Matsoukas, J.M. Design and Synthesis of a Potent Cyclic Analogue of the Myelin Basic Protein Epitope MBP72-85: Importance of the Ala81 Carboxyl Group and of a Cyclic Conformation for Induction of Experimental Allergic Encephalomyelitis. J. Med. Chem. 1999, 42, 1170–1177.
  23. Lourbopoulos, A.; Matsoukas, M.-T.; Katsara, M.; Deraos, G.; Giannakopoulou, A.; Lagoudaki, R.; Grigoriadis, N.; Matsoukas, J.; Apostolopoulos, V. Cyclization of PLP139-151 peptide reduces its encephalitogenic potential in experimental autoimmune encephalomyelitis. Bioorganic Med. Chem. 2018, 26, 2221–2228.
  24. Katsara, M.; Tselios, T.; Deraos, S.; Deraos, G.; Matsoukas, M.T.; Lazoura, E.; Matsoukas, J.; Apostolopoulos, V. Round and round we go: Cyclic peptides in disease. Curr. Med. Chem. 2006, 13, 2221–2232.
  25. Katsara, M.; Deraos, G.; Tselios, T.; Matsoukas, M.-T.; Friligou, I.; Matsoukas, J.; Apostolopoulos, V. Design and Synthesis of a Cyclic Double Mutant Peptide (cyclo(87−99)MBP87−99) Induces Altered Responses in Mice after Conjugation to Mannan: Implications in the Immunotherapy of Multiple Sclerosis. J. Med. Chem. 2008, 52, 214–218.
  26. Katsara, M.; Yuriev, E.; Ramsland, P.A.; Deraos, G.; Tselios, T.; Matsoukas, J.; Apostolopoulos, V. A double mutation of MBP83–99 peptide induces IL-4 responses and antagonizes IFN-γ responses. J. Neuroimmunol. 2008, 200, 77–89.
  27. Matsoukas, J.; Apostolopoulos, V.; Kalbacher, H.; Papini, A.-M.; Tselios, T.; Chatzantoni, K.; Biagioli, T.; Lolli, F.; Deraos, S.; Papathanassopoulos, P.; et al. Design And Synthesis of a Novel Potent Myelin Basic Protein Epitope 87−99 Cyclic Analogue: Enhanced Stability and Biological Properties of Mimics Render Them a Potentially New Class of Immunomodulators. J. Med. Chem. 2005, 48, 1470–1480.
  28. Deraos, G.; Rodi, M.; Kalbacher, H.; Chatzantoni, K.; Karagiannis, F.; Synodinos, L.; Plotas, P.; Papalois, A.; Dimisianos, N.; Papathanasopoulos, P.; et al. Properties of myelin altered peptide ligand cyclo(87-99)(Ala91,Ala96)MBP87-99 render it a promising drug lead for immunotherapy of multiple sclerosis. Eur. J. Med. Chem. 2015, 101, 13–23.
  29. Deraos, G.; Chatzantoni, K.; Matsoukas, M.-T.; Tselios, T.; Deraos, S.; Katsara, M.; Papathanasopoulos, P.; Vynios, D.; Apostolopoulos, V.; Mouzaki, A.; et al. Citrullination of Linear and Cyclic Altered Peptide Ligands from Myelin Basic Protein (MBP87−99) Epitope Elicits a Th1 Polarized Response by T Cells Isolated from Multiple Sclerosis Patients: Implications in Triggering Disease. J. Med. Chem. 2008, 51, 7834–7842.
  30. Deraos, G.; Kritsi, E.; Matsoukas, M.-T.; Christopoulou, K.; Kalbacher, H.; Zoumpoulakis, P.; Apostolopoulos, V.; Matsoukas, J. Design of Linear and Cyclic Mutant Analogues of Dirucotide Peptide (MBP82–98) against Multiple Sclerosis: Conformational and Binding Studies to MHC Class II. Brain Sci. 2018, 8, 213.
  31. Lourbopoulos, A.; Deraos, G.; Matsoukas, M.T.; Touloumi, O.; Giannakopoulou, A.; Kalbacher, H.; Grigoriadis, N.; Apostolopoulos, V.; Matsoukas, J. Cyclic MOG35-55 ameliorates clinical and neuropathological features of experimental autoimmune encephalomyelitis. Bioorg. Med. Chem. 2017, 25, 4163–4174.
  32. Apostolopoulos, V.; Barnes, N.; Pietersz, G.A.; McKenzie, I.F. Ex vivo targeting of the macrophage mannose receptor generates anti-tumor CTL responses. Vaccine 2000, 18, 3174–3184.
  33. Sheng, K.C.; Kalkanidis, M.; Pouniotis, D.S.; Esparon, S.; Tang, C.K.; Apostolopoulos, V.; Pietersz, G.A. Delivery of antigen using a novel mannosylated dendrimer potentiates immunogenicity in vitro and in vivo. Eur. J. Immunol. 2008, 38, 424–436.
  34. Sheng, K.C.; Kalkanidis, M.; Pouniotis, D.S.; Wright, M.D.; Pietersz, G.A.; Apostolopoulos, V. The adjuvanticity of a mannosylated antigen reveals TLR4 functionality essential for subset specialization and functional maturation of mouse dendritic cells. J. Immunol. 2008, 181, 2455–2464.
  35. Sheng, K.C.; Pouniotis, D.S.; Wright, M.D.; Tang, C.K.; Lazoura, E.; Pietersz, G.A.; Apostolopoulos, V. Mannan derivatives induce phenotypic and functional maturation of mouse dendritic cells. Immunology 2006, 118, 372–383.
  36. Tang, C.K.; Sheng, K.C.; Apostolopoulos, V.; Pietersz, G.A. Protein/peptide and DNA vaccine delivery by targeting C-type lectin receptors. Expert Rev. Vaccines 2008, 7, 1005–1018.
  37. Tang, C.K.; Sheng, K.C.; Pouniotis, D.; Esparon, S.; Son, H.Y.; Kim, C.W.; Pietersz, G.A.; Apostolopoulos, V. Oxidized and reduced mannan mediated MUC1 DNA immunization induce effective anti-tumor responses. Vaccine 2008, 26, 3827–3834.
  38. Acres, B.; Apostolopoulos, V.; Balloul, J.M.; Wreschner, D.; Xing, P.X.; Ali-Hadji, D.; Bizouarne, N.; Kieny, M.P.; McKenzie, I.F. MUC1-specific immune responses in human MUC1 transgenic mice immunized with various human MUC1 vaccines. Cancer Immunol. Immunother. 2000, 48, 588–594.
  39. Apostolopoulos, V.; Lofthouse, S.A.; Popovski, V.; Chelvanayagam, G.; Sandrin, M.S.; McKenzie, I.F. Peptide mimics of a tumor antigen induce functional cytotoxic T cells. Nat. Biotechnol. 1998, 16, 276–280.
  40. Apostolopoulos, V.; McKenzie, I.F. Role of the mannose receptor in the immune response. Curr. Mol. Med. 2001, 1, 469–474.
  41. Apostolopoulos, V.; Pietersz, G.A.; Gordon, S.; Martinez-Pomares, L.; McKenzie, I.F. Aldehyde-mannan antigen complexes target the MHC class I antigen-presentation pathway. Eur. J. Immunol. 2000, 30, 1714–1723.
  42. Apostolopoulos, V.; Pietersz, G.A.; Loveland, B.E.; Sandrin, M.S.; McKenzie, I.F. Oxidative/reductive conjugation of mannan to antigen selects for T1 or T2 immune responses. Proc. Natl. Acad. Sci. USA 1995, 92, 10128–10132.
  43. Apostolopoulos, V.; Pietersz, G.A.; McKenzie, I.F. Cell-mediated immune responses to MUC1 fusion protein coupled to mannan. Vaccine 1996, 14, 930–938.
  44. Davis, W.C.; Konzek, R.L.; Haas, K.; Estes, D.M.; Hamilton, M.J.; Call, D.R.; Apostolopoulos, V.; McKenzie, I.F. Use of the mannan receptor to selectively target vaccine antigens for processing and antigen presentation through the MHC class I and class II pathways. Ann. N. Y. Acad. Sci. 2002, 969, 119–125.
  45. Lees, C.J.; Apostolopoulos, V.; Acres, B.; Ong, C.S.; Popovski, V.; McKenzie, I.F. The effect of T1 and T2 cytokines on the cytotoxic T cell response to mannan-MUC1. Cancer Immunol. Immunother. 2000, 48, 644–652.
  46. Lees, C.J.; Apostolopoulos, V.; Acres, B.; Ramshaw, I.; Ramsay, A.; Ong, C.S.; McKenzie, I.F. Immunotherapy with mannan-MUC1 and IL-12 in MUC1 transgenic mice. Vaccine 2000, 19, 158–162.
  47. Lees, C.J.; Apostolopoulos, V.; McKenzie, I.F. Cytokine production from murine CD4 and CD8 cells after mannan-MUC1 immunization. J. Interferon Cytokine Res. 1999, 19, 1373–1379.
  48. Lofthouse, S.A.; Apostolopoulos, V.; Pietersz, G.A.; Li, W.; McKenzie, I.F. Induction of T1 (cytotoxic lymphocyte) and/or T2 (antibody) responses to a mucin-1 tumour antigen. Vaccine 1997, 15, 1586–1593.
  49. Tang, C.K.; Lodding, J.; Minigo, G.; Pouniotis, D.S.; Plebanski, M.; Scholzen, A.; McKenzie, I.F.; Pietersz, G.A.; Apostolopoulos, V. Mannan-mediated gene delivery for cancer immunotherapy. Immunology 2007, 120, 325–335.
  50. Sandrin, M.S.; Vaughan, H.A.; Xing, P.X.; McKenzie, I.F. Natural human anti-Gal alpha(1,3)Gal antibodies react with human mucin peptides. Glycoconj. J. 1997, 14, 97–105.
  51. Vaughan, H.A.; Ho, D.W.; Karanikas, V.; Sandrin, M.S.; McKenzie, I.F.; Pietersz, G.A. The immune response of mice and cynomolgus monkeys to macaque mucin 1-mannan. Vaccine 2000, 18, 3297–3309.
  52. Vaughan, H.A.; Ho, D.W.; Karanikas, V.A.; Ong, C.S.; Hwang, L.A.; Pearson, J.M.; McKenzie, I.F.; Pietersz, G.A. Induction of humoral and cellular responses in cynomolgus monkeys immunised with mannan-human MUC1 conjugates. Vaccine 1999, 17, 2740–2752.
  53. Apostolopoulos, V.; Osinski, C.; McKenzie, I.F. MUC1 cross-reactive Gal alpha(1,3)Gal antibodies in humans switch immune responses from cellular to humoral. Nat. Med. 1998, 4, 315–320.
  54. Apostolopoulos, V.; Pietersz, G.A.; Tsibanis, A.; Tsikkinis, A.; Drakaki, H.; Loveland, B.E.; Piddlesden, S.J.; Plebanski, M.; Pouniotis, D.S.; Alexis, M.N.; et al. Pilot phase III immunotherapy study in early-stage breast cancer patients using oxidized mannan-MUC1 . Breast Cancer Res. 2006, 8, R27.
  55. Apostolopoulos, V.; Pietersz, G.A.; Tsibanis, A.; Tsikkinis, A.; Stojanovska, L.; McKenzie, I.F.; Vassilaros, S. Dendritic cell immunotherapy: Clinical outcomes. Clin. Transl. Immunology 2014, 3, e21.
  56. Karanikas, V.; Hwang, L.A.; Pearson, J.; Ong, C.S.; Apostolopoulos, V.; Vaughan, H.; Xing, P.X.; Jamieson, G.; Pietersz, G.; Tait, B.; et al. Antibody and T cell responses of patients with adenocarcinoma immunized with mannan-MUC1 fusion protein. J. Clin. Investig. 1997, 100, 2783–2792.
  57. Karanikas, V.; Lodding, J.; Maino, V.C.; McKenzie, I.F. Flow cytometric measurement of intracellular cytokines detects immune responses in MUC1 immunotherapy. Clin. Cancer Res. 2000, 6, 829–837.
  58. Karanikas, V.; Thynne, G.; Mitchell, P.; Ong, C.S.; Gunawardana, D.; Blum, R.; Pearson, J.; Lodding, J.; Pietersz, G.; Broadbent, R.; et al. Mannan Mucin-1 Peptide Immunization: Influence of Cyclophosphamide and the Route of Injection. J. Immunother. 2001, 24, 172–183.
  59. Loveland, B.E.; Zhao, A.; White, S.; Gan, H.; Hamilton, K.; Xing, P.X.; Pietersz, G.A.; Apostolopoulos, V.; Vaughan, H.; Karanikas, V.; et al. Mannan-MUC1-pulsed dendritic cell immunotherapy: A phase I trial in patients with adenocarcinoma. Clin. Cancer Res. 2006, 12, 869–877.
  60. Mitchell, P.L.; Quinn, M.A.; Grant, P.T.; Allen, D.G.; Jobling, T.W.; White, S.C.; Zhao, A.; Karanikas, V.; Vaughan, H.; Pietersz, G.; et al. A phase 2, single-arm study of an autologous dendritic cell treatment against mucin 1 in patients with advanced epithelial ovarian cancer. J. Immunother. Cancer 2014, 2, 16.
  61. Prince, H.M.; Wall, D.M.; Ritchie, D.; Honemann, D.; Harrrison, S.; Quach, H.; Thompson, M.; Hicks, R.; Lau, E.; Davison, J.; et al. In vivo tracking of dendritic cells in patients with multiple myeloma. J. Immunother. 2008, 31, 166–179.
  62. Vassilaros, S.; Tsibanis, A.; Tsikkinis, A.; Pietersz, G.A.; McKenzie, I.F.; Apostolopoulos, V. Up to 15-year clinical follow-up of a pilot Phase III immunotherapy study in stage II breast cancer patients using oxidized mannan-MUC1. Immunotherapy 2013, 5, 1177–1182.
  63. Agnes, M.C.; Tan, A.; Jordens, R.; Geluk, A.; Roep, B.O.; Ottenhoff, T.; Drijfhout, J.W.; Koning, F. Strongly increased efficiency of altered peptide ligands by mannosylation. Int. Immunol. 1998, 10, 1299–1304.
  64. Chen, J.; Fang, H.; Hu, Y.; Wu, J.; Zhang, S.; Feng, Y.; Lin, L.; Tian, H.; Chen, X. Combining mannose receptor mediated nanovaccines and gene regulated PD-L1 blockade for boosting cancer immunotherapy. Bioact. Mater. 2022, 7, 167–180.
  65. Mommaas, A.M.; Mulder, A.A.; Jordens, R.; Out, C.; Tan, M.C.; Cresswell, P.; Kluin, P.M.; Koning, F. Human epidermal Langerhans cells lack functional mannose receptors and a fully developed endosomal/lysosomal compartment for loading of HLA class II molecules. Eur. J. Immunol. 1999, 29, 571–580.
  66. Motoyama, K.; Mitsuyasu, R.; Akao, C.; Abu, H., II; Sato, N.; Tanaka, T.; Higashi, T.; Arima, H. Potential Use of Thioalkylated Mannose-Modified Dendrimer (G3)/alpha-Cyclodextrin Conjugate as an NF-kappaB siRNA Carrier for the Treatment of Fulminant Hepatitis. Mol. Pharm. 2015, 12, 3129–3136.
  67. Motoyama, K.; Mitsuyasu, R.; Akao, C.; Tanaka, T.; Ohyama, A.; Sato, N.; Higashi, T.; Arima, H. Design and evaluation of thioalkylated mannose-modified dendrimer (G3)/alpha-cyclodextrin conjugates as antigen-presenting cell-selective siRNA carriers. AAPS J. 2014, 16, 1298–1308.
  68. Tan, M.C.; Mommaas, A.M.; Drijfhout, J.W.; Jordens, R.; Onderwater, J.J.; Verwoerd, D.; Mulder, A.A.; van der Heiden, A.N.; Ottenhoff, T.H.; Cella, M.; et al. Mannose receptor mediated uptake of antigens strongly enhances HLA-class II restricted antigen presentation by cultured dendritic cells. Adv. Exp. Med. Biol. 1997, 417, 171–174.
  69. Katsara, M.; Yuriev, E.; Ramsland, P.A.; Deraos, G.; Tselios, T.; Matsoukas, J.; Apostolopoulos, V. Mannosylation of mutated MBP83–99 peptides diverts immune responses from Th1 to Th2. Mol. Immunol. 2008, 45, 3661–3670.
  70. Tseveleki, V.; Tselios, T.; Kanistras, I.; Koutsoni, O.; Karamita, M.; Vamvakas, S.-S.; Apostolopoulos, V.; Dotsika, E.; Matsoukas, J.; Lassmann, H.; et al. Mannan-conjugated myelin peptides prime non-pathogenic Th1 and Th17 cells and ameliorate experimental autoimmune encephalomyelitis. Exp. Neurol. 2015, 267, 254–267.
  71. Dagkonaki, A.; Avloniti, M.; Evangelidou, M.; Papazian, I.; Kanistras, I.; Tseveleki, V.; Lampros, F.; Tselios, T.; Jensen, L.T.; Möbius, W.; et al. Mannan-MOG35-55 Reverses Experimental Autoimmune Encephalomyelitis, Inducing a Peripheral Type 2 Myeloid Response, Reducing CNS Inflammation, and Preserving Axons in Spinal Cord Lesions. Front. Immunol. 2020, 11.
  72. Degano, M.; Garcia, K.C.; Apostolopoulos, V.; Rudolph, M.G.; Teyton, L.; Wilson, I.A. A functional hot spot for antigen recognition in a superagonist TCR/MHC complex. Immunity 2000, 12, 251–261.
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