Taming the TCR: Antigen-Specific Immunotherapeutic Agents for Autoimmune Diseases

REFERENCES

• Miller SD, Turley DM, Podojil JR. Antigen-specific tolerance strategies for the prevention and treatment of autoimmune disease. Nat Rev Immunol 2007;7:665–677.
   PubMed Web of Science ®Google Scholar
• Sun JB, Czerkinsky C, Holmgren J. Mucosally induced immunological tolerance, regulatory T cells and the adjuvant effect by cholera toxin B subunit. Scand J Immunol 2010;71:1–11.
   PubMed Web of Science ®Google Scholar
• Thorstenson KM, Khoruts A. Generation of anergic and potentially immuno-regulatory CD25+CD4 T cells in vivo after induction of peripheral tolerance with intravenous or oral antigen. J Immunol 2001;167:188–195.
   PubMed Web of Science ®Google Scholar
• Walczak A, Siger M, Ciach A, et al. Transdermal application of myelin peptides in multiple sclerosis treatment. JAMA Neurol 2013:1–6.
   Google Scholar
• Ludvigsson J, Krisky D, Casas R, et al. GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus. N Engl J Med 2012;366:433–442.
   PubMed Web of Science ®Google Scholar
• Wherrett DK, Bundy B, Becker DJ, et al. Antigen-based therapy with glutamic acid decarboxylase (GAD) vaccine in patients with recent-onset type 1 diabetes: a randomised double-blind trial. Lancet 2011;378:319–327.
   PubMed Web of Science ®Google Scholar
• Schulze MS, Wucherpfennig KW. The mechanism of HLA-DM-induced peptide exchange in the MHC class II antigen presentation pathway. Curr Opin Immunol 2012;24:105–111.
   PubMed Web of Science ®Google Scholar
• van den Hoorn T, Paul P, Jongsma ML, Neefjes J. Routes to manipulate MHC class II antigen presentation. Curr Opin Immunol 2011;23:88–95.
   PubMed Web of Science ®Google Scholar
• van der Merwe PA, Dushek O. Mechanisms for T cell receptor triggering. Nat Rev Immunol 2011;11:47–55.
   PubMed Web of Science ®Google Scholar
• Fooksman DR, Vardhana S, Vasiliver-Shamis G, et al. Functional anatomy of T cell activation and synapse formation. Ann Rev Immunol 2010;28:79–105.
   PubMed Web of Science ®Google Scholar
• Dustin ML, Depoil D. New insights into the T cell synapse from single molecule techniques. Nat Rev Immunol 2011;11:672–684.
   PubMed Web of Science ®Google Scholar
• Schubert DA, Gordo S, Sabatino JJ, Jr., et al. Self-reactive human CD4 T cell clones form unusual immunological synapses. J Exp Med 2012;209:335–352.
   PubMed Web of Science ®Google Scholar
• Guy CS, Vignali DA. Organization of proximal signal initiation at the TCR:CD3 complex. Immunol Rev 2009;232:7–21.
   PubMed Web of Science ®Google Scholar
• Smith-Garvin JE, Koretzky GA, Jordan MS. T cell activation. Ann Rev Immunol 2009;27:591–619.
   PubMed Web of Science ®Google Scholar
• Zhu J, Paul WE. Peripheral CD4+ T-cell differentiation regulated by networks of cytokines and transcription factors. Immunol Rev 2010;238:247–262.
   PubMed Web of Science ®Google Scholar
• Hemmer B, Pinilla C, Gran B, et al. Contribution of individual amino acids within MHC molecule or antigenic peptide to TCR ligand potency. J Immunol 2000;164:861–871.
   PubMed Web of Science ®Google Scholar
• Evavold BD, Sloan-Lancaster J, Wilson KJ, et al. Specific T cell recognition of minimally homologous peptides: evidence for multiple endogenous ligands. Immunity 1995;2:655–663.
   PubMed Web of Science ®Google Scholar
• Snoke K, Alexander J, Franco A, et al. The inhibition of different T cell lines specific for the same antigen with TCR antagonist peptides. J Immunol 1993;151:6815–6821.
   PubMed Web of Science ®Google Scholar
• Alexander J, Snoke K, Ruppert J, et al. Functional consequences of engagement of the T cell receptor by low affinity ligands. J Immunol 1993;150:1–7.
   PubMed Web of Science ®Google Scholar
• Evavold BD, Sloan-Lancaster J, Allen PM. Tickling the TCR: selective T-cell functions stimulated by altered peptide ligands. Immunol Today 1993;14:602–609.
   PubMedGoogle Scholar
• Evavold BD, Allen PM. Separation of IL-4 production from Th cell proliferation by an altered T cell receptor ligand. Science 1991;252:1308–1310.
   PubMed Web of Science ®Google Scholar
• Sloan-Lancaster J, Evavold BD, Allen PM. Induction of T-cell anergy by altered T-cell-receptor ligand on live antigen-presenting cells. Nature 1993;363:156–159.
   PubMed Web of Science ®Google Scholar
• De Magistris MT, Alexander J, Coggeshall M, et al. Antigen analog-major histocompatibility complexes act as antagonists of the T cell receptor. Cell 1992;68:625–634.
   PubMed Web of Science ®Google Scholar
• Ostrov D, Krieger J, Sidney J, et al. T cell receptor antagonism mediated by interaction between T cell receptor junctional residues and peptide antigen analogues. J Immunol 1993;150:4277–4283.
   PubMed Web of Science ®Google Scholar
• Yang W, Grey HM. Study of the mechanism of TCR antagonism using dual-TCR-expressing T cells. J Immunol 2003;170:4532–4538.
   PubMed Web of Science ®Google Scholar
• Robertson JM, Evavold BD. Cutting edge: dueling TCRs: peptide antagonism of CD4+ T cells with dual antigen specificities. J Immunol 1999;163:1750–1754.
   PubMed Web of Science ®Google Scholar
• Madrenas J, Schwartz RH, Germain RN. Interleukin 2 production, not the pattern of early T-cell antigen receptor-dependent tyrosine phosphorylation, controls anergy induction by both agonists and partial agonists. Proc Natl Acad Sci USA 1996;93:9736–9741.
   PubMed Web of Science ®Google Scholar
• Matsushita S, Nishimura Y. Partial activation of human T cells by peptide analogs on live APC: induction of clonal anergy associated with protein tyrosine dephosphorylation. Hum Immunol 1997;53:73–80.
   PubMed Web of Science ®Google Scholar
• Vukmanović S, Santori FR. Self-peptide/MHC and TCR antagonism: physiological role and therapeutic potential. Cell Immunol 2005;233:75–84.
   PubMed Web of Science ®Google Scholar
• Madrenas J, Wange RL, Wang JL, et al. Zeta phosphorylation without ZAP-70 activation induced by TCR antagonists or partial agonists. Science 1995;267:515–518.
   PubMed Web of Science ®Google Scholar
• Madrenas J, Chau LA, Smith J, et al. The efficiency of CD4 recruitment to ligand-engaged TCR controls the agonist/partial agonist properties of peptide-MHC molecule ligands. J Exp Med 1997;185:219–229.
   PubMed Web of Science ®Google Scholar
• La Face DM, Couture C, Anderson K, et al. Differential T cell signaling induced by antagonist peptide-MHC complexes and the associated phenotypic responses. J Immunol 1997;158:2057–2064.
   PubMed Web of Science ®Google Scholar
• Kersh EN, Shaw AS, Allen PM. Fidelity of T cell activation through multistep T cell receptor zeta phosphorylation. Science 1998;281:572–575.
   PubMed Web of Science ®Google Scholar
• Sloan-Lancaster J, Shaw AS, Rothbard JB, Allen PM. Partial T cell signaling: altered phospho-zeta and lack of zap70 recruitment in APL-induced T cell anergy. Cell 1994;79:913–922.
   PubMed Web of Science ®Google Scholar
• Kersh EN, Kersh GJ, Allen PM. Partially phosphorylated T cell receptor ζ molecules can inhibit T cell activation. J Exp Med 1999;190:1627–1636.
   PubMed Web of Science ®Google Scholar
• Vidal K, Daniel C, Hill M, et al. Differential requirements for CD4 in TCR-ligand interactions. J Immunol 1999;163:4811–4818.
   PubMed Web of Science ®Google Scholar
• Hampl J, Chien YH, Davis MM. CD4 augments the response of a T cell to agonist but not to antagonist ligands. Immunity 1997;7:379–385.
   PubMed Web of Science ®Google Scholar
• Racioppi L, Matarese G, D'Oro U, et al. The role of CD4-Lck in T-cell receptor antagonism: evidence for negative signaling. Proc Natl Acad Sci USA 1996;93:10360–10365.
   PubMed Web of Science ®Google Scholar
• Stefanova I, Hemmer B, Vergelli M, et al. TCR ligand discrimination is enforced by competing ERK positive and SHP-1 negative feedback pathways. Nat Immunol 2003;4:248–254.
   PubMed Web of Science ®Google Scholar
• Kilgore NE, Carter JD, Lorenz U, Evavold BD. Cutting edge: dependence of TCR antagonism on Src homology 2 domain-containing protein tyrosine phosphatase activity. J Immunol 2003;170:4891–4895.
   PubMed Web of Science ®Google Scholar
• Huang J, Sugie K, La Face DM, et al. TCR antagonist peptides induce formation of APC-T cell conjugates and activate a Rac signaling pathway. Eur J Immunol 2000;30:50–58.
   PubMed Web of Science ®Google Scholar
• Ruppert J, Alexander J, Snoke K, et al. Effect of T-cell receptor antagonism on interaction between T cells and antigen-presenting cells and on T-cell signaling events. Proc Natl Acad Sci USA 1993;90:2671–2675.
   PubMed Web of Science ®Google Scholar
• Sumen C, Dustin ML, Davis MM. T cell receptor antagonism interferes with MHC clustering and integrin patterning during immunological synapse formation. J Cell Biol 2004;166:579–590.
   PubMed Web of Science ®Google Scholar
• Wülfing C, Rabinowitz JD, Beeson C, et al. Kinetics and extent of T cell activation as measured with the calcium signal. J Exp Med 1997;185:1815–1825.
   PubMed Web of Science ®Google Scholar
• Chen YZ, Lai ZF, Nishi K, Nishimura Y. Modulation of calcium responses by altered peptide ligands in a human T cell clone. Eur J Immunol 1998;28:3929–3939.
   PubMed Web of Science ®Google Scholar
• Racioppi L, Ronchese F, Matis LA, Germain RN. Peptide-major histocompatibility complex class II complexes with mixed agonist/antagonist properties provide evidence for ligand-related differences in T-cell receptor-dependent intracellular signaling. J Exp Med 1993;177:1047–1060.
   PubMed Web of Science ®Google Scholar
• Grakoui A, VanDyk LF, Dowdy SF, Allen PM. Molecular basis for the lack of T cell proliferation induced by an altered peptide ligand. Int Immunol 1998;10:969–979.
   PubMed Web of Science ®Google Scholar
• Ryan KR, McNeil LK, Dao C, et al. Modification of peptide interaction with MHC creates TCR partial agonists. Cell Immunol 2004;227:70–78.
   PubMed Web of Science ®Google Scholar
• Anderton SM, Radu CG, Lowrey PA, et al. Negative selection during the peripheral immune response to antigen. J Exp Med 2001;193:1–11.
   PubMed Web of Science ®Google Scholar
• Ford ML, Evavold BD. Regulation of polyclonal T cell responses by an MHC anchor-substituted variant of myelin oligodendrocyte glycoprotein 35–55. J Immunol 2003;171:1247–1254.
   PubMed Web of Science ®Google Scholar
• McCue D, Ryan KR, Wraith DC, Anderton SM. Activation thresholds determine susceptibility to peptide-induced tolerance in a heterogeneous myelin-reactive T cell repertoire. J Neuroimmunol 2004;156:96–106.
   PubMed Web of Science ®Google Scholar
• Lazarski CA, Chaves FA, Jenks SA, et al. The kinetic stability of MHC class II: peptide complexes is a key parameter that dictates immunodominance. Immunity 2005;23:29–40.
   PubMed Web of Science ®Google Scholar
• Baumgartner CK, Ferrante A, Nagaoka M, et al. Peptide-MHC class II complex stability governs CD4 T cell clonal selection. J Immunol 2010;184:573–581.
   PubMed Web of Science ®Google Scholar
• Weaver JM, Chaves FA, Sant AJ. Abortive activation of CD4 T cell responses during competitive priming in vivo. Proc Natl Acad Sci USA 2009;106:8647–8652.
   PubMed Web of Science ®Google Scholar
• Kersh GJ, Miley MJ, Nelson CA, et al. Structural and functional consequences of altering a peptide MHC anchor residue. J Immunol 2001;166:3345–3354.
   PubMed Web of Science ®Google Scholar
• Sharma SD, Nag B, Su XM, et al. Antigen-specific therapy of experimental allergic encephalomyelitis by soluble class II major histocompatibility complex-peptide complexes. Proc Natl Acad Sci USA 1991;88:11465–11469.
   PubMed Web of Science ®Google Scholar
• Nicolle MW, Nag B, Sharma SD, et al. Specific tolerance to an acetylcholine receptor epitope induced in vitro in myasthenia gravis CD4+ lymphocytes by soluble major histocompatibility complex class II-peptide complexes. J Clin Invest 1994;93:1361–1369.
   PubMed Web of Science ®Google Scholar
• Radu CG, Ober BT, Colantonio L, et al. Expression and characterization of recombinant soluble peptide: I-A complexes associated with murine experimental autoimmune diseases. J Immunol 1998;160:5915–5921.
   PubMed Web of Science ®Google Scholar
• Appel H, Gauthier L, Pyrdol J, Wucherpfennig KW. Kinetics of T-cell receptor binding by bivalent HLA-DR. Peptide complexes that activate antigen-specific human T-cells. J Biol Chem 2000;275:312–321.
   PubMed Web of Science ®Google Scholar
• Nolte-'t Hoen EN, Amoroso MG, Veenstra J, et al. Effector and regulatory T cells derived from the same T cell clone differ in MHC class II-peptide multimer binding. Eur J Immunol 2004;34:3359–3369.
   PubMed Web of Science ®Google Scholar
• Dzhambazov B, Nandakumar KS, Kihlberg J, et al. Therapeutic vaccination of active arthritis with a glycosylated collagen type II peptide in complex with MHC class II molecules. J Immunol 2006;176:1525–1533.
   PubMed Web of Science ®Google Scholar
• Chang JW, Mechling DE, Bachinger HP, Burrows GG. Design, engineering, and production of human recombinant t cell receptor ligands derived from human leukocyte antigen DR2. J Biol Chem 2001;276:24170–24176.
   PubMed Web of Science ®Google Scholar
• Burrows GG, Chang JW, Bachinger HP, et al. Design, engineering and production of functional single-chain T cell receptor ligands. Protein Eng 1999;12:771–778.
   PubMedGoogle Scholar
• Casares S, Zong CS, Radu DL, et al. Antigen-specific signaling by a soluble, dimeric peptide/major histocompatibility complex class II/Fc chimera leading to T helper cell type 2 differentiation. J Exp Med 1999;190:543–553.
   PubMed Web of Science ®Google Scholar
• Zuo L, Cullen CM, DeLay ML, et al. A single-chain class II MHC-IgG3 fusion protein inhibits autoimmune arthritis by induction of antigen-specific hyporesponsiveness. J Immunol 2002;168:2554–2559.
   PubMed Web of Science ®Google Scholar
• Li L, Yi Z, Wang B, Tisch R. Suppression of ongoing T cell-mediated autoimmunity by peptide-MHC class II dimer vaccination. J Immunol 2009;183:4809–4816.
   PubMed Web of Science ®Google Scholar
• Cochran JR, Cameron TO, Stern LJ. The relationship of MHC-peptide binding and T cell activation probed using chemically defined MHC class II oligomers. Immunity 2000;12:241–250.
   PubMed Web of Science ®Google Scholar
• Kozono H, White J, Clements J, et al. Production of soluble MHC class II proteins with covalently bound single peptides. Nature 1994;369:151–154.
   PubMed Web of Science ®Google Scholar
• Karabekian Z, Lytton SD, Silver PB, et al. Antigen/MHC class II/Ig dimers for study of uveitogenic T cells: IRBP p161–180 presented by both IA and IE molecules. Invest Ophthalmol Vis Sci 2005;46:3769–3776.
   PubMed Web of Science ®Google Scholar
• Casares S, Bona CA, Brumeanu TD. Enzymatically mediated engineering of multivalent MHC class II-peptide chimeras. Protein Eng 2001;14:195–200.
   PubMedGoogle Scholar
• Matsui K, Boniface JJ, Steffner P, et al. Kinetics of T-cell receptor binding to peptide/I-Ek complexes: correlation of the dissociation rate with T-cell responsiveness. Proc Natl Acad Sci USA 1994;91:12862–12866.
   PubMed Web of Science ®Google Scholar
• Matsui K, Boniface JJ, Reay PA, et al. Low affinity interaction of peptide-MHC complexes with T cell receptors. Science 1991;254:1788–1791.
   PubMed Web of Science ®Google Scholar
• Wang C, Mooney JL, Meza-Romero R, et al. Recombinant TCR ligand induces early TCR signaling and a unique pattern of downstream activation. J Immunol 2003;171:1934–1940.
   PubMed Web of Science ®Google Scholar
• Hamad AR, O'Herrin SM, Lebowitz MS, et al. Potent T cell activation with dimeric peptide-major histocompatibility complex class II ligand: the role of CD4 coreceptor. J Exp Med 1998;188:1633–1640.
   PubMed Web of Science ®Google Scholar
• Lin M, Stoica-Nazarov C, Surls J, et al. Reversal of type 1 diabetes by a new MHC II-peptide chimera: “single-epitope-mediated suppression” to stabilize a polyclonal autoimmune T-cell process. Eur J Immunol 2010;40:2277–22788.
   PubMed Web of Science ®Google Scholar
• Preda I, McEvoy RC, Lin M, et al. Soluble, dimeric HLA DR4-peptide chimeras: an approach for detection and immunoregulation of human type-1 diabetes. Eur J Immunol 2005;35:2762–2775.
   PubMed Web of Science ®Google Scholar
• Appel H, Seth NP, Gauthier L, Wucherpfennig KW. Anergy induction by dimeric TCR ligands. J Immunol 2001;166:5279–5285.
   PubMed Web of Science ®Google Scholar
• Harauz G, Musse AA. A tale of two citrullines –structural and functional aspects of myelin basic protein deimination in health and disease. Neurochem Res 2007;32:137–158.
   PubMed Web of Science ®Google Scholar
• Sinha S, Miller L, Subramanian S, et al. Binding of recombinant T cell receptor ligands (RTL) to antigen presenting cells prevents upregulation of CD11b and inhibits T cell activation and transfer of experimental autoimmune encephalomyelitis. J Neuroimmunol 2010;225:52–61.
   PubMed Web of Science ®Google Scholar
• Vandenbark AA, Meza-Romero R, Benedek G, et al. A novel regulatory pathway for autoimmune disease: binding of partial MHC class II constructs to monocytes reduces CD74 expression and induces both specific and bystander T-cell tolerance. J Autoimmun 2013;40:96–110.
   PubMed Web of Science ®Google Scholar
• Thomas S, Kumar R, Preda-Pais A, et al. A model for antigen-specific T-cell anergy: displacement of CD4-p56(lck) signalosome from the lipid rafts by a soluble, dimeric peptide-MHC class II chimera. J Immunol 2003;170:5981–5992.
   PubMed Web of Science ®Google Scholar
• Prasad S, Xu D, Miller SD. Tolerance strategies employing antigen-coupled apoptotic cells and carboxylated PLG nanoparticles for the treatment of type 1 diabetes. Rev Diabet Stud 2012;9:319–327.
   PubMedGoogle Scholar
• Getts DR, Turley DM, Smith CE, et al. Tolerance induced by apoptotic antigen-coupled leukocytes is induced by PD-L1+ and IL-10-producing splenic macrophages and maintained by T regulatory cells. J Immunol 2011;187:2405–2417.
   PubMed Web of Science ®Google Scholar
• Constantinescu CS, Farooqi N, O'Brien K, Gran B. Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS). Brit J Pharmacol 2011;164:1079–1106.
   PubMed Web of Science ®Google Scholar
• Pachner AR. Experimental models of multiple sclerosis. Curr Opin Neurol 2011;24:291–299.
   PubMed Web of Science ®Google Scholar
• Stromnes IM, Goverman JM. Passive induction of experimental allergic encephalomyelitis. Nat Protoc 2006;1:1952–1960.
   PubMed Web of Science ®Google Scholar
• Stromnes IM, Goverman JM. Active induction of experimental allergic encephalomyelitis. Nat Protoc 2006;1:1810–1819.
   PubMed Web of Science ®Google Scholar
• Alzabin S, Williams RO. Effector T cells in rheumatoid arthritis: lessons from animal models. FEBS Letts 2011;585:3649–3659.
   PubMed Web of Science ®Google Scholar
• Anderson MS, Bluestone JA. The NOD mouse: a model of immune dysregulation. Ann Rev Immunol 2005;23:447–485.
   PubMed Web of Science ®Google Scholar
• Baggi F, Antozzi C, Toscani C, Cordiglieri C. Acetylcholine receptor-induced experimental myasthenia gravis: what have we learned from animal models after three decades? Arch Immunol Ther Exp 2012;60:19–30.
   PubMed Web of Science ®Google Scholar
• Margot CD, Ford ML, Evavold BD. Amelioration of established experimental autoimmune encephalomyelitis by an MHC anchor-substituted variant of proteolipid protein 139–151. J Immunol 2005;174:3352–3358.
   PubMed Web of Science ®Google Scholar
• Ford ML, Evavold BD. An MHC anchor-substituted analog of myelin oligodendrocyte glycoprotein 35–55 induces IFN-gamma and autoantibodies in the absence of experimental autoimmune encephalomyelitis and optic neuritis. Eur J Immunol 2004;34:388–397.
   PubMed Web of Science ®Google Scholar
• Sabatino JJ, Jr., Shires J, Altman JD, et al. Loss of IFN-gamma enables the expansion of autoreactive CD4+ T cells to induce experimental autoimmune encephalo­myelitis by a nonencephalitogenic myelin variant antigen. J Immunol 2008;180:4451–4457.
   PubMed Web of Science ®Google Scholar
• Wasserman HA, Beal CD, Zhang Y, et al. MHC variant peptide-mediated anergy of encephalitogenic T cells requires SHP-1. J Immunol 2008;181:6843–6849.
   PubMed Web of Science ®Google Scholar
• Myers LK, Sakurai Y, Rosloniec EF, et al. An analog peptide that suppresses collagen-induced arthritis. Am J Med Sci 2004;327:212–216.
   PubMed Web of Science ®Google Scholar
• Rosloniec EF, Whittington KB, Zaller DM, Kang AH. HLA-DR1 (DRB1*0101) and DR4 (DRB1*0401) use the same anchor residues for binding an immunodominant peptide derived from human type II collagen. J Immunol 2002;168:253–259.
   PubMed Web of Science ®Google Scholar
• Sakurai Y, Brand DD, Tang B, et al. Analog peptides of type II collagen can suppress arthritis in HLA-DR4 (DRB1*0401) transgenic mice. Arthritis Res Ther 2006;8:R150.
   PubMed Web of Science ®Google Scholar
• Tisch R, Wang B, Serreze DV. Induction of glutamic acid decarboxylase 65-specific Th2 cells and suppression of autoimmune diabetes at late stages of disease is epitope dependent. J Immunol 1999;163:1178–1187.
   PubMed Web of Science ®Google Scholar
• Kennedy MK, Tan LJ, Dal Canto MC, et al. Inhibition of murine relapsing experimental autoimmune encephalomyelitis by immune tolerance to proteolipid protein and its encephalitogenic peptides. J Immunol 1990;144:909–915.
   PubMed Web of Science ®Google Scholar
• Kennedy MK, Tan LJ, Dal Canto MC, Miller SD. Regulation of the effector stages of experimental autoimmune encephalomyelitis via neuroantigen-specific tolerance induction. J Immunol 1990;145:117–126.
   PubMed Web of Science ®Google Scholar
• Vandenbark AA, Celnik B, Vainiene M, et al. Myelin antigen-coupled splenocytes suppress experimental autoimmune encephalomyelitis in Lewis rats through a partially reversible anergy mechanism. J Immunol 1995;155:5861–5867.
   PubMed Web of Science ®Google Scholar
• Tan LJ, Kennedy MK, Miller SD. Regulation of the effector stages of experimental autoimmune encephalomyelitis via neuroantigen-specific tolerance induction. II. Fine specificity of effector T cell inhibition. J Immunol 1992;148:2748–2755.
   PubMed Web of Science ®Google Scholar
• Su XM, Sriram S. Treatment of chronic relapsing experimental allergic encephalomyelitis with the intravenous administration of splenocytes coupled to encephalitogenic peptide 91–103 of myelin basic protein. J Neuroimmunol 1991;34:181–190.
   PubMed Web of Science ®Google Scholar
• Tan LJ, Kennedy MK, Dal Canto MC, Miller SD. Successful treatment of paralytic relapses in adoptive experimental autoimmune encephalomyelitis via neuroantigen-specific tolerance. J Immunol 1991;147:1797–1802.
   PubMed Web of Science ®Google Scholar
• Tan LJ, Vanderlugt CL, McRae BL, Miller SD. Regulation of the effector stages of experimental autoimmune encephalomyelitis via neuroantigen-specific tolerance induction. III. A role for anergy/deletion. Autoimmunity 1998;27:13–28.
   PubMed Web of Science ®Google Scholar
• Vandenbark AA, Vainiene M, Ariail K, et al. Prevention and treatment of relapsing autoimmune encephalomyelitis with myelin peptide-coupled splenocytes. J Neurosci Res 1996;45:430–438.
   PubMed Web of Science ®Google Scholar
• Smith CE, Miller SD. Multi-peptide coupled-cell tolerance ameliorates ongoing relapsing EAE associated with multiple pathogenic autoreactivities. J Autoimmun 2006;27:218–231.
   PubMed Web of Science ®Google Scholar
• Fife BT, Guleria I, Gubbels BM, et al. Insulin-induced remission in new-onset NOD mice is maintained by the PD-1-PD-L1 pathway. J Exp Med 2006;203:2737–2747.
   PubMed Web of Science ®Google Scholar
• Fife BT, Pauken KE, Eagar TN, et al. Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal. Nat Immunol 2009;10:1185–1192.
   PubMed Web of Science ®Google Scholar
• Vogt AB, Kropshofer H, Kalbacher H, et al. Ligand motifs of HLA-DRB5*0101 and DRB1*1501 molecules delineated from self-peptides. J Immunol 1994;153:1665–1673.
   PubMed Web of Science ®Google Scholar
• Wucherpfennig KW, Sette A, Southwood S, et al. Structural requirements for binding of an immunodominant myelin basic protein peptide to DR2 isotypes and for its recognition by human T cell clones. J Exp Med 1994;179:279–290.
   PubMed Web of Science ®Google Scholar
• Hemmer B, Vergelli M, Tranquill L, et al. Human T-cell response to myelin basic protein peptide (83–99): extensive heterogeneity in antigen recognition, function, and phenotype. Neurology 1997;49:1116–1126.
   PubMed Web of Science ®Google Scholar
• Vergelli M, Hemmer B, Utz U, 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.
   PubMed Web of Science ®Google Scholar
• Vergelli M, Hemmer B, Kalbus M, et al. Modifications of peptide ligands enhancing T cell responsiveness imply large numbers of stimulatory ligands for autoreactive T cells. J Immunol 1997;158:3746–3752.
   PubMed Web of Science ®Google Scholar
• Ausubel LJ, Bieganowska KD, Hafler DA. Cross-reactivity of T-cell clones specific for altered peptide ligands of myelin basic protein. Cell Immunol 1999;193:99–107.
   PubMed Web of Science ®Google Scholar
• Bielekova B, Goodwin B, Richert N, 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.
   PubMed Web of Science ®Google Scholar
• Kappos L, Comi G, Panitch H, 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. The altered peptide ligand in relapsing MS study group. Nat Med 2000;6:1176–1182.
   PubMed Web of Science ®Google Scholar
• Kim HJ, Antel JP, Duquette P, et al. Persistence of immune responses to altered and native myelin antigens in patients with multiple sclerosis treated with altered peptide ligand. Clin Immunol 2002;104:105–114.
   PubMed Web of Science ®Google Scholar
• Yadav V, Bourdette DN, Bowen JD, et al. Recombinant T-cell receptor ligand (RTL) for treatment of multiple sclerosis: a double-blind, placebo-controlled, phase 1, dose-escalation study. Autoimmun Dis 2012. Epub 2012/4/15. doi:10.1155/2012/954739.
   PubMedGoogle Scholar
• Lutterotti A, Yousef S, Sputtek A, et al. Antigen-specific tolerance by autologous myelin peptide-coupled cells: a phase 1 trial in multiple sclerosis. Sci Transl Med 2013;5:188ra75.
   PubMed Web of Science ®Google Scholar
• Khare M, Rodriguez M, David CS. HLA class II transgenic mice authenticate restriction of myelin oligodendrocyte glycoprotein-specific immune response implicated in multiple sclerosis pathogenesis. Int Immunol 2003;15:535–546.
   PubMed Web of Science ®Google Scholar
• Greer JM, Csurhes PA, Muller DM, Pender MP. Correlation of blood T cell and antibody reactivity to myelin proteins with HLA type and lesion localization in multiple sclerosis. J Immunol 2008;180:6402–6410.
   PubMed Web of Science ®Google Scholar
• Greer JM. Autoimmune T-cell reactivity to myelin proteolipids and glycolipids in multiple sclerosis. Mult Scler Int 2013;2013:151427.
   Google Scholar
• Kerlero de Rosbo N, Hoffman M, Mendel I, et al. Predominance of the autoimmune response to myelin oligodendrocyte glycoprotein (MOG) in multiple sclerosis: reactivity to the extracellular domain of MOG is directed against three main regions. Eur J Immunol 1997;27:3059–3069.
   PubMed Web of Science ®Google Scholar
• Kerlero de Rosbo N, Milo R, Lees MB, et al. Reactivity to myelin antigens in multiple sclerosis. Peripheral blood lymphocytes respond predominantly to myelin oligodendrocyte glycoprotein. J Clin Invest 1993;92:2602–2608.
   PubMed Web of Science ®Google Scholar
• Geluk A, van Meijgaarden KE, Roep BO, Ottenhoff TH. Altered peptide ligands of islet autoantigen Imogen 38 inhibit antigen specific T cell reactivity in human type-1 diabetes. J Autoimmun 1998;11:353–61.
   PubMed Web of Science ®Google Scholar
• Gebe JA, Masewicz SA, Kochik SA, et al. Inhibition of altered peptide ligand-mediated antagonism of human GAD65-responsive CD4+ T cells by non-antagonizable T cells. Eur J Immunol 2004;34:3337–3345.
   PubMed Web of Science ®Google Scholar
• Masewicz SA, Papadopoulos GK, Swanson E, et al. Modulation of T cell response to hGAD65 peptide epitopes. Tissue Antigens 2002;59:101–112.
   PubMed Web of Science ®Google Scholar
• Nepom GT, Lippolis JD, White FM, et al. Identification and modulation of a naturally processed T cell epitope from the diabetes-associated autoantigen human glutamic acid decarboxylase 65 (hGAD65). Proc Natl Acad Sci USA 2001;98:1763–1768.
   PubMed Web of Science ®Google Scholar
• Alleva DG, Gaur A, Jin L, et al. Immunological characterization and therapeutic activity of an altered-peptide ligand, NBI-6024, based on the immunodominant type 1 diabetes autoantigen insulin B-chain (9–23) peptide. Diabetes 2002;51:2126–2134.
   PubMed Web of Science ®Google Scholar
• Alleva DG, Crowe PD, Jin L, et al. A disease-associated cellular immune response in type 1 diabetics to an immunodominant epitope of insulin. J Clin Invest 2001;107:173–180.
   PubMed Web of Science ®Google Scholar
• Alleva DG, Maki RA, Putnam AL, et al. Immunomodulation in type 1 diabetes by NBI-6024, an altered peptide ligand of the insulin B epitope. Scand J Immunol 2006;63:59–69.
   PubMed Web of Science ®Google Scholar
• Walter M, Philotheou A, Bonnici F, et al. No effect of the altered peptide ligand NBI-6024 on beta-cell residual function and insulin needs in new-onset type 1 diabetes. Diabetes Care 2009;32:2036–2040.
   PubMed Web of Science ®Google Scholar
• Boissier MC, Semerano L, Challal S, et al. Rheumatoid arthritis: from autoimmunity to synovitis and joint destruction. J Autoimmun 2012;39:222–228.
   PubMed Web of Science ®Google Scholar
• Andersson EC, Hansen BE, Jacobsen H, et al. Definition of MHC and T cell receptor contacts in the HLA-DR4 restricted immunodominant epitope in type II collagen and characterization of collagen-induced arthritis in HLA-DR4 and human CD4 transgenic mice. Proc Natl Acad Sci USA 1998;95:7574–7579.
   PubMed Web of Science ®Google Scholar
• Zhou Q, Cheng Y, Lu H, et al. Inhibition of T-cell activation with HLA-DR1/DR4 restricted non-T-cell stimulating peptides. Hum Immunol 2003;64:857–865.
   PubMed Web of Science ®Google Scholar
• Ohnishi Y, Tsutsumi A, Matsumoto I, et al. Altered peptide ligands control type II collagen-reactive T cells from rheumatoid arthritis patients. Mod Rheumatol 2006;16:226–228.
   PubMedGoogle Scholar
• Cheng YJ, Zhou Q, Li ZG. The inhibitory effect of altered collagen II peptide on HLA-DRB1-restricted T-cell activation. Scand J Immunol 2005;61:260–265.
   PubMed Web of Science ®Google Scholar
• Li X, Li R, Li Z. Altered influenza virus haemagglutinin peptides inhibit T cell responses to type II collagen in rheumatoid arthritis. Ann Rheum Dis 2005;64:1790–1791.
   PubMed Web of Science ®Google Scholar
• Li R, Li X, Li Z. Altered collagen II peptides inhibited T-cell activation in rheumatoid arthritis. Clin Immunol 2006;118:317–323.
   PubMed Web of Science ®Google Scholar
• Boehm BO, Rosinger S, Sauer G, et al. Protease-resistant human GAD-derived altered peptide ligands decrease TNF-alpha and IL-17 production in peripheral blood cells from patients with type 1 diabetes mellitus. Mol Immunol 2009;46:2576–2584.
   PubMed Web of Science ®Google Scholar
• van Aalst D, Kalbacher H, Palesch D, et al. A proinsulin 74–90-derived protease-resistant, altered peptide ligand increases TGF-beta 1 secretion in PBMC from patients with type 1 diabetes mellitus. J Leukoc Biol 2010;87:943–948.
   PubMed Web of Science ®Google Scholar
• Boots AM, Hubers H, Kouwijzer M, et al. Identification of an altered peptide ligand based on the endogenously presented, rheumatoid arthritis-associated, human cartilage glycoprotein-39(263–275) epitope: an MHC anchor variant peptide for immune modulation. Arthritis Res Ther 2007;9:R71.
   PubMed Web of Science ®Google Scholar
• Matsoukas J, Apostolopoulos V, Kalbacher H, 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.
   PubMed Web of Science ®Google Scholar
• Tselios T, Daliani I, Probert L, et al. Treatment of experimental allergic encephalomyelitis (EAE) induced by guinea pig myelin basic protein epitope 72–85 with a human MBP87–99 analogue and effects of cyclic peptides. Bioorg Med Chem 2000;8:1903–1909.
   PubMed Web of Science ®Google Scholar
• Tselios T, Probert L, Daliani I, et al. 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.
   PubMed Web of Science ®Google Scholar
• Tselios T, Apostolopoulos V, Daliani I, et al. Antagonistic effects of human cyclic MBP 87–99 altered peptide ligands in experimental allergic encephalomyelitis and human T-cell proliferation. J Med Chem 2002;45:275–283.
   PubMed Web of Science ®Google Scholar
• Kowalczyk W, de la Torre BG, Andreu D. Strategies and limitations in dendrimeric immunogen synthesis. The influenza virus M2e epitope as a case study. Bioconjug Chem 2010;21:102–110.
   PubMed Web of Science ®Google Scholar
• Xia J, Siegel M, Bergseng E, et al. Inhibition of HLA-DQ2-mediated antigen presentation by analogues of a high affinity 33-residue peptide from alpha2-gliadin. J Am Chem Soc 2006;128:1859–1867.
   PubMed Web of Science ®Google Scholar
• Xia J, Bergseng E, Fleckenstein B, et al. Cyclic and dimeric gluten peptide analogues inhibiting DQ2-mediated antigen presentation in celiac disease. Bioorg Med Chem. 2007;15:6565–6573.
   PubMed Web of Science ®Google Scholar
• Cloake NC, Beaino W, Trifilieff E, Greer JM. Thiopalmitoylation of altered peptide ligands enhances their protective effects in an animal model of multiple sclerosis. J Immunol 195:2244–2251.
   Google Scholar
• Pfender NA, Grosch S, Roussel G, et al. Route of uptake of palmitoylated encephalitogenic peptides of myelin proteolipid protein by antigen-presenting cells: importance of the type of bond between lipid chain and peptide and relevance to autoimmunity. J Immunol 2008;180:1398–1404.
   PubMed Web of Science ®Google Scholar
• Dessen A, Lawrence CM, Cupo S, et al. X-ray crystal structure of HLA-DR4 (DRA*0101, DRB1*0401) complexed with a peptide from human collagen II. Immunity 1997;7:473–81.
   PubMed Web of Science ®Google Scholar
• Gebe JA, Novak EJ, Kwok WW, et al. T cell selection and differential activation on structurally related HLA-DR4 ligands. J Immunol 2001;167:3250–3256.
   PubMed Web of Science ®Google Scholar
• Jacobson EM, Huber A, Tomer Y. The HLA gene complex in thyroid autoimmunity: from epidemiology to etiology. J Autoimmun 2008;30:58–62.
   PubMed Web of Science ®Google Scholar
• Medrano LM, Dema B, López-Larios A, et al. HLA and celiac disease susceptibility: new genetic factors bring open questions about the HLA influence and gene-dosage effects. PloS One 2012;7:e48403.
   PubMed Web of Science ®Google Scholar
• Noble JA, Valdes AM. Genetics of the HLA region in the prediction of type 1 diabetes. Curr Diab Rep 2011;11:533–542.
   PubMed Web of Science ®Google Scholar
• Gough SCL, Simmonds MJ. The HLA region and autoimmune disease: associations and mechanisms of action. Curr Genomics 2007;8:453–465.
   PubMed Web of Science ®Google Scholar
• Mangalam AK, Taneja V, David CS. HLA class II molecules influence susceptibility versus protection in inflammatory diseases by determining the cytokine profile. J Immunol 2013;190:513–519.
   PubMed Web of Science ®Google Scholar
• Greer JM. The role of HLA in MS susceptibility and phenotype. Curr Top Behav Neurosci 2014. Epub 2014/12/17. doi:10.1007/7854_2014_357.
   Google Scholar
• Kuchroo VK, Greer JM, Kaul D, et al. A single TCR antagonist peptide inhibits experimental allergic encephalomyelitis mediated by a diverse T cell repertoire. J Immunol 1994;153:3326–3336.
   PubMed Web of Science ®Google Scholar
• Nicholson LB, Murtaza A, Hafler BP, et al. A T cell receptor antagonist peptide induces T cells that mediate bystander suppression and prevent autoimmune encephalomyelitis induced with multiple myelin antigens. Proc Natl Acad Sci USA 1997;94:9279–9284.
   PubMed Web of Science ®Google Scholar
• Santambrogio L, Lees MB, Sobel RA. Altered peptide ligand modulation of experimental allergic encephalomyelitis: immune responses within the CNS. J Neuroimmunol 1998;81:1–13.
   PubMed Web of Science ®Google Scholar
• Das MP, Nicholson LB, Greer JM, Kuchroo VK. Autopathogenic T helper cell type 1 (Th1) and protective Th2 clones differ in their recognition of the autoantigenic peptide of myelin proteolipid protein. J Exp Med 1997;186:867–876.
   PubMed Web of Science ®Google Scholar
• Nicholson LB, Greer JM, Sobel RA, et al. An altered peptide ligand mediates immune deviation and prevents autoimmune encephalomyelitis. Immunity 1995;3:397–405.
   PubMed Web of Science ®Google Scholar
• Greer JM, Klinguer C, Trifilieff E, et al. Encephalitogenicity of murine, but not bovine, DM20 in SJL mice is due to a single amino acid difference in the immunodominant encephalitogenic epitope. Neurochem Res 1997;22:541–547.
   PubMed Web of Science ®Google Scholar
• Anderton SM, Kissler S, Lamont AG, Wraith DC. Therapeutic potential of TCR antagonists is determined by their ability to modulate a diverse repertoire of autoreactive T cells. Eur J Immunol 1999;29:1850–1857.
   PubMed Web of Science ®Google Scholar
• Anderton SM, Manickasingham SP, Burkhart C, et al. Fine specificity of the myelin-reactive T cell repertoire: implications for TCR antagonism in autoimmunity. J Immunol 1998;161:3357–3364.
   PubMed Web of Science ®Google Scholar
• Karin N, Mitchell DJ, Brocke S, et al. Reversal of experimental autoimmune encephalomyelitis by a soluble peptide variant of a myelin basic protein epitope: T cell receptor antagonism and reduction of interferon gamma and tumor necrosis factor alpha production. J Exp Med 1994;180:2227–2237.
   PubMed Web of Science ®Google Scholar
• Li R, Li X, Li Z. Altered collagen II 263–272 peptide immunization induces inhibition of collagen-induced arthritis through a shift toward Th2-type response. Tissue Antigens 2009;73:341–347.
   PubMed Web of Science ®Google Scholar
• Zhao J, Li R, He J, et al. Mucosal administration of an altered CII263–272 peptide inhibits collagen-induced arthritis by suppression of Th1/Th17 cells and expansion of regulatory T cells. Rheumatol Int 2008;29:9–16.
   PubMed Web of Science ®Google Scholar
• Katz-Levy Y, Kirshner SL, Sela M, Mozes E. Inhibition of T-cell reactivity to myasthenogenic epitopes of the human acetylcholine receptor by synthetic analogs. Proc Natl Acad Sci USA 1993;90:7000–7004.
   PubMed Web of Science ®Google Scholar
• Aruna BV, Ben-David H, Sela M, Mozes E. A dual altered peptide ligand down-regulates myasthenogenic T cell responses and reverses experimental autoimmune myasthenia gravis via up-regulation of Fas-FasL-mediated apoptosis. Immunology 2006;118:413–424.
   PubMed Web of Science ®Google Scholar
• Aruna BV, Sela M, Mozes E. Suppression of myasthenogenic responses of a T cell line by a dual altered peptide ligand by induction of CD4+CD25+ regulatory cells. Proc Natl Acad Sci USA 2005;102:10285–10290.
   PubMed Web of Science ®Google Scholar
• Ben-David H, Sharabi A, Dayan M, et al. The role of CD8+CD28 regulatory cells in suppressing myasthenia gravis-associated responses by a dual altered peptide ligand. Proc Natl Acad Sci USA 2007;104:17459–17464.
   PubMed Web of Science ®Google Scholar
• Ben-David H, Venkata Aruna B, Sela M, Mozes E. A dual altered peptide ligand inhibits myasthenia gravis associated responses by inducing phosphorylated extracellular-regulated kinase 1,2 that upregulates CD4+CD25+Foxp3+ cells. Scand J Immunol 2007;65:567–576.
   PubMed Web of Science ®Google Scholar
• Faber-Elmann A, Paas-Rozner M, Sela M, Mozes E. Altered peptide ligands act as partial agonists by inhibiting phospholipase C activity induced by myasthenogenic T cell epitopes. Proc Natl Acad Sci USA 1998;95:14320–14325.
   PubMed Web of Science ®Google Scholar
• Katz-Levy Y, Paas-Rozner M, Kirshner S, et al. A peptide composed of tandem analogs of two myasthenogenic T cell epitopes interferes with specific autoimmune responses. Proc Natl Acad Sci USA 1997;94:3200–3205.
   PubMed Web of Science ®Google Scholar
• Paas-Rozner M, Dayan M, Paas Y, et al. Oral administration of a dual analog of two myasthenogenic T cell epitopes down-regulates experimental autoimmune myasthenia gravis in mice. Proc Natl Acad Sci USA 2000;97:2168–2173.
   PubMed Web of Science ®Google Scholar
• Paas-Rozner M, Sela M, Mozes E. The nature of the active suppression of responses associated with experimental autoimmune myasthenia gravis by a dual altered peptide ligand administered by different routes. Proc Natl Acad Sci USA 2001;98:12642–12647.
   PubMed Web of Science ®Google Scholar
• Casares S, Hurtado A, McEvoy RC, et al. Down-regulation of diabetogenic CD4+ T cells by a soluble dimeric peptide-MHC class II chimera. Nat Immunol 2002;3:383–391.
   PubMed Web of Science ®Google Scholar
• Casares S, Bona CA, Brumeanu TD. Engineering and characterization of a murine MHC class II-immunoglobulin chimera expressing an immunodominant CD4 T viral epitope. Protein Eng 1997;10:1295–1301.
   PubMedGoogle Scholar
• Masteller EL, Warner MR, Ferlin W, et al. Peptide-MHC class II dimers as therapeutics to modulate antigen-specific T cell responses in autoimmune diabetes. J Immunol 2003;171:5587–5595.
   PubMed Web of Science ®Google Scholar
• Judkowski V, Pinilla C, Schroder K, et al. Identification of MHC class II-restricted peptide ligands, including a glutamic acid decarboxylase 65 sequence that stimulate diabetogenic T cells from transgenic BDC2.5 nonobese diabetic mice. J Immunol 2001;166:908–917.
   PubMed Web of Science ®Google Scholar
• Sinha S, Miller LM, Subramanian S, et al. RTL551 treatment of EAE reduces CD226 and T-bet+ CD4 T Cells in periphery and prevents infiltration of T-bet+ IL-17, IFN-γ producing T cells into CNS. PloS One 2011;6(7):e21868.
   PubMed Web of Science ®Google Scholar
• Vandenbark AA, Rich C, Mooney J, et al. Recombinant TCR ligand induces tolerance to myelin oligodendrocyte glycoprotein 35–55 peptide and reverses clinical and histological signs of chronic experimental autoimmune encephalomyelitis in HLA-DR2 transgenic mice. J Immunol 2003;171:127–133.
   PubMed Web of Science ®Google Scholar
• Gong Y, Wang Z, Liang Z, et al. Soluble MOG35–55/I-Ab dimers ameliorate experimental autoimmune encephalomyelitis by reducing encephalito­genic T cells. PloS One 2012;7:e47435.
   PubMed Web of Science ®Google Scholar
• Huan J, Subramanian S, Jones R, et al. Monomeric recombinant TCR ligand reduces relapse rate and severity of experimental autoimmune encephalomyelitis in SJL/J mice through cytokine switch. J Immunol 2004;172:4556–4566.
   PubMed Web of Science ®Google Scholar
• Huan J, Kaler LJ, Mooney JL, et al. MHC class II derived recombinant T cell receptor ligands protect DBA/1LacJ mice from collagen-induced arthritis. J Immunol 2008;180:1249–1257.
   PubMed Web of Science ®Google Scholar
• Spack EG, McCutcheon M, Corbelletta N, et al. Induction of tolerance in experimental autoimmune myasthenia gravis with solubilized MHC class II:acetylcholine receptor peptide complexes. J Autoimmun 1995;8:787–807.
   PubMed Web of Science ®Google Scholar