Immunomodulatory regulation by heat-labile enterotoxins and potential therapeutic applications

References

• Gill DM, Clements JD, Robertson DC, et al. Subunit number and arrangement in Escherichia coli heat-labile enterotoxin. Infect Immun. 1981 Sep;33(3):677–682.
   PubMed Web of Science ®Google Scholar
• Hajishengallis G, Connell TD. Type II heat-labile enterotoxins: structure, function, and immunomodulatory properties. Vet Immunol Immunopathol. 2013Mar15;152(1–2):68–77.
   PubMed Web of Science ®Google Scholar
• Liang S, Hajishengallis G. Heat-Labile enterotoxins as adjuvants or Anti-Inflammatory agents. Immunol Invest. 2010Jan1;39(4–5):449–467.
   PubMed Web of Science ®Google Scholar
• Hatlem D, Heggelund JE, Burschowsky D, et al. 1H, 13C, 15N backbone assignment of the human heat-labile enterotoxin B-pentamer and chemical shift mapping of neolactotetraose binding. Biomol NMR Assign. 2017 Apr;11(1):99–104.
   PubMed Web of Science ®Google Scholar
• Sixma TK, Kalk KH, van Zanten BA, et al. Refined structure of Escherichia coli heat-labile enterotoxin, a close relative of cholera toxin. J Mol Biol. 1993 Apr 5;230(3):890–918.
   PubMed Web of Science ®Google Scholar
• van den Akker F, Sarfaty S, Twiddy EM, et al. Crystal structure of a new heat-labile enterotoxin, LT-IIb. Structure. 1996 Jun 15;4(6):665–678.
   PubMed Web of Science ®Google Scholar
• Created with BioRender.com [Internet]. BioRender; [2021 April 20]. [ cited 2021 Apr 20]. Available from: https://biorender.com
   Google Scholar
• Duan Q, Xia P, Nandre R, et al. Review of newly identified functions associated with the Heat-Labile toxin of enterotoxigenic Escherichia coli. Front Cell Infect Microbiol. 2019;9:292.
   PubMed Web of Science ®Google Scholar
• Lycke N, Lebrero-Fernández C. ADP-ribosylating enterotoxins as vaccine adjuvants. Curr Opin Pharmacol. 2018 Aug;41:42–51.
   PubMed Web of Science ®Google Scholar
• Arce S, Nawar HF, Russell MW, et al. Differential binding of Escherichia coli enterotoxins LT-IIa and LT-IIb and of cholera toxin elicits differences in apoptosis, proliferation, and activation of lymphoid cells. Infect Immun. 2005 May;73(5):2718–2727.
   PubMed Web of Science ®Google Scholar
• Cong Y, Weaver CT, Elson CO. The mucosal adjuvanticity of cholera toxin involves enhancement of costimulatory activity by selective up-regulation of B7.2 expression. J Immunol. 1997 Dec 1;159(11):5301–5308.
   PubMed Web of Science ®Google Scholar
• Connell TD. Cholera toxin, LT-I, LT-IIa and LT-IIb: the critical role of ganglioside binding in immunomodulation by type I and type II heat-labile enterotoxins. Expert Rev Vaccines. 2007 Oct;6(5):821–834.
   PubMed Web of Science ®Google Scholar
• Greene CJ, Chadwick CM, Mandell LM, et al. LT-IIb(T13I), a non-toxic type II heat-labile enterotoxin, augments the capacity of a ricin toxin subunit vaccine to evoke neutralizing antibodies and protective immunity. PLoS One. 2013;8(8):e69678.
   PubMed Web of Science ®Google Scholar
• Norton EB, Lawson LB, Mahdi Z, et al. The A subunit of Escherichia coli heat-labile enterotoxin functions as a mucosal adjuvant and promotes IgG2a, IgA, and Th17 responses to vaccine antigens. Infect Immun. 2012 Jul;80(7):2426–2435.
   PubMed Web of Science ®Google Scholar
• Biswas K, Richmond A, Rayman P, et al. GM2 expression in renal cell carcinoma: potential role in tumor-induced T-cell dysfunction. Cancer Res. 2006 Jul 1;66(13):6816–6825.
   PubMed Web of Science ®Google Scholar
• Liang S, Hosur KB, Nawar HF, et al. In vivo and in vitro adjuvant activities of the B subunit of Type IIb heat-labile enterotoxin (LT-IIb-B5) from Escherichia coli. Vaccine. 2009 Jul 9;27(32):4302–4308.
   PubMed Web of Science ®Google Scholar
• Lopez PHH, Schnaar RL. Gangliosides in cell recognition and membrane protein regulation. Curr Opin Struct Biol. 2009 Oct;19(5):549–557.
   PubMed Web of Science ®Google Scholar
• Nagafuku M, Okuyama K, Onimaru Y, et al. CD4 and CD8 T cells require different membrane gangliosides for activation. Proc Natl Acad Sci USA. 2012 Feb 7;109(6):E336–342.
   PubMed Web of Science ®Google Scholar
• Arce S, Nawar HF, Muehlinghaus G, et al. In vitro induction of immunoglobulin A (IgA)- and IgM-secreting plasma blasts by cholera toxin depends on T-cell help and is mediated by CD154 up-regulation and inhibition of gamma interferon synthesis. Infect Immun. 2007 Mar;75(3):1413–1423.
   PubMed Web of Science ®Google Scholar
• Iwabuchi K. Gangliosides in the immune system: role of Glycosphingolipids and Glycosphingolipid-Enriched lipid rafts in immunological functions. Methods Mol Biol. 2018;1804:83–95.
   PubMedGoogle Scholar
• Sonnino S, Chiricozzi E, Grassi S, et al. Gangliosides in membrane organization. Prog Mol Biol Transl Sci. 2018;156:83–120.
   PubMed Web of Science ®Google Scholar
• Cui X-B, Peng H, Li S, et al. Prognostic value of PLCE1 expression in upper gastrointestinal cancer: a systematic review and meta-analysis. Asian Pac J Cancer Prev. 2014;15(22):9661–9666.
   PubMedGoogle Scholar
• Julien S, Bobowski M, Steenackers A, et al. How do gangliosides regulate RTKs signaling? Cells. 2013 Dec 6;2(4):751–767.
   PubMedGoogle Scholar
• Regina Todeschini A, Hakomori S. Functional role of glycosphingolipids and gangliosides in control of cell adhesion, motility, and growth, through glycosynaptic microdomains. Biochim Biophys Acta. 2008 Mar;1780(3):421–433.
   PubMed Web of Science ®Google Scholar
• Prinetti A, Loberto N, Chigorno V, et al. Glycosphingolipid behaviour in complex membranes. Biochim Biophys Acta - Biomembr. 2009 Jan;1788(1):184–193.
   Web of Science ®Google Scholar
• Rueda R. The role of dietary gangliosides on immunity and the prevention of infection. Br J Nutr. 2007 Oct;98(Suppl 1):S68–73.
   PubMedGoogle Scholar
• Qamsari ES, Nourazarian A, Bagheri S, et al. Ganglioside as a therapy target in various types of cancer. Asian Pac J Cancer Prev. 2016 Jun 1;17(4):1643–1647.
   PubMedGoogle Scholar
• Furukawa K, Hamamura K, Aixinjueluo W, et al. Biosignals modulated by Tumor-Associated Carbohydrate antigens: novel targets for cancer therapy. Ann N Y Acad Sci. 2006 Nov 1;1086(1):185–198.
   PubMedGoogle Scholar
• Yu RK, Tsai Y-T, Ariga T, et al. Structures, biosynthesis, and functions of gangliosides--an overview. J Oleo Sci. 2011;60(10):537–544.
   PubMed Web of Science ®Google Scholar
• Krengel U, Bousquet PA. Molecular recognition of gangliosides and their potential for cancer immunotherapies. Front Immunol. 2014;5:325.
   PubMed Web of Science ®Google Scholar
• Anderson RG. The caveolae membrane system. Annu Rev Biochem. 1998;67(1):199–225.
   PubMedGoogle Scholar
• Hakomori SS. The glycosynapse. Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):225–232.
   PubMed Web of Science ®Google Scholar
• Simons K, Toomre D. Lipid rafts and signal transduction. Nat Rev Mol Cell Biol. 2000 Oct;1(1):31–39.
   PubMed Web of Science ®Google Scholar
• Merritt EA, Sarfaty S, van den Akker F, et al. Crystal structure of cholera toxin B-pentamer bound to receptor GM1 pentasaccharide. Protein Sci. 1994 Feb;3(2):166–175.
   PubMed Web of Science ®Google Scholar
• Popa I, Portoukalian J. Relationship between lipids and cutaneous immunity: example of the gangliosides. Pathol Biol. 2003 Jul;51(5):253–255.
   PubMedGoogle Scholar
• Groux-Degroote S, Guérardel Y, Gangliosides: DP, et al. Analysis, and roles in cancer. Chembiochem. 2017 Jul 4;18(13):1146–1154.
   PubMed Web of Science ®Google Scholar
• Rabu C, McIntosh R, Jurasova Z, et al. Glycans as targets for therapeutic antitumor antibodies. Future Oncol. 2012 Aug;8(8):943–960.
   PubMed Web of Science ®Google Scholar
• Martin M, Metzger DJ, Michalek SM, et al. Comparative analysis of the mucosal adjuvanticity of the type II heat-labile enterotoxins LT-IIa and LT-IIb. Infect Immun. 2000 Jan;68(1):281–287.
   PubMed Web of Science ®Google Scholar
• El-Kassas S, Faraj R, Martin K, et al. Cell clustering and delay/arrest in T-cell division implicate a novel mechanism of immune modulation by E. coli heat-labile enterotoxin B-subunits. Cell Immunol. 2015 Jun;295(2):150–162.
   PubMed Web of Science ®Google Scholar
• Hajishengallis G, Ri T, Martin MH, et al. Toll-like receptor 2 mediates cellular activation by the B subunits of type II heat-labile enterotoxins. Infect Immun. 2005 Mar;73(3):1343–1349.
   PubMed Web of Science ®Google Scholar
• Lee CH, Masso-Welch P, Hajishengallis G, et al. TLR2-dependent modulation of dendritic cells by LT-IIa-B5, a novel mucosal adjuvant derived from a type II heat-labile enterotoxin. J Leukoc Biol. 2011 Nov;90(5):911–921.
   PubMed Web of Science ®Google Scholar
• Bagley K, Xu R, Ota-Setlik A, et al. The catalytic A1 domains of cholera toxin and heat-labile enterotoxin are potent DNA adjuvants that evoke mixed Th1/Th17 cellular immune responses. Hum Vaccin Immunother. 2015;11(9):2228–2240.
   PubMed Web of Science ®Google Scholar
• Nashar TO, Betteridge ZE, Mitchell RN. Evidence for a role of ganglioside GM1 in antigen presentation: binding enhances presentation of Escherichia coli enterotoxin B subunit (EtxB) to CD4(+) T cells. Int Immunol. 2001 Apr;13(4):541–551.
   PubMed Web of Science ®Google Scholar
• Hajishengallis G, Nawar H, Tapping RI, et al. The Type II Heat-Labile enterotoxins LT-IIa and LT-IIb and their respective B pentamers differentially induce and regulate cytokine production in human monocytic cells. IAI. 2004 Nov;72(11):6351–6358.
   Google Scholar
• Liang S, Wang M, Triantafilou K, et al. The A subunit of type IIb enterotoxin (LT-IIb) suppresses the proinflammatory potential of the B subunit and its ability to recruit and interact with TLR2. J Immunol. 2007 Apr 15;178(8):4811–4819.
   PubMed Web of Science ®Google Scholar
• Czerkinsky C, Anjuere F, McGhee JR, et al. Mucosal immunity and tolerance: relevance to vaccine development. Immunol Rev. 1999 Aug;170(1):197–222.
   PubMedGoogle Scholar
• Hajishengallis G, Arce S, Gockel CM, et al. Immunomodulation with enterotoxins for the generation of secretory immunity or tolerance: applications for oral infections. J Dent Res. 2005 Dec;84(12):1104–1116.
   PubMed Web of Science ®Google Scholar
• Connell TD, Metzger D, Sfintescu C, et al. Immunostimulatory activity of LT-IIa, a type II heat-labile enterotoxin of Escherichia coli. Immunol Lett. 1998 Jun;62(2):117–120.
   PubMed Web of Science ®Google Scholar
• Nawar HF, Arce S, Russell MW, et al. Mucosal adjuvant properties of mutant LT-IIa and LT-IIb enterotoxins that exhibit altered ganglioside-binding activities. Infect Immun. 2005 Mar;73(3):1330–1342.
   PubMed Web of Science ®Google Scholar
• la Sala A, He J, Laricchia-Robbio L, et al. Cholera toxin inhibits IL-12 production and CD8alpha+ dendritic cell differentiation by cAMP-mediated inhibition of IRF8 function. J Exp Med. 2009 Jun 8;206(6):1227–1235.
   PubMed Web of Science ®Google Scholar
• Martin M, Metzger DJ, Michalek SM, et al. Distinct cytokine regulation by cholera toxin and type II heat-labile toxins involves differential regulation of CD40 ligand on CD4(+) T cells. Infect Immun. 2001 Jul;69(7):4486–4492.
   PubMed Web of Science ®Google Scholar
• Tsai H-C, Velichko S, Lee S, et al. Cholera toxin enhances interleukin-17A production in both CD4+ and CD8+ cells via a cAMP/protein kinase A-mediated interleukin-17A promoter activation. Immunology. 2018 Jul;154(3):500–509.
   PubMed Web of Science ®Google Scholar
• Takahashi I, Marinaro M, Kiyono H, et al. Mechanisms for Mucosal immunogenicity and adjuvancy of Escherichia coli labile enterotoxin. J Infect Dis. 1996 Mar 1;173(3):627–635.
   PubMed Web of Science ®Google Scholar
• Petrovska L, Lopes L, Simmons CP, et al. Modulation of dendritic cell endocytosis and antigen processing pathways by Escherichia coli heat-labile enterotoxin and mutant derivatives. Vaccine. 2003 Mar 28;21(13–14):1445–1454.
   PubMed Web of Science ®Google Scholar
• Nawar HF, Greene CJ, Lee CH, et al. LT-IIc, a new member of the type II heat-labile enterotoxin family, exhibits potent immunomodulatory properties that are different from those induced by LT-IIa or LT-IIb. Vaccine. 2011 Jan;29(4):721–727.
   PubMed Web of Science ®Google Scholar
• Martin M, Hajishengallis G, Metzger DJ, et al. Recombinant antigen-enterotoxin A2/B chimeric mucosal immunogens differentially enhance antibody responses and B7-dependent costimulation of CD4(+) T cells. Infect Immun. 2001 Jan;69(1):252–261.
   PubMed Web of Science ®Google Scholar
• Huang J, Duan Q, Zhang W. Significance of enterotoxigenic Escherichia coli (ETEC) Heat-Labile toxin (LT) Enzymatic subunit epitopes in LT enterotoxicity and immunogenicity. Appl Environ Microbiol. 2018 Aug 1;84(15). https://doi.org/10.1128/AEM.00849-18.
   Google Scholar
• Norton EB, Branco LM, Clements JD. Evaluating the A-subunit of the Heat-Labile Toxin (LT) as an immunogen and a protective antigen against enterotoxigenic Escherichia coli (ETEC). PLoS One. 2015;10(8):e0136302.
   PubMed Web of Science ®Google Scholar
• Agren LC, Ekman L, Löwenadler B, et al. Adjuvanticity of the cholera toxin A1-based gene fusion protein, CTA1-DD, is critically dependent on the ADP-ribosyltransferase and Ig-binding activity. J Immunol. 1999 Feb 15;162(4):2432–2440.
   PubMed Web of Science ®Google Scholar
• Hu JC, Greene CJ, King-Lyons ND, et al. The divergent CD8+ T cell adjuvant properties of LT-IIb and LT-IIc, two Type II Heat-Labile enterotoxins, are conferred by their ganglioside-Binding B subunits. PLoS One. 2015;10(11):e0142942.
   Google Scholar
• Greene CJ, Hu JC, Vance DJ, et al. Enhancement of humoral immunity by the type II heat-labile enterotoxin LT-IIb is dependent upon IL-6 and neutrophils. J Leukoc Biol. 2016 Aug;100(2):361–369.
   PubMed Web of Science ®Google Scholar
• Vance DJ, Greene CJ, Rong Y, et al. Comparative adjuvant effects of Type II Heat-Labile enterotoxins in combination with two different candidate ricin toxin vaccine antigens. Clin Vaccine Immunol. 2015 Dec;22(12):1285–1293.
   PubMed Web of Science ®Google Scholar
• Nashar TO, Hirst TR, Williams NA. Modulation of B-cell activation by the B subunit of Escherichia coli enterotoxin: receptor interaction up-regulates MHC class II, B7, CD40, CD25 and ICAM-1. Immunology. 1997 Aug;91(4):572–578.
   PubMed Web of Science ®Google Scholar
• Turcanu V, Hirst TR, Williams NA. Modulation of human monocytes by Escherichia coli heat-labile enterotoxin B-subunit; altered cytokine production and its functional consequences. Immunology. 2002 Jul;106(3):316–325.
   PubMed Web of Science ®Google Scholar
• Matousek MP, Nedrud JG, Harding CV. Distinct effects of recombinant cholera toxin B subunit and holotoxin on different stages of class II MHC antigen processing and presentation by macrophages. J Immunol. 1996 Jun 1;156(11):4137–4145.
   PubMed Web of Science ®Google Scholar
• Nashar TO, Webb HM, Eaglestone S, et al. Potent immunogenicity of the B subunits of Escherichia coli heat-labile enterotoxin: receptor binding is essential and induces differential modulation of lymphocyte subsets. Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):226–230.
   PubMed Web of Science ®Google Scholar
• Scharton-Kersten T, Yu JM, Vassell R, et al. Transcutaneous immunization with bacterial ADP-ribosylating exotoxins, subunits, and unrelated adjuvants. Infect Immun. 2000 Sep;68(9):5306–5313.
   PubMed Web of Science ®Google Scholar
• Chong C, Friberg M, Clements JD. LT(R192G), a non-toxic mutant of the heat-labile enterotoxin of Escherichia coli, elicits enhanced humoral and cellular immune responses associated with protection against lethal oral challenge with Salmonella spp. Vaccine. 1998 Apr;16(7):732–740.
   PubMed Web of Science ®Google Scholar
• Douce G, Giannelli V, Pizza M, et al. Genetically detoxified mutants of heat-labile toxin from Escherichia coli are able to act as oral adjuvants. Infect Immun. 1999 Sep;67(9):4400–4406.
   PubMed Web of Science ®Google Scholar
• Giuliani MM, Del Giudice G, Giannelli V, et al. Mucosal adjuvanticity and immunogenicity of LTR72, a novel mutant of Escherichia coli heat-labile enterotoxin with partial knockout of ADP-ribosyltransferase activity. J Exp Med. 1998 Apr 6;187(7):1123–1132.
   PubMed Web of Science ®Google Scholar
• Norton EB, Lawson LB, Freytag LC, et al. Characterization of a mutant Escherichia coli heat-labile toxin, LT(R192G/L211A), as a safe and effective oral adjuvant. Clin Vaccine Immunol. 2011 Apr;18(4):546–551.
   PubMedGoogle Scholar
• Petrovsky N. Comparative safety of vaccine adjuvants: a summary of current evidence and future needs. Drug Saf. 2015 Nov;38(11):1059–1074.
   PubMed Web of Science ®Google Scholar
• Lavelle EC, Jarnicki A, McNeela E, et al. Effects of cholera toxin on innate and adaptive immunity and its application as an immunomodulatory agent. J Leukoc Biol. 2004 May;75(5):756–763.
   PubMed Web of Science ®Google Scholar
• Lei Y, Zhao F, Shao J, et al. Application of built-in adjuvants for epitope-based vaccines. PeerJ. 2019;6:e6185.
   PubMed Web of Science ®Google Scholar
• Odumosu O, Nicholas D, Yano H, et al. AB toxins: a paradigm switch from deadly to desirable. Toxins (Basel). 2010 Jul;2(7):1612–1645.
   PubMed Web of Science ®Google Scholar
• Ríos-Huerta R, Monreal-Escalante E, Govea-Alonso DO, et al. Expression of an immunogenic LTB-based chimeric protein targeting Zaire ebolavirus epitopes from GP1 in plant cells. Plant Cell Rep. 2017 Feb;36(2):355–365.
   PubMed Web of Science ®Google Scholar
• Do VT, Jang J, Park J, et al. Recombinant adenovirus carrying a core neutralizing epitope of porcine epidemic diarrhea virus and heat-labile enterotoxin B of Escherichia coli as a mucosal vaccine. Arch Virol. 2020 Mar;165(3):609–618.
   PubMed Web of Science ®Google Scholar
• Byrd W. Mucosal immunization of BALB/c mice using enterotoxigenic Escherichia coli colonization factors CFA/I and CS6 administered with and without a mutant heat-labile enterotoxin. Vaccine. 2003 May;21(17–18):1884–1893.
   PubMed Web of Science ®Google Scholar
• Riddle MS, Maciel M, Porter CK, et al. A first in human clinical trial assessing the safety and immunogenicity of transcutaneously delivered enterotoxigenic Escherichia coli fimbrial tip adhesin with heat-labile enterotoxin with mutation R192G. Vaccine. 2020 Oct;38(45):7040–7048.
   PubMed Web of Science ®Google Scholar
• Rollenhagen JE, Jones F, Hall E, et al. Establishment, validation, and application of a new world primate model of enterotoxigenic Escherichia coli disease for vaccine development. Infect Immun. 2019 Feb;87(2). https://doi.org/10.1128/IAI.00634-18.
   Google Scholar
• Luiz WB, Rodrigues JF, Crabb JH, et al. Maternal vaccination with a Fimbrial Tip Adhesin and passive protection of neonatal mice against lethal human enterotoxigenic Escherichia coli challenge. Young VB, editor. Infect Immun. 2015 Dec;83(12):4555–4564.
   PubMed Web of Science ®Google Scholar
• Akhtar M, Qadri F, Bhuiyan TR, et al. Kinetics of antibody-secreting cell and fecal IgA responses after oral cholera vaccination in different age groups in a cholera endemic country. Vaccine. 2017 Jan 5;35(2):321–328.
   PubMed Web of Science ®Google Scholar
• Pan S-C, Hsieh S-M, Lin C-F, et al. A randomized, double-blind, controlled clinical trial to evaluate the safety and immunogenicity of an intranasally administered trivalent inactivated influenza vaccine with adjuvant LTh(αK): a phase I study. Vaccine. 2019 Mar 28;37(14):1994–2003.
   PubMed Web of Science ®Google Scholar
• Behrens RH, Cramer JP, Jelinek T, et al. Efficacy and safety of a patch vaccine containing heat-labile toxin from Escherichia coli against travellers’ diarrhoea: a phase 3, randomised, double-blind, placebo-controlled field trial in travellers from Europe to Mexico and Guatemala. Lancet Infect Dis. 2014 Mar;14(3):197–204.
   PubMed Web of Science ®Google Scholar
• Frech SA, DuPont HL, Bourgeois AL, et al. Use of a patch containing heat-labile toxin from Escherichia coli against travellers’ diarrhoea: a phase II, randomised, double-blind, placebo-controlled field trial. Lancet. 2008 Jun;371(9629):2019–2025.
   PubMed Web of Science ®Google Scholar
• Steffen R, Cramer JP, Burchard G, et al. Efficacy of a travelers’ diarrhea vaccine system in travelers to India. J Travel Med. 2013 Dec;20(6):374–379.
   PubMed Web of Science ®Google Scholar
• McKenzie R, Bourgeois AL, Frech SA, et al. Transcutaneous immunization with the heat-labile toxin (LT) of enterotoxigenic Escherichia coli (ETEC): protective efficacy in a double-blind, placebo-controlled challenge study. Vaccine. 2007 May 4;25(18):3684–3691.
   PubMed Web of Science ®Google Scholar
• Facciabene A, Aurisicchio L, Elia L, et al. Vectors encoding carcinoembryonic antigen fused to the B subunit of heat-labile enterotoxin elicit antigen-specific immune responses and antitumor effects. Vaccine. 2007 Dec 21;26(1):47–58.
   PubMed Web of Science ®Google Scholar
• Masso-Welch P, Girald BS, King-Lyons ND, et al. LT-IIc, A bacterial Type II Heat-Labile enterotoxin, induces specific lethality in triple negative breast cancer cells by modulation of autophagy and induction of apoptosis and necroptosis. Int J Mol Sci. 2018 Dec 26;20(1):85.
   PubMed Web of Science ®Google Scholar
• Aspord C, Thivolet C. Nasal administration of CTB-insulin induces active tolerance against autoimmune diabetes in non-obese diabetic (NOD) mice: nasal tolerance in NOD mice. Clin Exp Immunol. 2002 Nov;130(2):204–211.
   PubMed Web of Science ®Google Scholar
• Gong Z, Pan L, Le Y, et al. Glutamic acid decarboxylase epitope protects against autoimmune diabetes through activation of Th2 immune response and induction of possible regulatory mechanism. Vaccine. 2010 May;28(24):4052–4058.
   PubMed Web of Science ®Google Scholar
• Kim N, Cheng KC, Kwon SS, et al. Oral administration of collagen conjugated with cholera toxin induces tolerance to type II collagen and suppresses chondritis in an animal model of autoimmune ear disease. Ann Otol Rhinol Laryngol. 2001 Jul;110(7 Pt 1):646–654.
   PubMed Web of Science ®Google Scholar
• Sun JB, Xiao BG, Lindblad M, et al. Oral administration of cholera toxin B subunit conjugated to myelin basic protein protects against experimental autoimmune encephalomyelitis by inducing transforming growth factor-β-secreting cells and suppressing chemokine expression. Int Immunol. 2000 Oct;12(10):1449–1457.
   PubMed Web of Science ®Google Scholar
• Scerbo MJ, Rupil LL, Bibolini MJ, et al. Protective effect of a synapsin peptide genetically fused to the B subunit of Escherichia coli heat-labile enterotoxin in rat autoimmune encephalomyelitis. J Neurosci Res. 2009 Aug 1;87(10):2273–2281.
   PubMed Web of Science ®Google Scholar
• Phipps PA, Stanford MR, Sun J-B, et al. Prevention of mucosally induced uveitis with a HSP60-derived peptide linked to cholera toxin B subunit. Eur J Immunol. 2003 Jan;33(1):224–232.
   PubMed Web of Science ®Google Scholar
• Raveney BJE, Richards C, Aknin M-L, et al. The B subunit of Escherichia coli Heat-Labile enterotoxin inhibits Th1 but not Th17 cell responses in established experimental autoimmune uveoretinitis. Invest Ophthalmol Vis Sci. 2008 Sep;49(9):4008–4017.
   PubMed Web of Science ®Google Scholar
• Kap YS, van Driel N, Arends R, et al. Immune modulation by a tolerogenic myelin oligodendrocyte glycoprotein (MOG)10-60 containing fusion protein in the marmoset experimental autoimmune encephalomyelitis model. Clin Exp Immunol. 2015 Apr;180(1):28–39.
   PubMed Web of Science ®Google Scholar
• Consonni A, Sharma S, Schön K, et al. A novel approach to reinstating tolerance in experimental autoimmune Myasthenia Gravis using a targeted fusion protein, mCTA1-T146. Front Immunol. 2017;8:1133.
   PubMed Web of Science ®Google Scholar
• Hansson C, Schön K, Kalbina I, et al. Feeding transgenic plants that express a tolerogenic fusion protein effectively protects against arthritis. Plant Biotechnol J. 2016 Apr;14(4):1106–1115.
   PubMed Web of Science ®Google Scholar
• Varian BJ, Poutahidis T, Haner G, et al. Consuming cholera toxin counteracts age-associated obesity. Oncotarget. 2019 Sep 17;10(53):5497–5509.
   PubMedGoogle Scholar