Heat-Labile Enterotoxins as Adjuvants or Anti-Inflammatory Agents

REFERENCES

• Agren, L. C., Ekman, L., Lowenadler, B., Nedrud, J. G., and Lycke, N. Y. (1999). 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. 162:2432–2440.
   PubMed Web of Science ®Google Scholar
• Akira, S., Takeda, K., Kaisho, T. (2001). Toll-like receptors: critical proteins linking innate and acquired immunity. Nat. Immunol. 2:675–680.
   PubMed Web of Science ®Google Scholar
• Aman, A. T., Fraser, S., Merritt, E. A., Rodigherio, C., Kenny, M., Ahn, M., Hol, W. G. N., Williams, N. A., Lencer, W. I., Hirst, T. R. (2001). A mutant cholera toxin B subunit that binds GM1- ganglioside but lacks immunomodulatory or toxic activity. Proc. Natl. Acad. Sci. USA 98:8536–8541.
   PubMed Web of Science ®Google Scholar
• Arce, S., Nawar, H. F., Russell, M. W., Connell, T. D. (2005). 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. 73:2718–2727.
   PubMed Web of Science ®Google Scholar
• Aspord, C., Czerkinsky, C., Durand, A., Stefanutti, A., Thivolet, C. (2002). a4 Integrins and L-selectin differently orchestrate T-cell activity during diabetes prevention following oral administration of CTB-insulin. J. Autoimmun. 19:223–232.
   PubMed Web of Science ®Google Scholar
• Beutler, B., Jiang, Z., Georgel, P., Crozat, K., Croker, B., Rutschmann, S., Du, X., Hoebe, K. (2006). Genetic analysis of host resistance: Toll-like receptor signaling and immunity at large. Annu. Rev. Immunol. 24:353–389.
   PubMed Web of Science ®Google Scholar
• Brenner, S., Prosch, S., Schenke-Layland, K., Riese, U., Gausmann, U., Platzer, C. (2003). cAMP-induced Interleukin-10 promoter activation depends on CCAAT/enhancer-binding protein expression and monocytic differentiation. J. Biol. Chem. 278:5597–5604.
   PubMed Web of Science ®Google Scholar
• Bromander, A., Holmgren, J., and Lycke, N. (1991). Cholera toxin stimulates IL-1 production and enhances antigen presentation by macrophages in vitro. J. Immunol. 146:2908–2914.
   PubMed Web of Science ®Google Scholar
• Chen, C.-H., Zhang, D.-H., LaPorte, J. M., Ray, A. (2000). Cyclic AMP activates p38 mitogen-activated protein kinase in Th2 Cells: Phosphorylation of GATA-3 and stimulation of Th2 cytokine gene expression. J Immunol 165: 5597–5605.
   PubMed Web of Science ®Google Scholar
• Cong, Y., Weaver, C. T., Elson, C. O. (1997). The mucosal adjuvanticity of cholera toxin involves enhancement of costimulatory activity by selective up-regulation of B7.2 expression. J. Immunol. 159:5301–5308.
   PubMed Web of Science ®Google Scholar
• Connell, T. D. (2007). 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 6: 821–834.
   PubMed Web of Science ®Google Scholar
• Czerkinsky, C., Anjuere, F., McGhee, J. R., George-Chandy, A., Holmgren, J., Kieny, M. P., Fujiyashi, K., Mestecky, J. F., Pierrefite-Carle, V., Rask, C., Sun, J. B. (1999). Mucosal immunity and tolerance: relevance to vaccine development. Immunol. Rev. 170:197–222.
   PubMed Web of Science ®Google Scholar
• Elson, C. O., Holland, S. P., Dertzbagh, M. T., Cuff, C. F., Anderson, A. O. (1995). Morphologic and functional alterations of mucosal T cells by cholera toxin and its B subunit. J. Immunol. 154:1032–1040.
   PubMed Web of Science ®Google Scholar
• Elson, C. O., Dertzbaugh, M. T. (2005). Mucosal adjuvants. Mucosal Immunology. J. Mestecky, J. Bienenstock, M. E., Lamm. San Diego, Elsevier/Academic Press:967–986.
   Google Scholar
• Fang, X., Yu, S. X., Lu, Y., Bast, Jr., R. C., Woodgett, J. R., Mills, G. B. (2000). Phosphorylation and inactivation of glycogen synthase kinase 3 by protein kinase A. Proc. Natl. Acad. Sci. USA 97:11960–11965.
   PubMed Web of Science ®Google Scholar
• Fontana, M. R., Manetti, R., Giannelli, V., Magagnoli, C., Marchini, A., Olivieri, R., Domenighini, M., Rappuoli, R., Pizza, M. (1995). Construction of nontoxic derivatives of cholera toxin and characterization of the immunological response against the A subunit. Infect. Immun. 63:2356–2360.
   PubMed Web of Science ®Google Scholar
• Gaffen, S. L., Hajishengallis G. (2008). A new inflammatory cytokine on the block: re‐thinking periodontal disease and the Th1/Th2 paradigm in the context of Th17 cells and IL-17. J. Dent. Res. 87:817–828.
   PubMed Web of Science ®Google Scholar
• Gaupp, S., Hartung, H.-P., Toyka, K., Jung, S. (1997). Modulation of experimental autoimmune neuritis in Lewis rats by oral application of myelin antigens. J. Neuroimmunol. 79:129–137.
   PubMed Web of Science ®Google Scholar
• Gearing, A. J. H. (2007). Targeting toll-like receptors for drug development: a summary of commercial approaches. Immunol. Cell Biol. 85:490–494.
   PubMed Web of Science ®Google Scholar
• Gill, D. M., Clements, J. D., Robertson, D. C., Finkelstein, R. A. (1981). Subunit number and arrangement in Escherichia coli heat-labile enterotoxin. Infect. Immun. 33:677–682.
   PubMed Web of Science ®Google Scholar
• Hajishengallis, G., Nikolova, E., Russell, M. W. (1992). Inhibition of Streptococcus mutans adherence to saliva-coated hydroxyapatite by human secretory immunoglobulin A antibodies to the cell surface protein antigen I/II: Reversal by IgA1 protease cleavage. Infect. Immun. 60:5057–5064.
   PubMed Web of Science ®Google Scholar
• Hajishengallis, G., Nawar, H., Tapping, R. I., Russell, M. W., and Connell, T. D. (2004). 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. Infect. Immun. 72:6351–6358.
   PubMed Web of Science ®Google Scholar
• Hajishengallis, G., Arce, S., Gockel, C. M., Connell, T. D., Russell, M. W. (2005a). Immunomodulation with enterotoxins for the generation of secretory immunity or tolerance: applications for oral infections. J. Dent. Res. 84:1104–1116.
   PubMed Web of Science ®Google Scholar
• Hajishengallis, G., Tapping, R. I., Martin, M. H., Nawar, H., Lyle, E. A., Russell, M. W., Connell, T. D. (2005b). Toll-like receptor 2 mediates cellular activation by the B subunits of type II heat-labile enterotoxins. Infect. Immun. 73:1343–1349.
   PubMed Web of Science ®Google Scholar
• Hajishengallis, G., Russell, M. W. (2008). Molecular approaches to vaccination against oral infections. Molecular Oral Microbiology. A. Rogers. Norfolk, UK, Caister Academic Press: 257–285.
   Google Scholar
• Holmes, R., Jobling, M. G., Connell, T. (1995). Cholera toxin and related enterotoxins of gram-negative bacteria. Bacterial toxins and virulence factors in disease. Handbook of Natural Toxins. J. Moss, B. Iglewski, M. Vaughn and A. T. Tu. New York, Marcel Dekker, Inc. 8: 225–255.
   Google Scholar
• Holmgren, J., Lycke, N., Czerkinsky, C. (1993). Cholera toxin and cholera B subunit as oral-mucosal adjuvant and antigen vector systems. Vaccine 11:1179–1184.
   PubMed Web of Science ®Google Scholar
• Holmgren, J., Czerkinsky, C., Eriksson, K., Mharandi, A. (2003). Mucosal immunisation and adjuvants: a brief overview of recent advances and challenges. Vaccine 21 Suppl 2:S89–95.
   PubMedGoogle Scholar
• Holmgren, J., Czerkinsky, C. (2005). Mucosal immunity and vaccines. Nat. Med. 11(4 Suppl): S45–53.
   PubMed Web of Science ®Google Scholar
• Holmgren, J., Svennerholm, A.-M. (2005). Mucosal immunity to bacteria. Mucosal Immunology, 3rd Ed. J. Mestecky, J. Bienenstock, M. E. Lamm Amsterdam, Elsevier/Academic Press:783–797.
   Google Scholar
• Iwasaki, A., Medzhitov, R. (2004). Toll-like receptor control of the adaptive immune responses. Nat. Immunol. 5:987–995.
   PubMed Web of Science ®Google Scholar
• Kolls, J. K., Linden, A. (2004). Interleukin-17 family members and inflammation. Immunity 21:467–476.
   PubMed Web of Science ®Google Scholar
• Krueger, J., Ray, A., Tamm, I., Sehgal, P. B. (1991). Expression and function of interleukin-6 in epithelial cells. J. Cell. Biochem. 45:327–334.
   PubMed Web of Science ®Google Scholar
• Kwissa, M., Kasturi, S. P., Pulendran, B. (2007). The science of adjuvants. Expert Rev. Vaccines 6:673–684.
   PubMed Web of Science ®Google Scholar
• la Sala, A., He, J., Laricchia-Robbio, L., Gorini, S., Iwasaki, A., Braun, M., Yap, G. S., Sher, A., Ozato, K., Kelsall, B. (2009). Cholera toxin inhibits IL-12 production and CD8alpha+ dendritic cell differentiation by cAMP-mediated inhibition of IRF8 function. J. Exp. Med. 206:1227–1235.
   PubMed Web of Science ®Google Scholar
• Lalli, E., Sassone-Corsi, P. (1994). Signal transduction and gene regulation: the nuclear response to cAMP. J. Biol. Chem. 269:17359–17362.
   PubMed Web of Science ®Google Scholar
• Langrish, C. L., Chen, Y., Blumenschein, W. M., Mattson, J., Basham, B., Sedgwick, J. D., McClanahan, T., Kastelein, R. A., Cua, D. J. (2005). IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201:233–240.
   PubMed Web of Science ®Google Scholar
• Lavelle, E. C., McNeela, E., Armstrong, M. A., Leavy, O., Higgins, S. C., Mills, K. H. (2003). Cholera toxin promotes the induction of regulatory T cells specific for bystander antigens by modulating dendritic cell activation. J. Immunol. 171:2384–2392.
   PubMed Web of Science ®Google Scholar
• Lavelle, E. C., Jarnicki, A., McNeela, E., Armstrong, M. E., Higgins, S. C., Leavy, O., Mills, K. H. (2004). Effects of cholera toxin on innate and adaptive immunity and its application as an immunomodulatory agent. J. Leukoc. Biol. 75:756–763.
   PubMed Web of Science ®Google Scholar
• Lee, J. B., Jang, J. E., Song, M. K., Chang, J. (2009). Intranasal delivery of cholera toxin induces th17-dominated T-cell response to bystander antigens. PLoS One 4:e5190.
   PubMed Web of Science ®Google Scholar
• Liang, S., Wang, M., Tapping, R. I., Stepensky, V., Nawar, H. F., Triantafilou, M., Triantafilou, K., Connell, T. D., Hajishengallis, G. (2007a). Ganglioside GD1a is an essential coreceptor for toll-like receptor 2 signaling in response to the B subunit of Type IIb enterotoxin. J. Biol. Chem. 282:7532–7542.
   PubMed Web of Science ®Google Scholar
• Liang, S., Wang, M., Triantafilou, K., Triantafilou, M., Nawar, H. F., Russell, M. W., Connell, T. D., Hajishengallis, G. (2007b). 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. 178:4811–4819.
   PubMed Web of Science ®Google Scholar
• Liang, S., Hosur, K. B., Lu, S., Nawar, H. F., Weber, B. R., Tapping, R. I., Connell, T. D., Hajishengallis, G. (2009a). Mapping of a microbial protein domain involved in binding and activation of the TLR2/TLR1 heterodimer. J. Immunol. 182:2978–2985.
   PubMed Web of Science ®Google Scholar
• Liang, S., Hosur, K. B., Nawar, H. F., Russell, M. W., Connell, T. D., Hajishengallis, G. (2009b). In vivo and in vitro adjuvant activities of the B subunit of Type IIb heat-labile enterotoxin (LT-IIb-B5) from Escherichia coli. Vaccine 27:4302–4308.
   PubMed Web of Science ®Google Scholar
• Liu, H., Komai-Koma, M., Xu, D., Liew, F. Y. (2006). Toll-like receptor 2 signaling modulates the functions of CD4+ CD25+ regulatory T cells. Proc. Natl. Acad. Sci. USA 103:7048–7053.
   PubMed Web of Science ®Google Scholar
• Liu, Y. J., Banchereau, J. (1997). Regulation of B-cell commitment to plasma cells or to memory B cells. Semin. Immunol. 9:235–240.
   PubMedGoogle Scholar
• Luross, J. A., Heaton, T., Hirst, T. R., Day, M. J., Williams, N. A. (2002). Escherichia coli heat-labile enterotoxin B subunit prevents autoimmune arthritis through induction of regulatory CD4+ T cells. Arthritis Rheumat. 46:1671–1682.
   PubMedGoogle Scholar
• Lycke, N., Tsuji, T., Holmgren, J. (1992). The adjuvant effect of Vibrio cholerae and Escherichia coli heat-labile enterotoxins is linked to their ADP-ribosyltransferase activity. Eur. J. Immunol. 22:2277–2281.
   PubMed Web of Science ®Google Scholar
• Marinaro, M., Staats, H. F., Hiroi, T., Jackson, R. J., Coste, M., Boyaka, P. N., Okahashi, N., Yamamoto, M., Kiyono, H., Bluethmann, H., Fujihashi, K., McGhee, J. R. (1995). Mucosal adjuvant effect of cholera toxin in mice results from induction of T helper 2 (Th2) cells and IL-4. J. Immunol. 155:4621–4629.
   PubMed Web of Science ®Google Scholar
• Martin, M., Metzger, D. J., Michalek, S. M., Connell, T. D., Russell, M. W. (2000). Comparative analysis of the mucosal adjuvanticity of the type II heat-labile enterotoxins LT-IIa and LT-IIb. Infect. Immun. 68:281–287.
   PubMed Web of Science ®Google Scholar
• Martin, M., Metzger, D. J., Michalek, S. M., Connell, T. D., Russell, M. W. (2001). Distinct cytokine regulation by cholera toxin and type II heat-labile toxins involves differential regulation of CD40 ligand on CD4(+) T cells. Infect. Immun. 69:4486–4492.
   PubMed Web of Science ®Google Scholar
• Martin, M., Rehani, K., Jope, R. S., Michalek, S. M. (2005). Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3. Nat. Immunol. 6(8):777–784.
   PubMed Web of Science ®Google Scholar
• Mendel, I., Shevach, E. M. (2002). The IL-10-producing competence of Th2 cells generated in vitro is IL-4 dependent. Eur. J. Immunol. 32:3216–3224.
   PubMed Web of Science ®Google Scholar
• Mestecky, J., Nguyen, H., Czerkinsky, C., Kiyono, H. (2008). Oral immunization: an update. Curr. Opin. Gastroenterol. 24:713–719.
   PubMed Web of Science ®Google Scholar
• Munoz, E., Zubiaga, A. M., Merrow, M., Sauter, N. P., Huber, B. T. (1990). Cholera toxin discriminates between T helper 1 and 2 cells in T cell receptor-mediated activation: role of cAMP in T cell proliferation. J. Exp. Med. 172:95–103.
   PubMed Web of Science ®Google Scholar
• Murphy, C. A., Langrish, C. L., Chen, Y., Blumenschein, W., McClanahan, T., Kastelein, R. A., Sedgwick, J. D., Cua, D. J. (2003). Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J. Exp. Med. 198:1951–1957.
   PubMed Web of Science ®Google Scholar
• Nashar, T. O., Webb, H. M., Eaglestone, S., Williams, N. A., Hirst, T. R. (1996). 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. USA 93:226–230.
   PubMed Web of Science ®Google Scholar
• Nashar, T. O., Hirst, T. R., Williams, N. A. (1997). 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 91:572–578.
   PubMed Web of Science ®Google Scholar
• Nawar, H. F., Arce, S., Russell, M. W., Connell, T. D. (2005). Mucosal adjuvant properties of mutant LT-IIa and LT-IIb enterotoxins that exhibit altered ganglioside-binding activities. Infect. Immun. 73:1330–1342.
   PubMed Web of Science ®Google Scholar
• Parry, G., Mackman, N. (1997). Role of cyclic AMP response element-binding protein in cyclic AMP inhibition of NF-kB-mediated transcription. J. Immunol. 159:5450–5456.
   PubMed Web of Science ®Google Scholar
• Petrovska, L., Lopes, L., Simmons, C. P., Pizza, M., Dougan, G., Chain, B. M. (2003). Modulation of dendritic cell endocytosis and antigen processing pathways by Escherichia coli heat-labile enterotoxin and mutant derivatives. Vaccine 21:1445–1454.
   PubMed Web of Science ®Google Scholar
• Phipps, P.A., Stanford, M. R., Sun, J.-B., Xiao, B.-G., Holmgren, J., Shinnick, T., Hasan, A., Mizushima, Y., Lehner, T. (2003). Prevention of mucosally induced uveitis with a HSP60-derived peptide linked to cholera toxin B subunit. Euro. J. Immunol. 33:224–232.
   PubMed Web of Science ®Google Scholar
• Pizza, M., Domenighini, M., Hol, W., Giannelli, V., Fontana, M. R., Giuliani, M. M., Magagnoli, C., Peppoloni, S., Manetti, R., Rappuoli, R. (1994). Probing the structure-activity relationship of Escherichia coli LT-A by site-directed mutagenesis. Mol. Microbiol. 14:51–60.
   PubMed Web of Science ®Google Scholar
• Pizza, M., Giuliani, M. M., Fontana, M. R., Monaci, E., Douce, G., Dougan, G., Mills, K. H., Rappuoli, R., Del Giudice, G. (2001). Mucosal vaccines: non toxic derivatives of LT and CT as mucosal adjuvants. Vaccine 19:2534–2541.
   PubMed Web of Science ®Google Scholar
• Raveney, B. J., Richards, C., Aknin, M. L., Copland, D. A., Burton, B. R., Kerr, E., Nicholson, L. B., Williams, N. A., Dick, A. D. (2008). 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. 49:4008–4017.
   PubMed Web of Science ®Google Scholar
• Ryan, E. J., McNeela, E., Pizza, M., Rappuoli, R., O’Neill, L., Mills, K. H. (2000). Modulation of innate and acquired immune responses by Escherichia coli heat-labile toxin: distinct pro- and anti-inflammatory effects of the nontoxic AB complex and the enzyme activity. J. Immunol. 165:5750–5759.
   PubMed Web of Science ®Google Scholar
• Sad, S., Marcotte, R., Mosmann, T. R. (1995). Cytokine-induced differentiation of precursor mouse CD8+ T cells into cytotoxic CD8+ T cells secreting Th1 or Th2 cytokines. Immunity 2: 271–279.
   PubMed Web of Science ®Google Scholar
• Satchell, K. J. (2003). Activation and suppression of the proinflammatory immune response by Vibrio cholerae toxins. Microbes Infect. 5:1241–1247.
   PubMed Web of Science ®Google Scholar
• Simons, K., Toomre, D. (2000). Lipid rafts and signal transduction. Nat. Rev. Mol. Cell Biol. 1:31–39.
   PubMed Web of Science ®Google Scholar
• Sun, J.-B., Li, B.-L., Czerkinsky, C., Holmgren, J. (2000). Enhanced immunological tolerance against allograft rejection by oral administration of allogeneic antigen linked to cholera toxin B subunit. Clin. Immunol. 97:130–139.
   PubMed Web of Science ®Google Scholar
• Sun, J. B., Rask, C., Olsson, T., Holmgren, J., Czerkinsky, C. (1996). Treatment of experimental autoimmune encephalomyelitis by feeding myelin basic protein conjugated to cholera toxin B subunit. Proc. Natl. Acad. Sci. USA 93:7196–201.
   PubMed Web of Science ®Google Scholar
• Takahashi, I., Marinaro, M., Kiyono, H., Jackson, R. J., Nakagawa, I., Fujihashi, K., Hamada, S., Clements, J. D., Bost, J. K. L., McGhee, J. R. (1996). Mechanisms for mucosal immunogenicity and adjuvancy of Escherichia coli labile enterotoxin. J. Infect. Dis. 173:627–635.
   PubMed Web of Science ®Google Scholar
• Triadafilopoulos, G., Pothoulakis, C., Weiss, R., Giampaolo, C., Lamont, J. L. (1989). Comparative study of Clostridium difficile toxin A and cholera toxin in rabbit ileum. Gastroenterology 97:1186–1192.
   PubMed Web of Science ®Google Scholar
• Triantafilou, M., Miyake, K., Golenbock, D. T., Triantafilou, K. (2002). Mediators of innate immune recognition of bacteria concentrate in lipid rafts and facilitate lipopolysaccharide-induced cell activation. J. Cell Sci. 115:2603–2611.
   PubMed Web of Science ®Google Scholar
• Trinchieri, G. (2003). Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat. Rev. Immunol. 3:133–146.
   PubMed Web of Science ®Google Scholar
• van den Akker, F., Sarfaty, S., Twiddy, E. M., Connell, T. D., Holmes, R. K., Hol, W. G. (1996). Crystal structure of a new heat-labile enterotoxin, LT-IIb. Structure 4:665–678.
   PubMed Web of Science ®Google Scholar
• van Loon, F. P., Clemens, J. D., Chakraborty, J., Rao, M. R., Kay, B. A., Sack, D. A., Yunus, M., Ali, M., Svennerholm, A. M., Holmgren, J. (1996). Field trial of inactivated oral cholera vaccines in Bangladesh: results from 5 years of follow-up. Vaccine 14:162–166.
   PubMed Web of Science ®Google Scholar
• Weaver, C. T., Hatton, R. D., Mangan, P. R., Harrington, L. E. (2007). IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu. Rev. Immunol. 25:821–852.
   PubMed Web of Science ®Google Scholar
• Wilson, A. D., Robinson, A., Irons, L., Stokes, C. R. (1993). Adjuvant action of cholera toxin and pertussis toxin in the induction of IgA antibody response to orally administered antigen. Vaccine 11:113–118.
   PubMed Web of Science ®Google Scholar
• Yamamoto, M., Kiyono, H., Yamamoto, S., Batanero, E., Kweon, M. N., Otake, S., Azuma, M., Takeda, Y., McGhee, J. R. (1999). Direct effects on antigen-presenting cells and T lymphocytes explain the adjuvanticity of a nontoxic cholera toxin mutant. J. Immunol. 162:7015–7021.
   PubMed Web of Science ®Google Scholar
• Yura, M., Takahashi, I., Terawaki, S., Hiroi, T., Kweon, M.-N., Yuki, Y., Kiyono, H. (2001). Nasal administration of cholera toxin (CT) suppresses clinical signs of experimental autoimmune encephalomyelitis (EAE). Vaccine 20:134–139.
   PubMed Web of Science ®Google Scholar