Psychopharmacology: neuroimmune signaling in psychiatric disease-developing vaccines against abused drugs using toll-like receptor agonists

  • Fang Yang
  • Thomas R. KostenEmail author



Since substance use disorders have few or no effective pharmacotherapies, researchers have developed vaccines as immune-therapies against nicotine, cocaine, methamphetamine, and opioids including fentanyl.


We focus on enhancing antibody (AB) production through stimulation of toll-like receptor-5 (TLR5) during active vaccination. The stimulating adjuvant is Entolimod, a novel protein derivative of flagellin. We review the molecular and cellular mechanisms underlying Entolimod’s actions on TLR5.


Entolimod shows excellent efficacy for increasing AB levels to levels well beyond those produced by anti-addiction vaccines alone in animal models and humans. These ABs also significantly block the behavioral effects of the targeted drug of abuse. The TLR5 stimulation involves a wide range of immune cell types such as dendritic, antigen presenting, T and B cells. Entolimod binding to TLR5 initiates an intracellular signaling cascade that stimulates cytokine production of tumor necrosis factor and two interleukins (IL-6 and IL-12). While cytokine release can be catastrophic in cytokine storm, Entolimod produces a modulated release with few side effects even at doses 30 times greater than doses needed in these vaccine studies. Entolimod has markedly increased AB responses to all of our anti-addiction vaccines in rodent models, and in normal humans.


Entolimod and TLR5 stimulation has broad application to vaccines and potentially to other psychiatric disorders like depression, which has critical inflammatory contributions that Entolimod could reduce.


Entolimod Toll-like receptor-5 Substance use disorder Vaccine 


Compliance with ethical standards

Conflict of interest

On behalf of both authors, the corresponding author states that there is no conflict of interest. Our vaccine studies are in collaboration with Cleveland Biologic Labs (CBLI) who are providing Entolimod free of charge.


  1. Akira S, Takeda K, Kaisho T (2001) Toll-like receptors : critical proteins linking innate and acquired immunity. Nat Immunol 2:675–680. CrossRefPubMedGoogle Scholar
  2. Bates JT, Honko AN, Graff AH, Kock ND, Mizel SB (2008) Mucosal adjuvant activity of flagellin in aged mice. Mech Ageing Dev 129:271–281. CrossRefPubMedPubMedCentralGoogle Scholar
  3. Blander JM, Medzhitov R (2006) Toll-dependent selection of microbial antigens for presentation by dendritic cells. Nature 440:808–812. CrossRefPubMedGoogle Scholar
  4. Brackett CM, Kojouharov B, Veith J, Greene KF, Burdelya LG, Gollnick SO, Abrams SI, Gudkov AV (2016) Toll-like receptor-5 agonist, entolimod, suppresses metastasis and induces immunity by stimulating an NK-dendritic-CD8 + T-cell axis. Proc Natl Acad Sci 113:E874–E883. CrossRefPubMedGoogle Scholar
  5. Bremer PT, Schlosburg JE, Lively JM, Janda KD (2014) Injection route and TLR9 agonist addition significantly impact heroin vaccine efficacy. Mol Pharm 11:1075–1080. CrossRefPubMedPubMedCentralGoogle Scholar
  6. Bremer PT, Kimishima A, Schlosburg JE, Zhou B, Collins KC, Janda KD (2016) Combatting synthetic designer opioids : a conjugate vaccine ablates lethal doses of fentanyl class drugs. Angew Chem Int Ed Eng 55:3772–3775. CrossRefGoogle Scholar
  7. Burdelya LG, Krivokrysenko VI, Tallant TC et al (2008) An agonist of toll-like receptor 5 has radioprotective activity in mouse and primate models. Science 320(80):226–230. CrossRefPubMedPubMedCentralGoogle Scholar
  8. Burdelya LG, Gleiberman AS, Toshkov I, Aygun-Sunar S, Bapardekar M, Manderscheid-Kern P, Bellnier D, Krivokrysenko VI, Feinstein E, Gudkov AV (2012) Toll-like receptor 5 agonist protects mice from dermatitis and oral mucositis caused by local radiation: implications for head-and-neck cancer radiotherapy. Int J Radiat Oncol Biol Phys 83:228–234. CrossRefPubMedGoogle Scholar
  9. Burdelya LG, Brackett CM, Kojouharov B, Gitlin II, Leonova KI, Gleiberman AS, Aygun-Sunar S, Veith J, Johnson C, Haderski GJ, Stanhope-Baker P, Allamaneni S, Skitzki J, Zeng M, Martsen E, Medvedev A, Scheblyakov D, Artemicheva NM, Logunov DY, Gintsburg AL, Naroditsky BS, Makarov SS, Gudkov AV (2013) Central role of liver in anticancer and radioprotective activities of toll-like receptor 5 agonist. Proc Natl Acad Sci 110:E1857–E1866. CrossRefPubMedGoogle Scholar
  10. Cai Z, Sanchez A, Shi Z, Zhang T, Liu M, Zhang D (2011) Activation of toll-like receptor 5 on breast cancer cells by flagellin suppresses cell proliferation and tumor growth. Cancer Res 71:2466–2475. CrossRefPubMedPubMedCentralGoogle Scholar
  11. Cai X, Tsuchikama K, Janda KD (2013a) Modulating cocaine vaccine potency through hapten fluorination. J Am Chem Soc 135:2971–2974. CrossRefPubMedPubMedCentralGoogle Scholar
  12. Cai X, Whitfield T, Hixon MS, Grant Y, Koob GF, Janda KD (2013b) Probing active cocaine vaccination performance through catalytic and noncatalytic hapten design. J Med Chem 56:3701–3709. CrossRefPubMedPubMedCentralGoogle Scholar
  13. Carroll FI, Abraham P, Gong PK, Pidaparthi RR, Blough BE, Che Y, Hampton A, Gunnell M, Lay JO Jr, Peterson EC, Owens SM (2009) The synthesis of haptens and their use for the development of monoclonal antibodies for treating methamphetamine abuse. J Med Chem 52:7301–7309. CrossRefPubMedPubMedCentralGoogle Scholar
  14. Cohen-Barak O, Wildeman J, Van De Wetering J et al (2015) Safety, pharmacokinetics, and pharmacodynamics of TV-1380, a novel mutated butyrylcholinesterase treatment for cocaine addiction, after single and multiple intramuscular injections in healthy subjects. J Clin Pharmacol 55:573–583. CrossRefPubMedPubMedCentralGoogle Scholar
  15. Collins KC, Schlosburg JE, Bremer PT, Janda KD (2016) Methamphetamine vaccines: improvement through Hapten design. J Med Chem 59:3878–3885. CrossRefPubMedPubMedCentralGoogle Scholar
  16. Cooper ACL, Angel JB, Seguin I et al (2008) CPG 7909 adjuvant plus hepatitis B virus vaccination in HIV-infected adults achieves long-term Seroprotection for up to 5 years linked references are available on JSTOR for this article : HIV / AIDS MAJOR ARTICLE CPG 7909 adjuvant plus hepatitis B virus V. Clin Infect Dis 46:1310–1314CrossRefGoogle Scholar
  17. Cornuz J, Zwahlen S, Jungi WF, Osterwalder J, Klingler K, van Melle G, Bangala Y, Guessous I, Müller P, Willers J, Maurer P, Bachmann MF, Cerny T (2008) A vaccine against nicotine for smoking cessation : a randomized controlled trial. PLoS One 3:e2547. CrossRefPubMedPubMedCentralGoogle Scholar
  18. Crellin NK, Garcia RV, Hadisfar O, Allan SE, Steiner TS, Levings MK (2005) Human CD4+ T cells express TLR5 and its ligand Flagellin enhances the suppressive capacity and expression of FOXP3 in CD4+CD25+ T regulatory cells. J Immunol 175:8051–8059. CrossRefPubMedGoogle Scholar
  19. Dantzer R, Kelley KW (2007) Twenty years of research on cytokine-induced sickness behavior. Brain Behav Immun 21:153–160. CrossRefPubMedGoogle Scholar
  20. Didierlaurent AM, Morel S, Lockman L, Giannini SL, Bisteau M, Carlsen H, Kielland A, Vosters O, Vanderheyde N, Schiavetti F, Larocque D, van Mechelen M, Garcon N (2009) AS04, an aluminum salt- and TLR4 agonist-based adjuvant system, induces a transient localized innate immune response leading to enhanced adaptive immunity. J Immunol 183:6186–6197. CrossRefPubMedGoogle Scholar
  21. Ding X, Bian G, Leigh ND, Qiu J, McCarthy PL, Liu H, Aygun-Sunar S, Burdelya LG, Gudkov AV, Cao X (2012) A TLR5 agonist enhances CD8+ T cell-mediated graft-versus-tumor effect without exacerbating graft-versus-host disease. J Immunol 189:4719–4727. CrossRefPubMedGoogle Scholar
  22. Duthie MS, Windish HP, Fox CB, Reed SG (2011) Use of defined TLR ligands as adjuvants within human vaccines. Immunol Rev 239:178–196. CrossRefPubMedPubMedCentralGoogle Scholar
  23. Eaves-Pyles T, Murthy K, Liaudet L, Virag L, Ross G, Soriano FG, Szabo C, Salzman AL (2001) Flagellin, a novel mediator of Salmonella-induced epithelial activation and systemic inflammation: IκBα degradation, induction of nitric oxide synthase, induction of Proinflammatory mediators, and cardiovascular dysfunction. J Immunol 166:1248–1260. CrossRefPubMedGoogle Scholar
  24. Elia L, Aurisicchio L, Facciabene A, Giannetti P, Ciliberto G, la Monica N, Palombo F (2007) CD4+CD25+regulatory T-cell-inactivation in combination with adenovirus vaccines enhances T-cell responses and protects mice from tumor challenge. Cancer Gene Ther 14:201–210. CrossRefPubMedGoogle Scholar
  25. Esterlis I, Hannestad JO, Perkins E, Bois F, D’Souza DC, Tyndale RF, Seibyl JP, Hatsukami DM, Cosgrove KP, O’Malley SS (2013) Effect of a nicotine vaccine on nicotine binding to b 2 *-nicotinic acetylcholine receptors in vivo in human tobacco smokers. Am J Psychiatry 170:399–407CrossRefGoogle Scholar
  26. Flores-langarica A, Marshall JL, Cook C et al (2012) Systemic Flagellin immunization stimulates mucosal CD103+ dendritic cells and drives Foxp3+ regulatory T cell and IgA responses in the mesenteric lymph node. J Immunol 189:5745–5754. CrossRefPubMedGoogle Scholar
  27. Fukuzawa N, Petro M, Baldwin WM, Gudkov AV, Fairchild RL (2011) A TLR5 agonist inhibits acute renal ischemic failure. J Immunol 187:3831–3839. CrossRefPubMedPubMedCentralGoogle Scholar
  28. Garaude J, Kent A, Van Rooijen N, Blander JM (2012) Cancer vaccines: simultaneous targeting of toll- and nod-like receptors induces effective tumor-specific immune responses. Sci Transl Med 4:120ra16. CrossRefPubMedGoogle Scholar
  29. Giannini SL, Hanon E, Moris P, van Mechelen M, Morel S, Dessy F, Fourneau MA, Colau B, Suzich J, Losonksy G, Martin MT, Dubin G, Wettendorff MA (2006) Enhanced humoral and memory B cellular immunity using HPV16 / 18 L1 VLP vaccine formulated with the MPL / aluminium salt combination ( AS04 ) compared to aluminium salt only. Vaccine 24:5937–5949. CrossRefPubMedGoogle Scholar
  30. Gribble EJ, Sivakumar PV, Ponce RA, Hughes SD (2007) Toxicity as a result of immunostimulation by biologics. Expert Opin Drug Metab Toxicol 3:209–234CrossRefGoogle Scholar
  31. Haile CN, Kosten TA, Shen XY, O'Malley PW, Winoske KJ, Kinsey BM, Wu Y, Huang Z, Lykissa ED, Naidu N, Cox JA, Arora R, Kosten TR, Orson FM (2015) Altered methamphetamine place conditioning in mice vaccinated with a Succinyl-methamphetamine-tetanus-toxoid vaccine. Am J Addict 24:748–755. CrossRefPubMedGoogle Scholar
  32. Haney M, Gunderson EW, Jiang H et al (2010) Cocaine-specific antibodies blunt the subjective effects of smoked cocaine in humans. Biol Psychiatry 67:59–65. CrossRefPubMedPubMedCentralGoogle Scholar
  33. Harris AC, Le Sage MG, Shelley D et al (2015) The anti-(+)-methamphetamine monoclonal antibody mAb7F9 attenuates acute (+)-methamphetamine effects on intracranial self-stimulation in rats. PLoS One 10:e0118787. CrossRefPubMedPubMedCentralGoogle Scholar
  34. Hatsukami DK, Jorenby DE, Gonzales D, Rigotti NA, Glover ED, Oncken CA, Tashkin DP, Reus VI, Akhavain RC, Fahim REF, Kessler PD, Niknian M, Kalnik MW, Rennard SI (2011) Immunogenicity and smoking-cessation outcomes for a novel nicotine immunotherapeutic. Clin Pharmacol Ther 89:392–399. CrossRefPubMedPubMedCentralGoogle Scholar
  35. Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, Goodlett DR, Eng JK, Akira S, Underhill DM, Aderem A (2001) The innate immune response to bacterial flagellin is mediated by toll-like receptor 5. Nature 410:1099–1103CrossRefGoogle Scholar
  36. Hicks MJ, Rosenberg JB, De BP et al (2012) AAV-directed persistent expression of a gene encoding anti-nicotine antibody for smoking cessation. Sci Transl Med 4:140ra187. CrossRefGoogle Scholar
  37. Hieda Y, Keyler DE, Vandevoort JT et al (1997) Active immunization alters the plasma nicotine concentration in rats. J Pharmocol Exp Ther 283:1076–1081Google Scholar
  38. Holbrook BC, Agostino RBD, Parks GD, Alexander-miller MA (2016) Adjuvanting an inactivated influenza vaccine with flagellin improves the function and quantity of the long-term antibody response in a nonhuman primate neonate model. Vaccine 34:4712–4717. CrossRefPubMedPubMedCentralGoogle Scholar
  39. Honko AN, Mizel SB (2005) Effects of Flagellin on innate and adaptive immunity. Immunol Res 33:83–101 doi: 10.1385/IRCrossRefGoogle Scholar
  40. Honko AN, Sriranganathan N, Lees CJ, Mizel SB (2006a) Flagellin is an effective adjuvant for immunization against lethal respiratory challenge with Yersinia pestis. Infect Immun 74:1113–1120. CrossRefPubMedPubMedCentralGoogle Scholar
  41. Honko AN, Sriranganathan N, Lees CJ, Mizel SB (2006b) Flagellin is an effective adjuvant for immunization against lethal respiratory challenge with Yersinia pestis. Infect Immun 74:1113–1120. CrossRefPubMedPubMedCentralGoogle Scholar
  42. Hossain MS, Ramachandiran S, Gewirtz AT, Waller EK (2014) Recombinant TLR5 agonist CBLB502 promotes NK cell-mediated anti-CMV immunity in mice. PLoS One 9(5):e96165.
  43. Ishizaka ST, Hawkins LD (2007) E6020: a synthetic toll-like receptor 4 agonist as a vaccine adjuvant. Expert Rev Vaccines 6:773–784CrossRefGoogle Scholar
  44. Islam D, Lombardini E, Ruamsap N, Imerbsin R, Khantapura P, Teo I, Neesanant P, Gonwong S, Yongvanitchit K, Swierczewski BE, Mason CJ, Shaunak S (2016) Controlling the cytokine storm in severe bacterial diarrhoea with an oral toll-like receptor 4 antagonist. Immunology 147:178–189. CrossRefPubMedGoogle Scholar
  45. Jenkins AJ, Keenan RM, Henningfield JE, Cone EJ (2002) Correlation between pharmacological effects and plasma cocaine concentrations after smoked a d m i n i s t r a t i o n. J Anal Toxicol 26:382–392CrossRefGoogle Scholar
  46. Jones RM, Sloane VM, Wu H, Luo L, Kumar A, Kumar MV, Gewirtz AT, Neish AS (2011) Flagellin administration protects gut mucosal tissue from irradiation-induced apoptosis via MKP-7 activity. Gut 60:648–657. CrossRefPubMedGoogle Scholar
  47. Kanzler H, Barrat FJ, Hessel EM, Coffman RL (2007) Therapeutic targeting of innate immunity with toll-like receptor agonists and antagonists. Nat Med 13:552–559. CrossRefPubMedGoogle Scholar
  48. Keyler DE, Hieda Y, Peter JS, Pentel PR (1999) Altered disposition of repeated nicotine doses in rats immunized against nicotine. Nicotine Tob Res 1:241–249. CrossRefPubMedGoogle Scholar
  49. Khong H, Overwijk WW (2016) Adjuvants for peptide-based cancer vaccines. J Immunother Cancer 4:1–11. CrossRefGoogle Scholar
  50. Kim S, Lalani S, Parekh VV, Vincent TL, Wu L, van Kaer L (2008) Impact of bacteria on the phenotype, functions, and therapeutic activities of invariant NKT cells in mice. J Clin Invest 118:2301–2315. CrossRefPubMedPubMedCentralGoogle Scholar
  51. Kim K, Kwon Y, Lee Y et al (2018) Virus-like particles presenting fl agellin exhibit unique adjuvant e ff ects on eliciting T helper type 1 humoral and cellular immune responses to poor immunogenic in fl uenza virus M2e protein vaccine. Virology 524:172–181. CrossRefPubMedGoogle Scholar
  52. Kozlova D, Sokolova V, Zhong M, Zhang E, Yang J, Li W, Yang Y, Buer J, Westendorf AM, Epple M, Yan H (2014) Calcium phosphate nanoparticles show an effective activation of the innate immune response in vitro and in vivo after functionalization with flagellin. Virol Sin 29:33–39. CrossRefPubMedGoogle Scholar
  53. Krivokrysenko VI, Toshkov IA, Gleiberman AS, Krasnov P, Shyshynova I, Bespalov I, Maitra RK, Narizhneva NV, Singh VK, Whitnall MH, Purmal AA, Shakhov AN, Gudkov AV, Feinstein E (2015) The toll-like receptor 5 agonist entolimod mitigates lethal acute radiation syndrome in non-human primates. PLoS One 10:1–31. CrossRefGoogle Scholar
  54. Kvello AMS, Andersen JM, Øiestad EL et al (2016) Pharmacological effects of a monoclonal antibody against 6-Monoacetylmorphine upon heroin-induced Locomotor activity and pharmacokinetics in mice. J Pharmacol Exp Ther 358:181–189. CrossRefPubMedGoogle Scholar
  55. Labastida-conde RG, Ramírez-pliego O, Peleteiro-olmedo M et al (2018) Flagellin is a Th1 polarizing factor for human CD4 + T cells and induces protection in a murine neonatal vaccination model of rotavirus infection. Vaccine 36:4188–4197. CrossRefPubMedGoogle Scholar
  56. Leigh ND, Bian G, Ding X et al (2014) A flagellin-derived toll-like receptor 5 agonist stimulates cytotoxic lymphocyte-mediated tumor immunity. PLoS One 9(1):e85587.
  57. Lockner JW, Ho SO, McCague KC et al (2013) Enhancing nicotine vaccine immunogenicity with liposomes. Bioorg Med Chem Lett 23:975–978. CrossRefPubMedGoogle Scholar
  58. Lockner JW, Eubanks LM, Choi JL, Lively JM, Schlosburg JE, Collins KC, Globisch D, Rosenfeld-Gunn RJ, Wilson IA, Janda KD (2015) Flagellin as carrier and adjuvant in cocaine vaccine development. Mol Pharm 12:653–662. CrossRefPubMedGoogle Scholar
  59. Loré K, Betts MR, Brenchley JM et al (2003) Toll-like receptor ligands modulate dendritic cells to augment cytomegalovirus- and HIV-1-specific T cell responses. J Immunol 171:4320–4328. CrossRefPubMedGoogle Scholar
  60. Ma Y, Zhang L, Li Q (2016) Expression levels of cytokines and chemokines increase in human peripheral blood mononuclear cells stimulated by activation of the toll-like receptor 5 pathway. Exp Ther Med 11:588–592. CrossRefPubMedGoogle Scholar
  61. Mardanova ES, Kotlyarov RY, Kuprianov VV, Stepanova LA, Tsybalova LM, Lomonossoff GP, Ravin NV (2016) High immunogenicity of plant-produced candidate in fl uenza vaccine based on the M2e peptide fused to flagellin. Bioengineered 7:28–32. CrossRefPubMedGoogle Scholar
  62. Martell BA, Orson FM, Poling J, Mitchell E, Rossen RD, Gardner T, Kosten TR (2009) Cocaine vaccine for the treatment of cocaine dependence in methadone-maintained patients: a randomized, double- blind, placebo-controlled efficacy trial. Arch Gen Psychiatry 66:1116–1123. CrossRefPubMedPubMedCentralGoogle Scholar
  63. McSorley SJ, Ehst BD, Yu Y, Gewirtz AT (2002) Bacterial Flagellin is an effective adjuvant for CD4+ T cells in vivo. J Immunol 169:3914–3919. CrossRefPubMedGoogle Scholar
  64. Means TK, Hayashi F, Smith KD, Aderem A, Luster AD (2003) The toll-like receptor 5 stimulus bacterial Flagellin induces maturation and chemokine production in human dendritic cells. J Immunol 170:5165–5175. CrossRefPubMedGoogle Scholar
  65. Miller M, Moreno A, Aarde S et al (2013) A methamphetamine vaccine attenuates methamphetamine- induced disruptions in thermoregulation and activity in rats. Biol Psychiatry 73:721–728. CrossRefPubMedGoogle Scholar
  66. Mizel SB, Bates JT (2010) Flagellin as an adjuvant: cellular mechanisms and potential. J Immunol 185:5677–5682. CrossRefPubMedPubMedCentralGoogle Scholar
  67. Mogensen TH (2009) Pathogen recognition and inflammatory signaling in innate immune defenses. Clin Microbiol Rev 22:240–273. CrossRefPubMedPubMedCentralGoogle Scholar
  68. Morefield GL, Hawkins LD, Ishizaka ST, Kissner TL, Ulrich RG (2007) Synthetic toll-like receptor 4 agonist enhances vaccine efficacy in an experimental model of toxic shock syndrome. Clin Vaccine Immunol 14:1499–1504. CrossRefPubMedPubMedCentralGoogle Scholar
  69. Moreno AY, Mayorov AV, Janda KD (2011) Impact of distinct chemical structures for the development of a methamphetamine vaccine. J Am Chem Soc 133:6587–6595. CrossRefPubMedPubMedCentralGoogle Scholar
  70. Murakami Y, Fukui R, Motoi Y, Shibata T, Saitoh SI, Sato R, Miyake K (2017) The protective effect of the anti-toll-like receptor 9 antibody against acute cytokine storm caused by immunostimulatory DNA. Sci Rep 7:44042. CrossRefPubMedPubMedCentralGoogle Scholar
  71. Murthy V, Reyes S, Geng L, Gao Y, Brimijoin S (2016) Cocaine hydrolase gene transfer demonstrates cardiac safety and efficacy against cocaine-induced QT prolongation in mice. J Pharmacol Exp Ther 356:720–725. CrossRefPubMedPubMedCentralGoogle Scholar
  72. Nasser AF, Fudala PJ, Zheng B, Liu Y, Heidbreder C (2014) A randomized, double-blind, placebo-controlled trial of RBP-8000 in cocaine abusers: pharmacokinetic profile of RBP-8000 and cocaine and effects of RBP-8000 on cocaine-induced physiological effects. J Addict Dis 33:289–302. CrossRefPubMedGoogle Scholar
  73. Nelson RA, Boyd SJ, Ziegelstein RC, Herning R, Cadet JL, Henningfield JE, Schuster CR, Contoreggi C, Gorelick DA (2006) Effect of rate of administration on subjective and physiological effects of intravenous cocaine in humans. Drug Alcohol Depend 82:19–24. CrossRefPubMedGoogle Scholar
  74. Netea MG, Van Der Meer JWM, Sutmuller RP et al (2005) From the Th1 / Th2 paradigm towards a toll-like Receptr/T-helper bias. Antimicrob Agents Chemother 49:3991–3996. CrossRefPubMedPubMedCentralGoogle Scholar
  75. Ohia-Nwoko O, Kosten TA, Haile CN (2016) Animal models and the development of vaccines to treat substance use disorders. Int Rev Neurobiol 126:263–291.
  76. Orson FM, Wang R, Brimijoin S, Kinsey BM, Singh RAK, Ramakrishnan M, Wang HY, Kosten TR (2014) The future potential for cocaine vaccines. Expert Opin Biol Ther 14:1271–1283. CrossRefPubMedPubMedCentralGoogle Scholar
  77. Perrin-Cocon L, Aublin-Gex A, Sestito SE, Shirey KA, Patel MC, André P, Blanco JC, Vogel SN, Peri F, Lotteau V (2017) TLR4 antagonist FP7 inhibits LPS-induced cytokine production and glycolytic reprogramming in dendritic cells, and protects mice from lethal influenza infection. Sci Rep 7:40791. CrossRefPubMedPubMedCentralGoogle Scholar
  78. Pravetoni M (2016) Biologics to treat substance use disorders: current status and new directions. Hum Vaccin Immunother 12:3005–3019. CrossRefPubMedPubMedCentralGoogle Scholar
  79. Pravetoni M, Le Naour M, Harmon TM et al (2012a) An oxycodone conjugate vaccine elicits drug-specific antibodies that reduce oxycodone distribution to brain and hot-plate analgesia. J Pharmacol Exp Ther 341:225–232. CrossRefPubMedPubMedCentralGoogle Scholar
  80. Pravetoni M, Raleigh M, Le Naour M et al (2012b) Co-administration of morphine and oxycodone vaccines reduces the distribution of 6-monoacetylmorphine and oxycodone to brain in rats. Vaccine 31:4617–4624. CrossRefGoogle Scholar
  81. Qian F, Yin J, Li M, Guo A, Li T, Zhou L, Wu X, Xu H (2016) Intranasal immunization with a peptide conjugated to Salmonella fl agellin induces both systemic and mucosal peptide-speci fi c antibody responses in mice. Microbiol Immunol 60:497–500. CrossRefPubMedGoogle Scholar
  82. Querec T, Bennouna S, Alkan S, Laouar Y, Gorden K, Flavell R, Akira S, Ahmed R, Pulendran B (2006) Yellow fever vaccine YF-17D activates multiple dendritic cell subsets via TLR2, 7, 8, and 9 to stimulate polyvalent immunity. J Exp Med 203:413–424. CrossRefPubMedPubMedCentralGoogle Scholar
  83. Raison CL, Rutherford RE, Woolwine BJ, Shuo C, Schettler P, Drake DF, Haroon E, Miller AH (2013) A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry 70:31–41. CrossRefPubMedPubMedCentralGoogle Scholar
  84. Raleigh M, Baruffaldi F, Peterson S et al (2019) A fentanyl vaccine alters fentanyl distribution and protects against fentanyl-induced effects in mice and rats. J Pharmacol Exp Ther 368(2):282–291.
  85. Ramakrishnan M, Kinsey BM, Singh RA, Kosten TR, Orson FM (2014) Hapten optimization for cocaine vaccine with improved cocaine recognition. Chem Biol Drug Des 84:354–363. CrossRefPubMedPubMedCentralGoogle Scholar
  86. Rech AJ, Vonderheide RH (2009) Clinical use of anti-CD25 antibody daclizumab to enhance immune responses to tumor antigen vaccination by targeting regulatory T cells. Ann N Y Acad Sci 1174:99–106. CrossRefPubMedGoogle Scholar
  87. Rhee SH, Im E, Pothoulakis C (2008) Toll-like receptor 5 engagement modulates tumor development and growth in a mouse Xenograft model of human Colon Cancer. Gastroenterology 135:518–528. CrossRefPubMedGoogle Scholar
  88. Rolla S, Ria F, Occhipinti S, di Sante G, Iezzi M, Spadaro M, Nicolo C, Ambrosino E, Merighi IF, Musiani P, Forni G, Cavallo F (2010) Erbb2 DNA vaccine combined with regulatory T cell deletion enhances antibody response and reveals latent low-avidity T cells: potential and limits of its therapeutic efficacy. J Immunol 184:6124–6132. CrossRefPubMedGoogle Scholar
  89. Rolli J, Loukili N, Levrand S, Rosenblatt-Velin N, Rignault-Clerc S, Waeber B, Feihl F, Pacher P, Liaudet L (2010) Bacterial flagellin elicits widespread innate immune defense mechanisms , apoptotic signaling , and a sepsis-like systemic inflammatory response in mice. Crit Care 14:R160CrossRefGoogle Scholar
  90. Rosenberg JB, Hicks MJ, De BP et al (2012) AAVrh.10-mediated expression of an anti-cocaine antibody mediates persistent passive immunization that suppresses cocaine-induced behavior. Hum Gene Ther 23:451–459. CrossRefPubMedPubMedCentralGoogle Scholar
  91. Salazar-Gonzalez R-M, Srinivasan A, Griffin A, Muralimohan G, Ertelt JM, Ravindran R, Vella AT, McSorley SJ (2007) Salmonella Flagellin induces bystander activation of splenic dendritic cells and hinders bacterial replication in vivo. J Immunol 179:6169–6175. CrossRefPubMedGoogle Scholar
  92. Sanders CJ, Moore DAI, Williams IR, Gewirtz AT (2008) Both Radioresistant and Hemopoietic cells promote innate and adaptive immune responses to Flagellin. J Immunol 180:7184–7192. CrossRefPubMedGoogle Scholar
  93. Schindler CW, Panlilio LV, Thorndike EB (2009) Effect of rate of delivery of intravenous cocaine on self-administration in rats. Pharmacol Biochem Behav 93:375–381. CrossRefPubMedPubMedCentralGoogle Scholar
  94. Sfondrini L, Rossini A, Besusso D, Merlo A, Tagliabue E, Menard S, Balsari A (2006) Antitumor activity of the TLR-5 ligand flagellin in mouse models of cancer. J Immunol 176:6624–6630. CrossRefPubMedGoogle Scholar
  95. Shim J, Rhee J, Jeong J, Koh Y (2016) Flagellin modulates the function of invariant NKT cells from patients with asthma via dendritic cells. Allergy, Asthma Immunol Res 8:206–215CrossRefGoogle Scholar
  96. Smethells JR, Swalve N, Brimijoin S, Gao Y, Parks RJ, Greer A, Carroll ME (2016) Long-term blockade of cocaine self-administration and Locomotor activation in rats by an adenoviral vector-delivered cocaine hydrolase. J Pharmacol Exp Ther 357:375–381. CrossRefPubMedPubMedCentralGoogle Scholar
  97. Smith KM, Pottage L, Thomas ER, Leishman AJ, Doig TN, Xu D, Liew FY, Garside P (2000) Th1 and Th2 CD4+ T cells provide help for B cell clonal expansion and antibody synthesis in a similar manner in vivo. J Immunol 165:3136–3144. CrossRefPubMedGoogle Scholar
  98. Søgaard OS, Lohse N, Harboe ZB, Offersen R, Bukh AR, Davis HL, Schønheyder HC, Østergaard L (2010) Improving the Immunogenicity of Pneumococcal Conjugate Vaccine in HIV-Infected Adults with a Toll-Like Receptor 9 Agonist Adjuvant : A Randomized , Controlled Trial. Clin Infect Dis 51:42–50. CrossRefPubMedGoogle Scholar
  99. Stevens MW, Henry RL, Owens SM, Schutz R, Gentry WB (2014) First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers. MAbs 6:1649–1656. CrossRefPubMedPubMedCentralGoogle Scholar
  100. Stevens MW, Gunnell MG, Tawney R, Owens SM (2016) Optimization of a methamphetamine conjugate vaccine for antibody production in mice. Int Immunopharmacol 35:137–141. CrossRefPubMedPubMedCentralGoogle Scholar
  101. Stills HF (2005) Adjuvants and antibody production: dispelling the myths associated with Freund’s complete and other adjuvants. ILAR J 46:280–293. CrossRefPubMedGoogle Scholar
  102. Tarrant JM (2010) Blood cytokines as biomarkers of in vivo toxicity in preclinical safety assessment: considerations for their use. Toxicol Sci 117:4–16. CrossRefPubMedPubMedCentralGoogle Scholar
  103. Taylor DN, Treanor JJ, Strout C, Johnson C, Fitzgerald T, Kavita U, Ozer K, Tussey L, Shaw A (2011) Induction of a potent immune response in the elderly using the TLR-5 agonist , flagellin , with a recombinant hemagglutinin influenza – flagellin fusion vaccine (VAX125, STF2.HA1 SI). Vaccine 29:4897–4902. CrossRefPubMedGoogle Scholar
  104. Uematsu S, Fujimoto K, Jang MH, Yang BG, Jung YJ, Nishiyama M, Sato S, Tsujimura T, Yamamoto M, Yokota Y, Kiyono H, Miyasaka M, Ishii KJ, Akira S (2008) Regulation of humoral and cellular gut immunity by lamina propria dendritic cells expressing toll-like receptor 5. Nat Immunol 9:769–776. CrossRefPubMedGoogle Scholar
  105. Vijay-Kumar M, Aitken JD, Sanders CJ, Frias A, Sloane VM, Xu J, Neish AS, Rojas M, Gewirtz AT (2008) Flagellin treatment protects against chemicals, Bacteria, viruses, and radiation. J Immunol 180:8280–8285. CrossRefPubMedGoogle Scholar
  106. Voss OH, Murakami Y, Pena MY, Lee HN, Tian L, Margulies DH, Street JM, Yuen PST, Qi CF, Krzewski K, Coligan JE (2016) Lipopolysaccharide-induced CD300b receptor binding to toll-like receptor 4 alters signaling to drive cytokine responses that enhance septic shock. Immunity 44:1365–1378. CrossRefPubMedPubMedCentralGoogle Scholar
  107. Wang L, Zhang W, Ge CH, Yin RH, Xiao Y, Zhan YQ, Yu M, Li CY, Ge ZQ, Yang XM (2017) Toll-like receptor 5 signaling restrains T-cell/natural killer T-cell activation and protects against concanavalin A–induced hepatic injury. Hepatology 65:2059–2073. CrossRefPubMedGoogle Scholar
  108. Woolverton WL, Wang Z (2004) Relationship between injection duration, transporter occupancy and reinforcing strength of cocaine. Eur J Pharmacol 486:251–257. CrossRefPubMedGoogle Scholar
  109. Yang H, Brackett CM, Morales-tirado VM et al (2015) The etoll-like receptor 5 agonist entolimod suppresses hepatic metastases in a murine model of ocular melanoma via an NK cell-dependent mechanism. Oncotarget 7:1–15. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of PsychiatryBaylor College of MedicineHoustonUSA

Personalised recommendations