Peptides for immunological purposes: Design, strategies and applications

Amino Acids

Volumn 45, Issue 2, 2013, Pages 257-268

  Gori, Alessandro ^a   Longhi, Renato ^a   Peri, Claudio ^a   Colombo, Giorgio ^a  

^a CNR   (Italy)

Author keywords

Antigenic peptides; Biomarker discovery; In silico epitope predictions; Molecular design; Structural vaccinology; Vaccine development

Indexed keywords

BIOLOGICAL MARKER; BIOPOLYMER; CANCER VACCINE; CD4 ANTIGEN; CD8 ANTIGEN; EPITOPE; GLYCOPEPTIDE; HUMORAL ANTIBODY; LIPOPEPTIDE; NANOPARTICLE; NEUTRALIZING ANTIBODY; PEPTIDE VACCINE;

ADAPTIVE IMMUNITY; ANTIGEN PRESENTING CELL; ANTIGEN RECOGNITION; CANCER RESEARCH; CASE STUDY; CELLULAR IMMUNITY; CLINICAL IMMUNOLOGY; DRUG DELIVERY SYSTEM; DRUG DESIGN; DRUG RESEARCH; DRUG SYNTHESIS; HUMAN; HUMORAL IMMUNITY; IMMUNOGENICITY; IMMUNOREACTIVITY; MOLECULAR MECHANICS; NONHUMAN; PHYSICAL CHEMISTRY; PRIORITY JOURNAL; PROTEIN CONFORMATION; PROTEIN INTERACTION; REVIEW; TUBERCULOSIS;

BIOLOGICAL MARKERS; DRUG DESIGN; EARLY DIAGNOSIS; HUMANS; PEPTIDES; VACCINES, SUBUNIT;

EID: 84880815590     PISSN: 09394451     EISSN: 14382199     Source Type: Journal    
DOI: 10.1007/s00726-013-1526-9     Document Type: Review

References (116)

1. Akagi T, Baba M, Akashi M (2012) Biodegradable nanoparticles as vaccine adjuvants and delivery systems: regulation of immune responses by nanoparticle-based vaccine. Adv Polym Sci 247:31-64
2. Alcaro MC, Lolli F, Migliorini P et al (2007) Peptides as autoimmune diseases antigenic probes - a peptide-based reverse approach to detect biomarkers of autoimmune diseases. Chem Today 25:14-16
3. Anderson KS, LaBaer J (2005) The sentinel within: exploiting the immune system for cancer biomarkers. J Proteome Res 4:1123-1133. doi: 10.1021/pr0500814
4. Anderton SM (2004) Post-translational modifications of self antigens: implications for autoimmunity. Curr Opin Immunol 16:753-758
5. Azoitei ML, Correia BE, Ban Y-EA et al (2011) Computation-guided backbone grafting of a discontinuous motif onto a protein scaffold. Science 334:373-376. doi: 10.1126/science.1209368
6. Baker M (2005) In biomarkers we trust? Nat Biotech 23:297-304. doi: 10.1038/nbt0305-297
7. Bay S, Lo-Man R, Osinaga E et al (1997) Preparation of a multiple antigen glycopeptide (MAG) carrying the Tn antigen. A possible approach to a synthetic carbohydrate vaccine. J Pept Res 49:620-625
8. Biomarkers definition working group (2001) Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clinical Pharmacol Therap 69:89-95. doi: 10.1067/mcp.2001.113989
9. Blennow K, Hampel H, Weiner M, Zetterberg H (2010) Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol 6:131-144
10. Bock JE, Gavenonis J, Kritzer Ja (2013) Getting in shape: controlling peptide bioactivity and bioavailability using conformational constraints. ACS Chem Biol 8:488-499. doi: 10.1021/cb300515u
11. Briand JP, Muller S, Van Regenmortel MH (1985) Synthetic peptides as antigens: pitfalls of conjugation methods. J Immunol Meth 78:59-69
12. Brien-simpson NMO, Ede NJ, Brown LE et al (1997) Polymerization of unprotected synthetic peptides: a view toward synthetic peptide vaccines. J Am Chem Soc 7863:1183-1188
13. Burton DR (2010) Scaffolding to build a rational vaccine design strategy. Proc Natl Acad Sci USA 107:17859-17860. doi: 10.1073/pnas.1012923107
14. Ca Smith, Kortemme T (2010) Structure-based prediction of the peptide sequence space recognized by natural and synthetic PDZ domains. J Mol Biol 402:460-474. doi: 10.1016/j.jmb.2010.07.032
15. Carotenuto A, D'Ursi AM, Nardi E et al (2001) Conformational analysis of a glycosylated human myelin oligodendrocyte glycoprotein peptide epitope able to detect antibody response in multiple sclerosis. J Med Chem 44:2378-2381
16. Carotenuto A, Alcaro MC, Saviello MR et al (2008) Designed glycopeptides with different beta-turn types as synthetic probes for the detection of autoantibodies as biomarkers of multiple sclerosis. J Med Chem 51:5304-5309. doi: 10.1021/jm800391y
17. Chatterjee J, Gilon C, Hoffman A, Kessler H (2008) N-methylation of peptides: a new perspective in medicinal chemistry. Acc Chem Res 41:1331-1342. doi: 10.1021/ar8000603
18. Chiarella P, Edelmann B, Fazio VM et al (2010) Antigenic features of protein carriers commonly used in immunisation trials. Biotech Lett 32:1215-1221. doi: 10.1007/s10529-010-0283-z
19. Correia BE, Ban Y-EA, Holmes Ma et al (2010) Computational design of epitope-scaffolds allows induction of antibodies specific for a poorly immunogenic HIV vaccine epitope. Structure 18:1116-1126. doi: 10.1016/j.str.2010.06.010
20. Der BS, Edwards DR, Kuhlman B (2012) Catalysis by a de novo zinc-mediated protein interface: implications for natural enzyme evolution and rational enzyme engineering. Biochemistry 51:3933-3940. doi: 10.1021/bi201881p
21. Dormitzer PR, Ulmer JB, Rappuoli R (2008) Structure-based antigen design: a strategy for next generation vaccines. Trends Biotech 26:659-667. doi: 10.1016/j.tibtech.2008.08.002
22. Fiorucci S, Zacharias M (2010) Prediction of protein-protein interaction sites using covering algorithms. Biophys J 98:1921-1930
23. Fitzmaurice CJ, Brown LE, Kronin V, Jackson DC (2000) The geometry of synthetic peptide-based immunogens affects the efficiency of T cell stimulation by professional antigen-presenting cells. Internat Immunol 12:527-535
24. Fleishman SJ, Ta Whitehead, Ekiert DC et al (2011) Computational design of proteins targeting the conserved stem region of influenza hemagglutinin. Science 332:816-821. doi: 10.1126/science.1202617
25. Floris M, Moro S (2012) Mimicking peptides. in silico. Mol Inform 31:12-20. doi: 10.1002/minf.201100093
26. Foster S, Duvall CL, Crownover EF et al (2010) Intracellular delivery of a protein antigen with an endosomal-releasing polymer enhances CD8 T-cell production and prophylactic vaccine efficacy. Bioconj Chem 21:2205-2212. doi: 10.1021/bc100204m
27. Francis MJ, Hastings GZ, Brown F et al (1991) Immunological evaluation of the multiple antigen peptide (MAP) system using the major immunogenic site of foot-mouth disease virus. Immunology 73:249-254
28. Frank R, Hargreaves R (2003) Clinical biomarkers in drug discovery and development. Nat Rev Drug Discov 2:566-580. doi: 10.1038/nrd1130
29. Fujita Y, Taguchi H (2011) Current status of multiple antigen-presenting peptide vaccine systems: application of organic and inorganic nanoparticles. Chem Cent J 5:48. doi: 10.1186/1752-153X-5-48
30. Fujita Y, Abdel-Aal A-BM, Wimmer N et al (2008) Synthesis and immunological evaluation of self-adjuvanting glycolipopeptide vaccine candidates. Bioorg Med Chem 16:8907-8913. doi: 10.1016/j.bmc.2008.08.064
31. Fung HK, Welsh WJ, Floudas CA, Wood R (2008) Computational de novo peptide and protein design: rigid templates versus flexible templates. Ind Eng Chem Res 47:993-1001
32. Galdiero S, Vitiello M, Finamore E et al (2012) Activation of monocytic cells by immunostimulatory lipids conjugated to peptide antigens. Mol BioSyst 8:3166-3177. doi: 10.1039/c2mb25064k
33. Genoni A, Morra G, Colombo G (2012) Identification of domains in protein structures from the analysis of intramolecular interactions. J Phys Chem B 116:3331-3343. doi: 10.1021/jp210568a
34. Girbal-Neuhauser E, Durieux JJ, Arnaud M et al (1999) The epitopes targeted by the rheumatoid arthritis-associated antifilaggrin autoantibodies are posttranslationally generated on various sites of (pro) filaggrin by deimination of arginine residues. J Immunol 162:585-594
35. Gonzalez S, González-Rodríguez AP, Suárez- Álvarez B et al (2011) Conceptual aspects of self and nonself discrimination. Selfnonself 2:19-25
36. Goodman CM, Choi S, Shandler S, DeGrado WF (2007) Foldamers as versatile frameworks for the design and evolution of function. Nat Chem Biol 3:252-262. doi: 10.1038/nchembio876
37. Greenbaum JA, Andersen PH, Blythe M et al (2007) Towards a consensus on datasets and evaluation metrics for developing B-cell epitope prediction tools. J Mol Recognit JMR 20:75-82
38. Ha Doyle, Mamula MJ (2001) Post-translational protein modifications in antigen recognition and autoimmunity. Trends Immunol 22:443-449
39. Haridas V (2009) From peptides to non-peptide alpha-helix inducers and mimetics. Eur J Org Chem 2009:5112-5128. doi: 10.1002/ejoc.200900280
40. Hervé M, Maillere B, Mourier G et al (1997) On the immunogenic properties of retro-inverso peptides. Total retro-inversion of T-cell epitopes causes a loss of binding to MHC II molecules. Mol Immunol 34:157-163
41. Herzenberg LA, Tokuhisa T, Herzenberg LA (1980) Carrier-priming leads to hapten-specific suppression. Nature 285:664-667. doi: 10.1038/285664a0
42. Hijnen M, Van Zoelen DJ, Chamorro C et al (2007) A novel strategy to mimic discontinuous protective epitopes using a synthetic scaffold. Vaccine 25:6807-6817. doi: 10.1016/j.vaccine.2007.06.027
43. Hoffman BM, Celis LM, Da Cull et al (2005) Differential influence of dynamic processes on forward and reverse electron transfer across a protein-protein interface. Proc Natl Acad Sci USA 102:3564-3569. doi: 10.1073/pnas.0408767102
44. How SH, Liam CK (2006) Melioidosis: a potentially life threatening infection. Med J Malaysia 61:386-394 quiz 395
45. Huang W, Nardelli B, Tam JP (1994) Lipophilic multiple antigen peptide system for peptide immunogen and synthetic vaccine. Mol Immunol 31:1191-1199
46. Jackson DC, Brien-simpson NO, Brown LE, Ede NJ (1997) Free radical induced polymerization of synthetic peptides into polymeric immunogens. Vaccine 15:1697-1705
47. Jackson DC, Lau YF, Le T et al (2004) A totally synthetic vaccine of generic structure that targets toll-like receptor two on dendritic cells and promotes antibody or cytotoxic T cell responses. Proc Natl Acad Sci USA 101:15440-15445
48. Katsikis PD, Schoenberger SP, Pulendran B (2007) Probing the "labyrinth" linking the innate and adaptive immune systems. Nat Immunol 8:899-901
49. Keskin O (2007) Binding induced conformational changes of proteins correlate with their intrinsic fluctuations: a case study of antibodies. BMC Struct Biol 7:31
50. Koga N, Tatsumi-Koga R, Liu G et al (2012) Principles for designing ideal protein structures. Nature 491:222-227. doi: 10.1038/nature11600
51. Kowalczyk W, De la Torre BG, Andreu D (2010) Strategies and limitations in dendrimeric immunogen synthesis. The influenza virus M2e epitope as a case study. Bioconj Chem 21:102-110. doi: 10.1021/bc9003316
52. Kowalczyk W, Mascaraque A, Sánchez-Navarro M et al (2012) Convergent synthesis of glycodendropeptides by click chemistry approaches. Eur J Org Chem 2012:4565-4573. doi: 10.1002/ejoc.201200428
53. Lassaux P, Peri C, Ferrer-Navarro M et al (2013) A structure-based strategy for epitope discovery in Burkholderia pseudomallei OppA antigen. Structure 21:167-175. doi: 10.1016/j.str.2012.10.005
54. Lewis SM, Ba Kuhlman (2011) Anchored design of protein-protein interfaces. PloS one 6:e20872. doi: 10.1371/journal.pone.0020872
55. Lindstrom TM, Robinson WH (2011) Fishing for biomarkers with antigen mimics. Cell 144:13-15. doi: 10.1016/j.cell.2010.12.022
56. Loddenkemper R, Hauer B (2010) Drug-resistant tuberculosis: a worldwide epidemic poses a new challenge. Deutsches Ärzteblatt international 107:10-19. doi: 10.3238/arztebl.2010.0010
57. Lolli F, Mazzanti B, Pazzagli M et al (2005a) The glycopeptide CSF114(Glc) detects serum antibodies in multiple sclerosis. J Neuroimmunol 167:131-137. doi: 10.1016/j.jneuroim.2005.05.016
58. Lolli F, Mulinacci B, Carotenuto A et al (2005b) An N-glucosylated peptide detecting disease-specific autoantibodies, biomarkers of multiple sclerosis. Proc Natl Acad Sci USA 102:10273-10278. doi: 10.1073/pnas.0503178102
59. Ludwig JA, Weinstein JN (2005) Biomarkers in cancer staging, prognosis and treatment selection. Nature Rev Canc 5:845-856. doi: 10.1038/nrc1739
60. Mahler M, Fritzler MJ, Blüthner M (2005) Identification of a SmD3 epitope with a single symmetrical dimethylation of an arginine residue as a specific target of a subpopulation of anti-Sm antibodies. Arthritis Res Ther 7:R19-R29. doi: 10.1186/ar1455
61. Mandell DJ, Kortemme T (2009) Computer-aided design of functional protein interactions. Nat Chem Biol 5:797-807. doi: 10.1038/nchembio.251
62. Masignani V, Rappuoli R, Pizza M (2002) Reverse vaccinology: a genome-based approach for vaccine development. Exp Opin Biol Ther 2:895-905. doi: 10.1517/14712598.2.8.895
63. Mazzucco S, Matà S, Vergelli M et al (1999) A synthetic glycopeptide of human myelin oligodendrocyte glycoprotein to detect antibody responses in multiple sclerosis and other neurological diseases. Bioorg Med Chem Lett 9:167-172
64. Moreau V, Granier C, Villard S et al (2006) Discontinuous epitope prediction based on mimotope analysis. Bioinformatics 22:1088-1095. doi: 10.1093/bioinformatics/btl012
65. Moyle PM, Toth I (2008) Self-adjuvanting lipopeptide vaccines. Curr Med Chem 15:506-516
66. Mulder GE, JaW Kruijtzer, Liskamp RMJ (2012) A combinatorial approach toward smart libraries of discontinuous epitopes of HIV gp120 on a TAC synthetic scaffold. Chem Comm 48:10007-10009. doi: 10.1039/c2cc35310e
67. Nikaido H (2009) Multidrug resistance in bacteria. Annual Rev Biochem 78:119-146. doi: 10.1146/annurev.biochem.78.082907.145923
68. Nikiforovich GV (2009) Computational molecular modeling in peptide drug design. Int J Pept Prot Res 44:513-531. doi: 10.1111/j.1399-3011.1994.tb01140.x
69. Novotný J, Handschumacher M, Haber E et al (1986) Antigenic determinants in proteins coincide with surface regions accessible to large probes (antibody domains). Proc Natl Acad Sci USA 83:226-230
70. Ofek G, Guenaga FJ, Schief WR et al (2010) Elicitation of structure-specific antibodies by epitope scaffolds. Proc Natl Acad Sci USA 107:17880-17887. doi: 10.1073/pnas.1004728107
71. Papini AM (2005) Simple test for multiple sclerosis. Nat Med 11:13. doi: 10.1038/nm0105-13
72. Papini AM (2009) The use of post-translationally modified peptides for detection of biomarkers of immune-mediated diseases. J Pept Sci 15:621-628. doi: 10.1002/psc.1166
73. Pedersen DS, Abell A (2011) 1,2,3-triazoles in peptidomimetic chemistry. Eur J Org Chem 2011:2399-2411. doi: 10.1002/ejoc.201100157
74. Peri C, Gagni P, Combi F et al (2013) Rational epitope design for protein targeting. ACS Chem Biol 8:397-404. doi: 10.1021/cb300487u
75. Peters AM (2000) Antibodies in nuclear medicine. Meth Mol Med 40:179-192
76. Ponomarenko J, Bui H-H, Li W et al (2008) ElliPro: a new structure-based tool for the prediction of antibody epitopes. BMC Bioinform 9:514. doi: 10.1186/1471-2105-9-514
77. Purcell AW, Zeng W, Na Mifsud et al (2003) Dissecting the role of peptides in the immune response: theory, practice and the application to vaccine design. J Pept Sci 9:255-281. doi: 10.1002/psc.456
78. Purcell AW, McCluskey J, Rossjohn J (2007) More than one reason to rethink the use of peptides in vaccine design. Nat Rev Drug Discov 6:404-414. doi: 10.1038/nrd2224
79. Reddy MM, Wilson R, Wilson J et al (2011) Identification of candidate IgG biomarkers for Alzheimer's disease via combinatorial library screening. Cell 144:132-142. doi: 10.1016/j.cell.2010.11.054
80. Renfrew PD, Choi EJ, Bonneau R, Kuhlman B (2012) Incorporation of noncanonical amino acids into rosetta and use in computational protein-peptide interface design. PLoS ONE 7:e32637. doi: 10.1371/journal.pone.0032637
81. Richter F, Blomberg R, Khare SD et al (2012) Computational design of catalytic dyads and oxyanion holes for ester hydrolysis. J Am Chem Soc 134:16197-16206. doi: 10.1021/ja3037367
82. Robinson WH, Steinman L, Utz PJ (2002) Protein and peptide array analysis of autoimmune disease. Biotechniques 28:66-69
83. Rosenthal KS (2005) Immune peptide enhancement of peptide-based vaccines. Frontiers Biosci 10:478-482
84. Rudd PM (2001) Glycosylation and the immune system. Science 291:2370-2376. doi: 10.1126/science.291.5512.2370
85. Rudd PM, Wormald MR, Stanfield RL et al (1999) Roles for glycosylation of cell surface receptors involved in cellular immune recognition. J Mol Biol 293:351-366. doi: 10.1006/jmbi.1999.3104
86. Rudd PM, Wormald MR, Ra Dwek (2004) Sugar-mediated ligand-receptor interactions in the immune system. Trends Biotech 22:524-530. doi: 10.1016/j.tibtech.2004.07.012
87. Sadler K, Zeng W, Jackson DC (2002) Synthetic peptide epitope-based polymers: controlling size and determining the efficiency of epitope incorporation. J Pept Res 60:150-158
88. Sammond DW, Bosch DE, Butterfoss GL et al (2011) Computational design of the sequence and structure of a protein-binding peptide. J Am Chem Soc 133:4190-4192
89. Scarabelli G, Morra G, Colombo G (2010) Predicting interaction sites from the energetics of isolated proteins: a new approach to epitope mapping. Biophys J 98:1966-1975. doi: 10.1016/j.bpj.2010.01.014
90. Schott ME, Wells DT, Schlom J, Abrams SI (1996) Comparison of linear and branched peptide forms (MAPs) in the induction of T helper responses to point-mutated ras immunogens. Cell Immun 174:199-209. doi: 10.1006/cimm.1996. 0310
91. Schutze MP, Leclerc C, Jolivet M et al (1985) Carrier-induced epitopic suppression, a major issue for future synthetic vaccines. J Immun 135:2319-2322
92. Sharav T, Wiesmüller K-H, Walden P (2007) Mimotope vaccines for cancer immunotherapy. Vaccine 25:3032-3037
93. Sheinerman FB, Norel R, Honig B (2000) Electrostatic aspects of protein-protein interactions. Curr Opin Struct Biol 10:153-159
94. Skwarczynski M, Zaman M, Urbani CN et al (2010) Polyacrylate dendrimer nanoparticles: a self-adjuvanting vaccine delivery system. Angew Chem Int Ed 49:5742-5745. doi: 10.1002/anie.201002221
95. Souroujon MC, Mochly-Rosen D (1998) Peptide modulators of protein-protein interactions in intracellular signaling. Nat Biotech 16:919-924. doi: 10.1038/nbt1098-919
96. Thornton JM, Edwards MS, Taylor WR, Barlow DJ (1986) Location of "continuous" antigenic determinants in the protruding regions of proteins. Eur Mol Biol Organiz J 5:409-413
97. Timmerman P, Puijk WC, Meloen RH (2007) Functional reconstruction and synthetic mimicry of a conformational epitope using CLIPS technology. J Mol Recog 20:283-299. doi: 10.1002/jmr
98. Timmerman P, Puijk WC, Boshuizen RS et al (2009) Functional reconstruction of structurally complex epitopes using CLIPS TM technology. Open Vaccine J 2:56-67
99. Tsunoda T (2004) Development for a novel cancer vaccine. Gan to kagaku ryoho Cancer chemotherapy 31:2095-2099
100. Ulucan O, Eyrisch S, Helms V (2012) Druggability of dynamic protein-protein interfaces. Curr Pharmac Des 18:4599-4606
101. Uto T, Wang X, Akagi T et al (2009) Improvement of adaptive immunity by antigen-carrying biodegradable nanoparticles. Biochem Biophys Res Comm 379:600-604. doi: 10.1016/j.bbrc.2008.12.122
102. Van Regenmortel MH (2001) Antigenicity and immunogenicity of synthetic peptides. Biol J Intern Association Biol Standardization 29:209-213
103. Van Regenmortel MHV (2009a) What is a B-cell epitope? Meth Mol Biol 524:3-20
104. Van Regenmortel MHV (2009b) Synthetic peptide vaccines and the search for neutralization B-cell. Open Vaccine J 2:33-44
105. Vossenaar ER, Van Venrooij WJ (2004) Anti-CCP antibodies, a highly specific marker for (early) rheumatoid arthritis. Clin Appl Immunol Rev 4:239-262. doi: 10.1016/j.cair.2003.11.001
106. Waldmann TA (1991) Monoclonal antibodies in diagnosis and therapy. Science 252:1657-1662
107. Wang W (2011) Selection of adjuvants for enhanced vaccine potency. World J Vacc 01:33-78. doi: 10.4236/wjv.2011.12007
108. Westhof E, Altschuh D, Moras D et al (1984) Correlation between segmental mobility and the location of antigenic determinants in proteins. Nature 311:123-126
109. Wiersinga WJ, Van Der Poll T, White NJ et al (2006) Melioidosis: insights into the pathogenicity of Burkholderia pseudomallei. Nat Rev Microbiol 4:272-282
110. Wilkinson BL, Day S, Chapman R et al (2012) Synthesis and immunological evaluation of self-assembling and self-adjuvanting tricomponent glycopeptide cancer-vaccine candidates. Chem Eur J 18:16540-16548. doi: 10.1002/chem. 201202629
111. Yin H, Slusky JS, Berger BW et al (2007) Computational design of peptides that target transmembrane helices. Science 315:1817-1822. doi: 10.1126/science.1136782
112. Yoshikawa T, Okada N, Oda A et al (2008) Development of amphiphilic gamma-PGA-nanoparticle based tumor vaccine: potential of the nanoparticulate cytosolic protein delivery carrier. Biochem Biophys Res Comm 366:408-413. doi: 10.1016/j.bbrc.2007.11.153
113. Zen A, Micheletti C, Keskin O, Nussinov R (2010) Comparing interfacial dynamics in protein-protein complexes: an elastic network approach. BMC Struct Biol 10:26. doi: 10.1186/1472-6807-10-26
114. Zeng W, Ghosh S, Lau YF et al (2002) Highly immunogenic and totally synthetic lipopeptides as self-adjuvanting immunocontraceptive vaccines. J Immun 169:4905-4912
115. Zhu X, Ramos TV, Gras-Masse H et al (2004) Lipopeptide epitopes extended by an Nepsilon-palmitoyl-lysine moiety increase uptake and maturation of dendritic cells through a toll-like receptor-2 pathway and trigger a Th1-dependent protective immunity. Eur J Immun 34:3102-3114
116. Zolnik BS, González-Fernández A, Sadrieh N, Ma Dobrovolskaia (2010) Nanoparticles and the immune system. Endocrinology 151:458-465. doi: 10.1210/en.2009-1082