477
Views
63
CrossRef citations to date
0
Altmetric
Review

Clinical investigations of Toll-like receptor agonists

, PhD & , MD
Pages 1051-1065 | Published online: 12 Jun 2008

Bibliography

  • Medzhitov R, Janeway CA. Innate immunity. N Engl J Med 2000;343:338-44
  • Janeway CA, Medzhitov R. Innate immune recognition. Ann Rev Immunol 2002;20:197-216
  • Hornung V, Rothenfusser S, Britsch S, et al. Quantitative expression of Toll-like receptor 1-10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J Immunol 2002;168:4531-7
  • Peiser L, Mukhopadhyay S, Gordon S. Scavenger receptors in innate immunity. Curr Opin Immunol 2002;14:123-8
  • Carneiro LAM, Magalhaes JG, Tattoli I, et al. Nod-like proteins in inflammation and disease. J Pathol 2008;214:136-48
  • Meylan E, Tschopp J, Karin M. Intracellular pattern recognition receptors in the host response. Nature 2006;442:39-44
  • Bottazzi B, Garlanda C, Salvatori G, et al. Pentraxins as a key component of innate immunity. Curr Opin Immunol 2006;18:10-5
  • O'Neill JA. Signal transduction pathways activated by the IL-1 receptor/Toll-like recptor superfamily. Curr Top Microbiol Immunol 2002;270:47-62
  • Underhill DM, Ozinsky A. Toll-like receptors: key mediators of microbe detection. Curr Opin Immunol 2002;14:103-10
  • Travassos LH, Giardin SE, Philpott DJ, et al. Toll-like receptor 2-dependent bacterial sensing does not occur via peptidoglycan recognition. EMBO Rep 2004;5:1000-6
  • Hayashi F, Smith KD, Ozinsky A, et al. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 2001;410:1099-103
  • O'Neill L. How Toll-like receptors signal: what we know and what we don't know. Curr Opin Immunol 2006;18:3-9
  • Hemmi H, Takeuchi O, Kawai T, et al. A Toll-like receptor recognizes bacterial DNA. Nature 2000;408:740-5
  • Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2001;2:675-80
  • Barton GM, Medzhitov R. Toll-like receptors and their ligands. Curr Top Microbiol Immunol 2002;270:81-92
  • Yamamoto M, Sato S, Moro K, et al. Cutting edge: a novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-beta promoter in the Toll-like receptor signaling. J Immunol 2002;169:6668-72
  • Uematsu S, Sato S, Yamamoto M, et al. Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR) 7- and TLR 9-mediated interferon-(alpha) induction. J Exp Med 2005;201:915-23
  • Johnson GB, Brunn GJ, Tang AH, Platt JL. Evolutionary clues to the functions of the Toll-like family as surveillance receptors. Trends Immunol 2003;24:19-24
  • Beg AA. Endgenous ligands of Toll-like receptors: implications for regulating inflammatory and immune responses. Trends Immunol 2002;23:509-12
  • Hemmi H, Kaisho O, Takeuchi S, et al. Small anti-viral compounds acitivate immune cells via the TLR7 MyD88-dependent signalling pathway. Nat Immunol 2002;3:196-200
  • Jurk M, Heil F, Vollmer J, et al. Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R848. Nat Immunol 2002;3:499
  • Diebold SS, Kaisho T, Hemmi H, et al. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 2004;303:1529-31
  • Lund JM, Alexopoulou L, Sato A, et al. Recognition of single-stranded RNA viruses by Toll-like receptor 7. Proc Natl Acad Sci USA 2004;101:5598-603
  • Testerman TL, Gerster JF, Imbertsen LM, et al. Cytokine induction by the immunomodulators imiquimod and S-27609. J Leukoc Biol 1995;58:365-72
  • Stanley MA. Imiquimod and the imidazoquinolones: mechanism of action and therapeutic potential. Clin Exp Dermatol 2002;27:571-7
  • Garland SM. Imiquimod. Curr Opin Infect Dis 2003;16:85-9
  • Schön MP, Schön M, Klotz KN. The small antitumoral immune response modifier imiquimod interacts with adenosine receptor signalling in a TLR7- and TLR8-independent fashion. J Invest Dermatol 2006;126:1338-47
  • Kanneganti TD, Ozoren N, Body-Malapel M, et al. Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature 2006;440:233-6
  • Meyer T, Nindl I, Schmook T, et al. Induction of apoptosis by Toll-like receptor-7 agonist in tissue cultures. Br J Dermatol 2003;149(Suppl 66):9-13
  • Schön M, Bong AB, Drewniok C, et al. Tumor-selective induction of apoptosis and the small-molecule immune response modifier imiquimod. J Natl Cancer Inst 2003;95:1138-49
  • Urosevic M, Maier T, Benninghoff B, et al. Mechanisms underlying imiquimod-induced regression of basal cell carcinoma in vivo. Arch Dermatol 2003;139:1325-32
  • Berman B, Sullivan TP, Araujo T, Nadji T. Expression of Fas-receptor on basal cell carcinomas after treatment with imiquiomod 5% cream or vehilcle. Br J Dermatol 2003;149(Suppl 66):59-61
  • Beutner KR, Tyring SK, Trofatter KF Jr, et al. Imiquimod, a patient applied immune response modifier for trteatment of external warts. Antimicrob Agents Chemother 1998;42:789-94
  • Beutner KR, Spruance SL, Hougham AJ, et al. Treatmant of genital warts with an immune response modifier (imiquimod). J Am Acad Dermatol 1998;38:230-9
  • Edwards L, Ferenzy A, Eron L, et al. Self-administered topical 5% imiquimod cream for external anogenital warts. Arch Dermatol 1998;134:25-30
  • Moore RA, Edwards JE, Hopwood J, Hicks D. Imiquimod for the treatment of genital warts: a quantitative systematic review. BMC Infect Dis 2001;1:3
  • Fife KH, Ferenzy A, Douglas JM Jr, et al. Treatment of external genital warts in men using 5% imiquimod cream applied three times a week once daily, twice daily, or three times a day. Sex Transm Dis 2001;28:226-31
  • Yan J, Chen SL, Wang HN, Wu TX. Meta-analysis of 5% imiquimod and 0.5% podophyllotoxin in the treatment of Condylomata acuminata. Dermatology 2006;213:218-23
  • Centers for Disease Control and Prevention: 1998 Guidelines for treatment of sexually transmitted diseases. MMWR 1998;47:88-95
  • Slade HB, Owens ML, Tomai MA, Miller RL. Imiquimod 5% cream (Aldara TM). Expert Opin Invest Drugs 1998;7:437-49
  • Schöfer H, van Ophoven A, Henke U, et al. Randomized, comparative trial on the sustained efficacy of topical imiquimod 5% cream versus conventional ablative methods in external anogenital warts. Eur J Dermatol 2006;16:642-8
  • Goldstein D, Hertzog P, Tomkinson E, et al. Administration of imiquimod, an interferon inducer, in asymptomatic human immunodeficiency virus-infected persons to determine safety and biologic response modification. J Infect Dis 1998;178:858-61
  • Gilson RJ, Shupack JL, Friedman-Kien AE, et al. A randomized, controlled, safety study using imiquimod for the topical treatment of anogenital warts in HIV-infected patients. Imiquimod Study Group. AIDS 1999;13:2397-404
  • Brown VL, Atkins CL, Ghali L, et al. Safety and efficacy of 5% imiquimod cream for the treatment of skin dysplasia in high-risk renal transplant recipients: randomized, double-blind, placebo-controlled trial. Arch Dermatol 2005;141:985-93
  • Ulrich C, Bichel J Euvrard S, et al. Topical immunomodulation under systemic immunosuppression: results of a multicentre, randomized, placebo-controlled safety and efficacy study of imiquimod 5% cream for the treatment of actinic keratoses in kidney, heart, and liver transplant patients. Br J Dermatol 2007;157(Suppl 2):25-31
  • Cusini M, Samaso F, Zerboni R, et al. 5% Imiquimod cream for external anogenital warts in HIV-infected patients under HAART therapy. Int J STD AIDS 2004;15:17-20
  • Kaspari M, Gutzmer R, Kaspari T, et al. Application of imiquimod by suppositories (anal tampons) efficiently prevents recurrences after ablation of anal canal condyloma. Br J Dermatol 2002;147:757-9
  • Alomar A, Bichel J, McRae S. Vehicle-controlled, randomized, double-blind study to assess safety and efficacy of imiquimod 5% cream applied once daily 3 days per week in one or two courses of treatment of actinic keratoses on the head. Br J Dermatol 2007;157:133-41
  • Jorizzo J, Dinehart S, Matheson R, et al. Vehicle-controlled, double-blind, randomized study of imiquimod 5% cream applied 3 days per week in one or two courses of treatment for actinic keratoses on the head. J Am Acad Dermatol 2007;57:265-8
  • Falagas ME, Angelousi AG, Peppas G. Imiquimod for the treatment of actinic keratoses: a meta analysis of randomized controlled trials. J Am Acad Dermatol 2006;55:537-8
  • Stockfleth E, Meyer T, Benninghoff B, et al. A randomized, double-blind, vehicle-controlled study to assess 5% imiquimod cream for the treatment of multiple actinic keratoses. Arch Dermatol 2002;138:1498-502
  • Salasche SJ, Levine N, Morrison L. Cycle therapy of actinic keratoses of the face and scalp with 5% topical imiquimod cream: an open-label trial. J Am Acad Dermatol 2002;47:571-7
  • Lebwohl M, Dinehart S, Whiting D, et al. Imiquimod 5% cream for the treatment of actinic keratosis: results from two phase III, randomized, double-blind, parallel group, vehicle-controlled trials. J Am Acad Dermatol 2004;50:714-21
  • Korman N, Moy R, Ling M, et al. Dosing with 5% imiquimod cream 3 times per week for the treatment of actinic keratosis: results of two phase 3, randomized, double-blind, parallel-group, vehicle-controlled trials. Arch Dermatol 2005;141:467-73
  • Hadley G, Derry S, Moore RA. Imiquimod for actinic keratosis: systematic review and meta-analysis. J Invest Dermatol 2006;126:1251-5
  • Stockfleth E, Christophers, Benninghoff B, Sterry W. Low incidence of new actinic keratoses after topical 5% imiquimod cream treatment: a long-term follow-up study. Arch Dermatol 2004;140:1542
  • Krawtchenko N, Roewert-Huber J, Ulrich M, et al. A randomized study of topical 5% imiquimod vs. topical 5-fluorouracil vs. cryosurgery in immunocompetent patients with actinic keratoses: a comparison of clinical and histological outcomes including 1-year follow-up. Br J Dermatol 2007;157(Suppl 2):34-40
  • Dinehart SM. The treatment of actinic keratoses. J Am Acad Dermatol 2000;42:25-8
  • Parrish JA. Immunosuppression, skin cancer, and ultraviolet A radiation. N Engl J Med 2003;353:2712-3
  • Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl J Med 2003;348:1681-91
  • Greenway HT, Cornell RC, Tanner DJ, et al. Treatment of basal cell carcinoma with intralesional interferon. J Am Acad Dermatol 1986;15:437-43
  • Beutner Geisse JK, Helmann D, Fox TL, et al. Therapeutic response of basal cell carcinoma to the immune response modifier imiquimod 5% cream. J Am Acad Dermatol 1999;41:1002-7
  • Marks R, Gebauer K, Shumack S, et al. Imiquimod 5% cream in the treatment of superficial basal cell carcinoma: results of a multicenter 6-week dose-response trial. J Am Acad Dermatol 2001;44:807-13
  • Geisse JK, Rich P, Pandya A, et al. Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: a double-blind, randomized, vehicle-controlled study. J Am Acad Dermatol 2002;47:390-8
  • Sterry W, Ruzicka T, Herrera E, et al. Imiquimod 5% cream for the treatment of superficial and nodular basal cell carcinoma: randomized studies comparing low-frequency dosing with and without occlusion. Br J Dermatol 2002;147:1227-36
  • Schulze HJ, Cribier B, Requena L, et al. Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from a randomized vehicle-controlled phase III study in Europe. Br J Dermatol 2005;152:939-47
  • Gollnick H, Barona CG, Frank RG, et al. Recurrence rate of superficial basal cell carcinoma following successful treatment with imiquimod 5% cream: interim 2-year results from an ongoing 5-year follow-up study in Europe. Eur J Dermatol 2005;15:374-81
  • Quirk C, Gebauer K, Owens M, Stampone P. Two-year interim results from a 5-year study evaluating clinical recurrence of superficial basal cell carcinoma after treatment with imiquimod 5% cream daily for 6 weeks. Australas J Dermatol 2006;47:258-65
  • Sparling JD, Checketts SR, Chapman MS. Imiquimod for plantar and periungual warts. Cutis 2001;68:397-9
  • Cutler K, Kagen MH, Don PC, et al. Treatment of facial verrucae with topical imiquimod cream in a patient with human immunodeficiency virus. Acta Derm Venereol 2000;80:134-5
  • Rinne D, Linhart C, Schöfer H. Lip papillomatosis in immunodeficiency: therapy with imiquimod. Br J Dermatol 2000;142:196-7
  • Hengge U, Esser S, Schultewolter T, et al. Self-administered topical 5% imiquimod for the treatment of common warts and mollusca contagiosa. Br J Dermatol 2000;143:1026-31
  • Gayed SL. Topical imiquimod cream 5% for resistant perianal warts in renal transplant patients. Int J STD AIDS 2002;13:501-3
  • Schmook T, Nindl I, Ulrich C, et al. Viral warts in organ transplant recipients: new aspects in therapy. Br J Dermatol 2003;149(Suppl 66):20-4
  • Wieland U, Brockmeyer NH, Weissenborn SJ, et al. Imiquimod-treatment of anal intraepithelial neoplasia in HIV-positive men. Arch Dermatol 2006;142:1438-44
  • Kreuter A, Potthoff A, Brockmeyer NH, et al. Imiquimod leads to a decrease of human papillomavirus DNA and to a sustained clearance of anal intraepithelial neoplasia in HIV-infected men. J Invest Dermatol 2008; online publication doi:10.1038/jid.2008.24
  • Bernstein DI, Harrison CJ, Tomai MA, Miller RL. Daily or weekly therapy with resiquimod (R-848) reduces genital recurrences in herpes simplex virus-infected guinea pigs during and after treatment. J Infect Dis 2001;183:844-9
  • Arevalo I, Ward B, Miller R, et al. Successful treatment of drug-resistent cutaneous leishmaniasis in humans by use of imiquimod, an immunomodulator. Clin Infect Dis 2001;33:1847-51
  • Harrison CJ, Lenski L, Voychechovski T, Bernstein DI. Modification of immunological responses and clinical disease during topical R-837 treatment of genital HSV-2 infection. Antiviral Res 1998;10:209-23
  • Miller RL, Imbertson LM, Reiter MJ, Gerster JF. Treatment of primary herpes simplex virus infection in guinea pigs by imiquimod. Antiviral Res 1999;44:31-42
  • Morrey JD, Day CW, Julander JG, et al. Effect of interferon-alpha and interferon-inducers on West Nile virus in mouse and hamster animal models. Antivir Chem Chemother 2004;15:101-9
  • Clejan S, Mandrea E, Pandrea IV, et al. Immune responses induced by intranasal imiquimod and implications for therapeutics in rhinovirus infection. J Cell Mol Med 2005;9:457-61
  • Shumack S, Robinson J, Kossard S, et al. Efficacy of topical 5% imiquimod cream for the treatment of nodular basal cell carcinoma: comparison of dosing regimes. Arch Dermatol 2002;138:1165-71
  • Peris K, Campione E, Micantonio T, et al. Imiquimod treatment of superficial and nodular basal cell carcinoma: 12-week open-label trial. Dermatol Surg 2005;31:318-23
  • Schiessl C, Wolber C, Tauber M, et al. Treatment of all basal cell carcinoma variants including large and high-risk lesions with 5% imiquimod cream: histological and clinical changes, outcome, and follow-up. J Drugs Dermatol 2007;6:507-13
  • Stockfleth E, Ulrich C, Hauschild A, et al. Successful treatment of basal cell carcinomas in a nevoid basal cell carcinoma syndrome with topical 5% imiquimod. Eur J Dermatol 2002;12:569-72
  • Wu JK, Siller G, Whitehead K. Treatment of Bowen's disease and basal cell carcinoma of the nose with imiquimod 5% cream. Australas J Dermatol 2003;44:123-5
  • Schroeder TL, Sengelmann RD. Squamous cell carcinoma in situ of the penis successfully treated with imiquimod 5% cream. J Am Acad Dermatol 2002;46:545-8
  • Konstantopoulou M, Lord MG, Macfarlane AW. Treatment of invasive squamous cell carcinoma with 5% imiquimod cream. Dermatol Online J 2006;13:10
  • Mackenzie-Wood A, Kossard S, de Launey J, et al. Imiquimod 5% cream in the treatment of Bowen's disease. J Am Acad Dermatol 2001;44:462-70
  • Peris K, Micantonio T, Fargnoli MC, et al. Imiquimod 5% cream in the treatment of Bowen's disease and invasive squamous cell carcinoma. J Am Acad Dermatol 2006;55:324-7
  • Goh MS. Invasive squamous cell carcinoma after treatment of carcinoma in situ with 5% imiquimod cream. Australas J Dermatol 2006;47:186-8
  • Martin-Garcia RF. Imiquimod: an effective alternative for the treatment of invasive cutaneous squamous cell carcinoma. Dermatol Surg 2005;31:371-4
  • Stockfleth E, Röwert J, Arndt R, et al. Detection of HPV in stucco keratosis and successful treatment with imiquimod 5%. Br J Dermatol 2000;143:846-50
  • Dendorfer M, Oppel T, Wollenberg A, Prinz JC. Topical treatment with imiquimod may induce regression of facial keratoakanthoma. Eur J Dermatol 2003;13:80-2
  • Peris K, Micantonio T, Fargnoli MC. Successful treatment of keratoacanthoma and actinic keratoses with imiquimod 5% cream. Eur J Dermatol 2003;13:413-4
  • Aroni K, Mastoraki A, Agrogiannis G, et al. Successful treatment of keratoacanthoma centrifugum marginatum with local application of imiquimod cream. Int J Dermatol 2007;46:1321-2
  • Zamponga JC, Flowers FP, Roth WI, Hassenein AM. Treatment of primary limited curaneous extramammary Paget's disease with topical imiquimod monotherapy: two case reports. J Am Acad Dermatol 2002;47(Suppl 4):S229-35
  • Quian Z, Zeitoun NC, Shieh S, et al. Successful treatment of extramammary Paget's disease with imiquimod. J Drugs Dermatol 2003;2:73-6
  • Ahmed I, Berth-Jones J. Imiquimod: a novel treatment for lentigo maligna. Br J Dermatol 2000;143:843-5
  • Rajpar SF, Mardsen JR. Imiquimod in the treatment of lentigo maligna. Br J Dermatol 2006;155:653-6
  • Steinman A, Funk JO, Schuler G, von den Driesch P. Topical imiquimod treatment of a cutaneous melanoma metastasis. J Am Acad Dermatol 2000;43:555-6
  • Wolf IH, Smolle J, Binder B, et al. Topical imiquimod in the treatment of metastatic melanoma to the skin. Arch Dermatol 2003;139:273-6
  • Ugurel S, Wagner A, Pfohler C, et al. Topical imiquimod eradicates skin metastases of malignant melanoma but fails to prevent rapid lymphogenous metastatic spread. Br J Dermatol 2002;147:621-4
  • Dummer R, Urosevic M, Kempf W, et al. Imiquimod induces complete clearance of a PUVA-resistant plaque in mycosis fungoides. Dermatology 2003;207:116-8
  • Berthelot C, Dickerson MC, Rady P, et al. Treatment of a patient with epidermodysplasia verruciformis carrying a novel EVER2 mutation with imiquimod. J Am Acad Dermatol 2007;56:882-6
  • Janssen K, Lucker GP, Houwing RH, van Rijssel R. Epidermodysplasia verruciformis: unsuccessful therapeutic approach with imiquimod. Int J Dermatol 2007;46(Suppl 3):45-7
  • Wagner TL, Ahonen CL, Couture AM, et al. Modulation of TH1 and TH2 cytokine production with the immune response modifiers R-848 and imiquimod. Cell Immunol 1999;191:10-9
  • Ahonen CL, Gibson SJ, Smith RM, et al. Dendritic cell maturation and subsequent enhanced T cell stimulation induced with the novel synthetic immune response modifier R-848. Cell Immunol 1999;197:62-72
  • Tomai MA, Gibson SJ, Imbertson LM, et al. Immunomodulating and antiviral activities of the imidazochinolines S-28643. Antivir Res 1995;28:253-64
  • Spruance SL, Tyring SK, Smith MH, Meng TC. Application of a topical immune response modifier, resiquimod gel, to modify the recurrence rate of recurrent genital herpes: a pilot study. J Infect Dis 2001;184:196-200
  • Wu JJ, Huang DB, Tyring SK. Resiquimod : a new immune response modifier with potential as a vaccine adjuvant for Th1 immune responses. Antiviral Res 2004;64:79-83
  • Mark KE, Corey L, Meng TC, et al. Topical resiquimod 0.01% gel decreases herpes simplex virus type 2 genital shedding: a randomized, controlled trial. J Infect Dis 2007;195:1324-31
  • Tomai MA, Miller RL, Lipson KE, et al. Immune response modifiers: Imiquimod and future drugs for modulating the immune response. Drug Discov Today 2006;3:343-52
  • Krieg AM. Development of TLR9 agonists for cancer therapy. J Clin Invest 2007;117:1184-94
  • Krieg AM. Anti-infective applications of Toll-like receptor 9 agonists. Proc Am Thorac Soc 2007;4:289-94
  • Iwasaki A, Medzhitov R. Toll-like receptor control of the adaptive immune responses. Nat Immunol 2005;5:987-95
  • Liu YJ. IPC: professional type 1 interferon producing cells and plasmacytoid dendritic cell precursors. Ann Rev Immunol 2005;23:275-306
  • McHutchinson JG, Bacon BR, Gordon SC, et al. Phase 1B, randomized, double-blind, dose-escalation trial of CPG 10101 in patients with chronic hepatitis C. Hepatology 2007;46:1341-9
  • Schmidt C. Clinical setbacks for toll-like receptor 9 agonists in cancer. Nat Biotechnol 2007;25:825-6
  • Stern BV, Boehm BO, Tary-Lehmann M. Vaccination with tumor peptide in CpG adjuvant proteins via IFN-gamma-dependent CD4 cell immunity. J Immunol 2002;168:6099-105
  • Miconnet I König S, Speiser D. CpG are efficient adjuvants for specific CTL induction against tumor antigen-derived peptide. J Immunol 2002;168:1212-8
  • Baines J, Celis E. Immune-mediated tumor regression induced by CpG-containing oligodeoxynucleotides. Clin Cancer Res 2003;9:2693-700
  • Zou W. Regulatory T cells, tumor immunity and immunotherapy. Nat Rev Immunol 2006;6:295-307
  • Bomford R. The comparative selectivity of adjuvants for humoral and cell-mediated immunity. II. Effect on delayed-type hypersensitivity in the mouse and guinea pig, and cell-mediated immunity to tumour antigens in the mouse of Freund's incomplete and complete adjuvants, alhydrogel, Corynebacterium parvum, Bordetella pertussis, muramyl dipeptide and saponin. Clin Exp Immunol 1980;39:435-41
  • Cox FE, Liew FY. T cell subsets and cytokines in parasitic infections. Immunol Today 1992;13:445-8
  • Merritt K, Johnson AG. Studies on the adjuvant action of bacterial endotoxins of antibody formation VI. Enhancement of antibody formation by nucleic acids. J Immunol 1965;94:416-22
  • Ellouz F, Adam A, Ciorubaru R, Lederer E. Minimal structural requirements for adjuvant activity of bacterial peptidoglycan derivatives. Biochem Biophys Res Comm 1974;59:1317-25
  • Neter E. Endotoxins and the immune response. Curr Top Microbiol Immunol 1969;47:82-124
  • Ribi E, Cantrell JL, Takayama K, et al. Lipid A and immunotherapy. Rev Infect Dis 1984;6:567-72
  • Puggioni F, Durham SR, Francis JN. Monophosphoryl lipid A (MPL) promotes allergen-induced immune deviation in favour of TH1 responses. Allergy 2005;60:678-84
  • Salkowski CA, Detore GR, Vogel SN. Lipopolysaccharide and monophosphoryl lipid A differentially regulate interleukin-12, gamma interferon, and interleukin-10 mRNA production in murine macrophages. Infect Immun 1997;65:3239-47
  • Henricson BE, Manthey CL, Perera PY, et al. Dissociation of lipopolysaccharide (LPS)-inducible gene expression in murine macrophages pretreated with smooth LPS versus monophosphoryl lipid A. Infect Immun 1993;61:2325-33
  • Persing DH, Coler RN, Lacy MJ, et al. Takint toll: lipid A mimetics as adjuvants and immunomodulators. Trends Microbiol 2002;10(Suppl):S32-7
  • Cluff CW, Baldridge JR, Stöver AG, et al. Synthetic Toll-like receptor 4 agonists stimulate innate resistance to infectious challenge. Infect Immun 2005;73:3044-52
  • Thoelen S, De Clercq N, Tornieporth N. A prophylactic hepatitis B vaccine with a novel adjuvant system. Vaccine 2001;19:2400-3
  • Bienzle Günther M, Neuhaus R, Neuhaus P. Successful hepatitis B vaccination in patients who underwent transplantation for hepatitis B virus-related cirrhosis: preliminary results. Liver Transpl 2002;8:562-4
  • Dupont J, Altcla J, Lepetic A, et al. A controlled clinical trial comparing the safety and immunogenicity of a new adjuvanted hepatitis B vaccine with a standard hepatitis B vaccine. Vaccine 2006;24:7167-74
  • Harper D, Franco EL, Wheeler C, et al. Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial. Lancet 2004;364:1757-65
  • Paavonen J, Jenkins D, Bosch FX, et al. Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial. Lancet 2007;369:2161-70
  • Butts C, Murray N, Maksymiuk A, et al. Randomized phase IIB trial of BLP25 liposome vaccine in stage IIIB and IV non-small-cell lung cancer. J Clin Oncol 2005;23:6674-81
  • Powell E, Chow LQM. BLP-25 liposomal vaccine: a promising potential therapy in nonsmall-cell lung cancer. Exp Rev Resp Med 2008;2:37-45
  • Baldridge JR, McGowan P, Evans JT. Taking a toll on human disease: Toll-like receptor 4 agonists as vaccine adjuvants and monotherapeutic agents. Expert Opin Biol Ther 2004;4:1129-38
  • Alderson MR, McGowan P, Baldridge JR, Probst P. TLR4 agonists as immunomodulatory agents. J Endotoxin Res 2006;12:313-9
  • Krieg AM. Therapeutic potential of Toll-like receptor 9 activation. Nat Rev Drug Discov 2006;5:471-84
  • Krieg AM, Yi AK, Matson S, et al. CpG motifs in bacterial DNA trigger direct B cell activation. Nature 1995;374:546-9
  • Sparwasser T, Vabulas RM, Villmow B, et al. Bacterial CpG-DNA activates dendritic cells in vivo: T helper cell-independent cytotoxic T cell responses to soluble protein. Eur J Immunol 2000;30:3591-7
  • Kim SK, Ragupathi G, Musselli C, et al. Comparison of the effect of different immunological adjuvants on the antibody and T-cell response to immunization with MUC1-KLH and GD3-KLH conjugate cancer vaccines. Vaccine 2000;18:597-603
  • Cooper CL, Davis H, Morris ML, et al. CpG 7909, an immunostimulatory TLR9 agonist oligodeoxynucleotide, as adjuvant to Engerix-B HBV vaccine in nhealthy adults: a double blind phase I/II study. J Clin Immunol 2004;24:693-702
  • Siegrist CA, Philgren M, Tougne C, et al. Co-administration of CpG oligonucleotides enhances the late affinity maturation process of human anti-hepatitis B vaccine response. Vaccine 2004;23:615-22
  • Barry M, Cooper C. Review of hepatitis B surface antigen-1018 ISS adjuvant-containing vaccine safety and efficacy. Expet Opin Biol Ther 2007;7:1731-7
  • Cooper CL, Davis H, Morris ML, et al. Safety and immunogenicity of CpG 7909 injection as an adjuvant to fluarix influenza vaccine. Vaccine 2006;22:3136-43
  • Fernandez-Cruz E, Moreno S, Navarro J, et al. Therapeutic immunization with an inactivated HIV-1 immunogen plus antiretrovirals versus antiretroviral therapy alone in asymptomatic HIV-infected subjects. Vaccine 2004;22:2966-73
  • Huang KH, Boisvert MP, Chung F, et al. Longitudinal changes in HIV-specific IFN-gamma secretion in subjects who received Remune TM vaccination prior to treatment interruption. J Immune Based Ther Vaccines 2006;4:7
  • AIDSmeds.com. IR103. Available from: http://www.aidsmeds.com/archive/IR103_1645.shtml [last accessed 2 June 2008]
  • Bernstein DI, Miller RL, Harrison CJ. Adjuvant effects of imiquimod on a herpes simplex virus type 2 glycoprotein vaccine in guinea pigs. J Infect Dis 1993;167:731-6
  • Harrison CJ, Miller RL, Bernstein DI. Post-therapy suppression of genital herpes simplex virus (HSV) recurrences and enhancement of HSV-specific T cell memory by imiquimod in guinea pigs. Antimicrob Agents Chemother 1994;38:2059-65
  • Vasilakos JP, Smith RMA, Gibson SJ, et al. Adjuvant activities of immune response modifier R-848: comparison with CpG ODN. Cell Immunol 2000;204:64-74
  • Johnston D, Zaidi B, Bystryn JC. TLR7 imidazoquinoline ligand 3M-019 is a potent adjuvant for pure protein prototype vaccines. Cancer Immunol Immunother 2007;56:1133-41
  • Lui MA. DNA vaccines: a review. J Int Med 2003;253:402-10
  • Zuber AK, Brave A, Engström G, et al. Topical delivery of imiquimod to a mouse model as a novel adjuvant for human immunodeficiency virus (HIV) DNA. Vaccine 2004;22:1791-8
  • Otero M, Calarota SA, Felber B, et al. Resiquimod is a modest adjuvant for HIV-1 gag-based genetic immunization in a mouse model. Vaccine 2004;22:1782-90
  • Thomsen LL, Topley P, Daly MG, et al. Imiquimod and resiquimod in a mouse model: adjuvants for DNA vaccination by particle-mediated immunotherapeutic delivery. Vaccine 2004;22:1799-809
  • Smorlesi A, Papalini F, Orlando F, et al. Imiquimod and S-27609 as adjuvants of DNA vaccinationin a transgenic murine model of HER2/neu-positive mammary carcinoma. Gene Ther 2005;12:1324-32
  • Fong L, Engleman EG. Dendritic cells in cancer immunotherapy. Ann Rev Immunol 2000;18:245-73
  • Schuler G, Schuler-Thurner B, Steinman RM. The use of dendritic cells in cancer immunotherapy. Curr Opin Immunol 2003;15:138-47
  • Okada H, Tahara H, Shurin MR, et al. Bone marrow-derived dendritic cells pulsed with a tumor-specific peptide elicit effective anti-tumor immunity against intercranial neoplasms. Int J Cancer 1998;78:196-201
  • Yu JS, Wheeler CJ, Zeltzer PM, et al. Vaccination of malignant glioma patients with peptide-pulsed dendritic cells elicits systemic cytotoxicity and intracranial T cell infiltration. Cancer Res 2001;61:842-7
  • Pulendran B. Modulating vaccine responses with dendritic cells and Toll-like receptors. Immunol Rev 2004;199:227-50
  • Rechtsteiner G, Warger T, Osterloh P, et al. Cutting edge: priming of CTL by transcutaneous peptide immunization with imiquimod. J Immunol 2005;174:2476-80
  • Prins RM, Craft N, Bruhn KW, et al. The TLR7 agonist, imiquimod, enhances dendritic cell survival and promotes tumor antigen specific T cell priming: relation to central nervous system antitumor immunity. J Immunol 2006;176:157-63
  • Craft N, Bruhn KW, Nguyen BD, et al. The TLR7 agonist imiquimod enhances anti-melanoma effects of a recombinant Listeria monocytogenes vaccine. J Immunol 2005;175:1983-90
  • Yang Y, Huang CT, Huang X, Pardoll DM. Persistent Toll-like receptor signals are required for reversal of regulatory T cell-mediated CD8 tolerance. Nat Immunol 2004;5:508-15
  • Krieg AM, Efler SM, Wittpoth M, et al. Induction of systemic TH1-like innate immunity in normal volunteers following subcutaneous but not intravenous administration of CPG 7909, a synthetic B-class CpG oligodeoxynucleotide TLR9 agonist. J Immunother 2004;27:460-71
  • Vicari AP, Schmalbach T, Lekstrom-Himes J, et al. Safety, pharmocokinetics and immune effects in normal volunteers of CPG 10101 (ACTILON), an investigational synthetic Toll-like receptor 9 agonist. Antivir Ther 2007;12:741-51
  • Sparwasser T, Mithke T, Lipford G, et al. Bacterial DNA causes septic shock. Nature 1997;386:336-7
  • Hasegawa K, Hayashi T. Synthetic CpG oligodeoxynucleotides accelerate the development of lupus nephritis during preactive phase In NZB × NZWF1 mice. Lupus 2003;2:838-45
  • Sauder DN. Imiquimod: modes of action. Br J Dermatol 2003;149(Suppl 66):5-8
  • Harrison LI, Skinner SL, Marbury TC, et al. Pharmacokonetics and safety of imiqimod 5% cream in the treatment of actinic keratoses of the face, scalp, or hands and arms. Arch Dermatol Res 2004;296:6-11
  • Stefanaki C, Nicolaidou E, Hadjivassiliou M, et al. Imiquimod-induced vitiligo in a patient with genital warts. J Eur Acad Dermatol Venereol 2006;20:755-66
  • Mendonca CO, Yates VM. Permanent facial hypopigmentation following treatment with imiquimod cream. Clin Exp Dermatol 2006;31:721-2
  • Mashiah J, Brenner S. Possible mechanisms in the induction of pemphigus foliaceus by topical imiquimod treatment. Arch Dermatol 2005;141:908-9
  • Taylor CL, Maslen M, Kapembwa M. A case of severe eczema following use of imiquimod 5% cream. Sex Transm Infect 2006;82:227-8
  • D'Addario SD, Carrington PR. Multiple keratoakanthomas as an untoward response to imiquimod therapy for actinic keratosis. Acta Derm Venereol 2006;86:366-8
  • Rajan N, Langtry JA. Generalized exacerbation of psoriasis associated with imiquimod cream treatment of superficial basal cell carcinomas. Clin Exp Dermatol 2006;31:140-1
  • van der Fits L, van der Wel LI, Laman JD, et al. In psoriasis lesional skin the type I interferon signalling pathway is activated, whereas interferon-alpha-sensitivity is unaltered. J Invest Dermatol 2004;122:51-60
  • Siegal FP, Kadowaki N, Shodell M, et al. The nature of the principle type I interferon-producing cells in human blood. Science 1999;284:1835-7
  • Urosevic M, Dummer R, Conrad C, et al. Disease-independent skin recruitment and activation of plasmacytoid dendritic cells following imiquimod treatment. J Natl Cancer Inst 2005;97:1143-53
  • Nestle FO, Conrad C, Tun-Kyi A, et al. Plasmacytoid predendritic cells (PDC) initiate psoriasis through IFN-a production. J Exp Med 2005;202:135-43
  • Lee E, Trepicchio WL, Oesterreicher JL, et al. Increased expression of interleukin 23p19 in lesional skin of patients with psoriasis vulgaris. J Exp Med 2004;199:125-30
  • Wilson NJ, Boniface K, Chan JR, et al. Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol 2007;8:950-7
  • Chan JR, Blumenschein W, Murphy E, et al. IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis. J Exp Med 2006;203:2577-87
  • Benson E. Imiquimod: potential risk of an immunostimulant. Australas J Dermatol 2004;45:123-4
  • Iwakura Y, Ishigame H. The IL23/IL17 axis in inflammation. J Clin Invest 2006;116:1218-22
  • Baechler EC, Gregersen PK, Behrens TW. The emerging role of interferon in human systemic lupus erythematosus. Curr Opin Immunol 2004;16:801-7
  • Lau CM, Broughton C, Tabor AS, et al. RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement. J Exp Med 2005;202:1171-7
  • Ronnblom L, Alm GV. A pivotal role for the natural interferon alpha-producing cells (plasmacytoid dendritic cells) in the pathogenesis of lupus. J Exp Med 2001;194:F59-63
  • Pockros PJ, Guyader D, Patton H, et al. Oral resiquimod in chronic HCV infection: safety and efficacy in 2 placebo-controlled, double-blind phase IIa studies. J Hepatol 2007;47:174-82
  • Horsmans Y, Berg T, Desager JP, et al. Isatoribine, an agonist of TLR7, reduces plasma virus concentration in chronic hepatitis C infections. Hepatology 2005;42:724-31
  • Heil F, Ahmad-Nejad P, Hemmi H, et al. The Toll-like receptor 7 (TLR7)-specific stimulus loxoribine uncovers a strong relationship within the TLR7, 8 and 9 subfamily. Eur J Immunol 2003;33:2987-97
  • Lee J, Chuang TH, Redecke V, et al. Molecular basis for the immunostimulatory activity of guanine nucleoside analogs: activation of Toll-like receptor 7. Proc Natl Acad Sci USA 2003;100:6646-51
  • Lee J, Wu CCN, Lee KJ, et al. Activation of anti-hepatitis C virus responses via Toll-like receptor 7. Proc Natl Acad Sci USA 2006;103:1828-33
  • Gordon KB, Gorski KS, Gibson SJ, et al. Synthetic TLR agonists reveal functional differences between human TLR7 and TLR8. J Immunol 2006;174:1259-68
  • Available from: www.invivogen.com
  • Agarwala SS, Kirkwood JM, Bryant J. Phase 1, randomized, double-blind trial of 7-allyl-8-oxoguanosine (loxoribine) in advanced cancer. Cytokines Cell Mol Ther 2000;6:171-6
  • Cuadros C, Lopez-Hernandez FJ, Dominguez AL, et al. Flagellin fusion proteins as adjuvants or vaccines induce specific immune responses. Infect Immun 2004;72:2810-6
  • Huleatt JW, Jacobs AR, Tang J, et al. Vaccination with recombinant fusion proteins incorporating Toll-like receptor ligands induces rapid cellular and humoral immunity. Vaccine 2007;25:763-75
  • Wille-Reece U, Flynn BJ, Lore K, et al. HIV Gag protein conjugated to a Toll-like receptor 7/8 agonist improves the magnitude and quality of Th1 and CD8+ T cell responses in nonhuman primates. Proc Natl Acad Sci USA 2005;102:15190-4
  • Huleatt JW, Nakaar V, Desai P, et al. Potent immunogenicity and efficacy of a universal influenza caccine candidate comprising a recombinant fusion protein linking influenza M2e to the TLR5 lignad flagellin. Vaccine 2008;26:201-14

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.