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A New Approach to Vaccine Adjuvants

Immunopotentiation by Intracellular T-Helper-Like Signals Transmitted by Loxoribine

  • Chapter
Vaccine Design

Part of the book series: Pharmaceutical Biotechnology ((PBIO,volume 6))

Abstract

Vaccination with innocuous antigens derived from pathogenic microorganisms is designed to provide protection against the significant morbidity and mortality associated with diseases caused by these pathogens. Vaccination is most important precisely in those patients who are most likely to have difficulty mounting an adequate immune response either to the intact pathogen or to the vaccinating antigen, that is, those patients with acquired permanent or temporary immunodeficiencies. These patients manifest defects in one or more cell lineages that can involve deficient antigen processing, antigen presentation in the context of appropriate major histocompatibility antigen (MHC) molecules, transmembrane signal transduction, signal transmission, cytokine generation, cytokine receptors, and so forth. Among the striking advantages of the compounds discussed in this chapter is the ability to overcome or ameliorate many obstacles to effective immune responses against the epitopes of pathogenic microorganisms. This property appears to be unique to the 7,8-disubstituted guanine nucleosides.

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References

  • Agarwala, S., Kirkwood, J. M., Bryant, J., Abels, R., and Troetschel, M., 1992, A double blind, phase I placebo-controlled study of the safety, pharmacokinetics, and immunological effect of single, ascending doses of 7-allyl-8-oxoguanosine in patients with advanced cancer, Proc. Am. Assoc. Cancer Res. 33:263 (abstract 1576).

    Google Scholar 

  • Ahmad, A., and Mond, J. J., 1984, Restoration of TNP-ficoll induced in vitro immune responsiveness in B cells from xid immune defective mice and in neonatal mice by 8-thioguanosine (8-sGuo), Fed. Proc. 43:1424 (abstract 49).

    Google Scholar 

  • Ahmad, A., and Mond, J. J., 1986, Restoration of in vitro responsiveness of xid B cells to TNP-ficoll by 8-mercaptoguanosine, J. Immunol. 136:1223–1226.

    PubMed  CAS  Google Scholar 

  • Bijsterbosch, M. K., Meade, C. J., Turner, G. A., and Klaus, G. G. B., 1985, B lymphocyte receptor and polyphosphoinositide degradation, Cell 41:999–1006.

    Article  PubMed  CAS  Google Scholar 

  • Braun, J., Citri, Y., Baltimore, D., Forouzanpour, F., King, L., Teheranizadeh, K., Bray, M., and Kliewer, S., 1986, B-Lyl cells: Immortal Ly-1+ B lymphocyte cell lines spontaneously arising in murine splenic cultures, Immunol. Rev. 93:5–21.

    Article  PubMed  CAS  Google Scholar 

  • Burleson, D. G., and Sage, H. J., 1976, Effect of lectins on the level of cAMP and cGMP in guinea pig lymphocytes: early responses of lymph node cells to mitogenic and non-mitogenic lectins. J. Immunol. 116:696–702.

    PubMed  CAS  Google Scholar 

  • Callard, R. E., Booth, R. J., Brown, M. H., and McCaughan, G. W., 1985, T cell-replacing factor in specific antibody responses to influenza virus by human blood B cells, Eur. J. Immunol. 15:52–59.

    Article  PubMed  CAS  Google Scholar 

  • Chen, R., Goodman, M. G., Argentieri, D., Bell, S. C., Burr, L. E., Come, J., Goodman, J. H., Klaubert, D. H., Maryanoff, B. E., Pope, B. L., Rampulla, M. S., Schott, M. R., and Reitz, A. B., 1994, Guanosine derivatives as immunostimulants. Discovery of loxoribine, Nucleosides Nucleotides 13:551–562.

    Article  Google Scholar 

  • Coffey R. G., Hadden E. M., and Hadden, J. W., 1977, Evidence for cyclic GMP and calcium mediation of lymphocyte activation by mitogens, J. Immunol. 119:1387–1394.

    PubMed  CAS  Google Scholar 

  • Coggeshall, K. M., and Cambier, J. C., 1984, B cell activation. VIII. Membrane immunoglobulins transduce signals via activation of phosphatidylinositol hydrolysis, J. Immunol. 133:3382–3386.

    PubMed  CAS  Google Scholar 

  • Diamantstein, T., and Ulmer, A., 1975, The antagonistic action of cyclic GMP and cyclic AMP on proliferation of B and T lymphocytes, Immunology 28:113–120.

    PubMed  CAS  Google Scholar 

  • Dosch, H.-M., Osundwa, V., and Lam, P., 1988, Activation of human B lymphocytes by 8′ substituted guanosine derivatives, Immunol. Lett. 17:125–131.

    Article  PubMed  CAS  Google Scholar 

  • Ellis, T. M., Fisher, R. I., Bodner, B., and Anderson, D. W., 1990, Enhancement of human lymphokine activated killer cell induction by a guanosine ribonucleoside, Proc. Am. Assoc. Cancer Res. 31:280 (abstract 1661).

    Google Scholar 

  • Feldbush, T. L., and Ballas, Z. K., 1985, Lymphokine-like activity of 8-mercaptoguanosine: Induction of T and B cell differentiation, J. Immunol. 134:3204–3211.

    PubMed  CAS  Google Scholar 

  • Feuerstein, N., and Mond, J. J., 1987a, “Numatrin” a nuclear matrix protein associated with induction of proliferation in B cells, J. Biol. Chem. 262: 11389–11397.

    PubMed  CAS  Google Scholar 

  • Feuerstein, N., and Mond, J. J., 1987b, Identification of a prominent nuclear protein associated with proliferation of normal and malignant B cells, J. Immunol. 139:1818–1822.

    PubMed  CAS  Google Scholar 

  • Goodman, M. G., 1985, Demonstration of T-cell-dependent and T-cell independent components of 8-mercaptbguanosine-mediated adjuvanticity, Proc. Soc. Exp. Biol. Med. 179:479–486.

    PubMed  CAS  Google Scholar 

  • Goodman, M. G., 1986a, Mechanism of synergy between T cell signals and C8-substituted guanine nucleosides in humoral immunity: B-lymphotropic cytokines induce responsiveness to 8-mercaptoguanosine, J. Immunol. 136:3335–3340.

    PubMed  CAS  Google Scholar 

  • Goodman, M. G., 1986b, Regulation of B cell activation by Prostaglandins: Cell cycle-specific effects on activation by anti-immunoglobulin and 8-mercaptoguanosine, J. Immunol. 137:3753–3757.

    PubMed  CAS  Google Scholar 

  • Goodman, M. G., 1987, Interaction between cytokines and 8-mercaptoguanosine in humoral immunity: Synergy with interferon, J. Immunol. 139:142–146.

    PubMed  CAS  Google Scholar 

  • Goodman, M. G., 1988a, Induction of interleukin 1 activity from macrophages by direct interaction with C8-substituted guanine ribonucleosides, Int. J. Immunopharmacol. 10:579–586.

    Article  PubMed  CAS  Google Scholar 

  • Goodman, M. G., 1988b, Role of salvage and phosphorylation in the immunostimulatory activity of C8-substituted guanine ribonucleosides, J. Immunol. 141:2394–2399.

    PubMed  CAS  Google Scholar 

  • Goodman, M. G., 1990, Demonstration of binding components specific for 7,8-disubstituted guanine ribonucleosides in murine B lymphocytes, J. Biol. Chem. 265:22467–22473.

    PubMed  CAS  Google Scholar 

  • Goodman, M. G., 1991, Cellular and biochemical studies of substituted guanine ribonucleoside immunostimulants, Immunopharmacology 21:51–68.

    Article  PubMed  CAS  Google Scholar 

  • Goodman, M. G., and Cherry, D. M., 1989, Ligand binding sites for a synthetic B cell growth and differentiation factor, Cell. Immunol. 123:417–426.

    Article  PubMed  CAS  Google Scholar 

  • Goodman, M. G., and Hennen, W. J., 1986, Distinct effects of dual substitution on inductive and differentiative activities of C8-substituted guanine ribonucleosides, Cell. Immunol. 102:395–402.

    Article  PubMed  CAS  Google Scholar 

  • Goodman, M. G., and Weigle, W. O., 1981, Activation of lymphocytes by brominated nucleoside and cyclic nucleotide analogues: Implications for the “second messenger” function of cyclic GMP, Proc. Natl. Acad. Sci. USA 78:7604–7608.

    Article  PubMed  CAS  Google Scholar 

  • Goodman, M. G., and Weigle, W. O., 1982a, Bromination of guanosine and cyclic GMP confers resistance to metabolic processing by B cells, J. Immunol. 129:2715–2717.

    PubMed  CAS  Google Scholar 

  • Goodman, M. G., and Weigle, W. O., 1982b, Induction of immunoglobulin secretion by a simple nucleoside derivative, J. Immunol. 128:2399–2404.

    PubMed  CAS  Google Scholar 

  • Goodman, M. G., and Weigle, W. O., 1983a, Manifold amplification of in vivo immunity in normal and immunodeficient mice by ribonucleosis derivatized at C8 of guanine, Proc. Natl. Acad. Sci. USA 80:3452–3455.

    Article  PubMed  CAS  Google Scholar 

  • Goodman, M. G., and Weigle, W. O., 1983b, Derivatized guanine nucleosides: A new class of adjuvant for in vitro antibody responses, J. Immunol. 130:2580–2585.

    PubMed  CAS  Google Scholar 

  • Goodman, M. G., and Weigle, W. O., 1983c, T cell-replacing activity of C8-derivatized guanine ribonucleosides, J. Immunol. 130:2042–2045.

    PubMed  CAS  Google Scholar 

  • Goodman, M. G., and Weigle, W. O., 1983d, Activation of lymphocytes by a thiol-derivatized nucleoside: Characterization of cellular parameters and responsive subpopulations, J. Immunol. 130:551–557.

    PubMed  CAS  Google Scholar 

  • Goodman, M. G., and Weigle, W. O., 1984a, Regulation of B lymphocyte proliferative responses by arachidonate metabolites: Effects on membrane-directed versus intracellular activators, J. Allergy Clin. Immunol. 74:418–425.

    Article  PubMed  CAS  Google Scholar 

  • Goodman, M. G., and Weigle, W. O., 1984b, Intracellular lymphocyte activation and carrier-mediated transport of C8-substituted guanine ribonucleosides, Proc. Natl. Acad. Sci. USA 81:862–866.

    Article  PubMed  CAS  Google Scholar 

  • Goodman, M. G., and Weigle, W. O., 1984c, Mechanism of 8-mercaptoguanosine mediated adjuvanticity: Roles of clonal expansion and cellular recruitment, J. Immunol. 133:2910–2914.

    PubMed  CAS  Google Scholar 

  • Goodman, M. G., and Weigle, W. O., 1985a, Dissociation of inductive from differentiative signals transmitted by C8-substituted guanine ribonucleosides to B cells from SJL mice, J. Immunol. 134:91–94.

    PubMed  CAS  Google Scholar 

  • Goodman, M. G., and Weigle, W. O., 1985b, Enhancement of the human antibody response by C8-substituted guanine ribonucleosides in synergy with interleukin 2, J. Immunol. 135:3284–3288.

    PubMed  CAS  Google Scholar 

  • Goodman, M. G., and Weigle, W. O., 1986, Enhancement of T cell proliferation and differentiation by 8-mercaptoguanosine, in: Purine and Pyrimidine Metabolism in Man V (W. L. Nyhan, L. F. Thompson, and R. W. E. Watts, eds.), Plenum Press, New York, pp. 443–449.

    Chapter  Google Scholar 

  • Goodman, M. G., Speizer, L., Bokoch, G. M., Kanter, J., and Brunton, L. L., 1990, Activity of an intracellular lymphocyte stimulator is independent of G-protein interactions, [Ca2+]i elevation, phosphoinositide hydrolysis, and protein kinase C translocation, J. Biol. Chem. 265:12248–12252.

    PubMed  CAS  Google Scholar 

  • Goodman, M. G., Gupta, S., Rosenthale, M. E., Capetola, R. J., Bell, S. C., and Weigle, W. O., 1991, C-kinase independent restoration of specific immune responsiveness in common variable immunodeficiency, Clin. Immunol. Immunopathol. 59:26–36.

    Article  PubMed  CAS  Google Scholar 

  • Greene, D.A., Lattimer, S.A., and Sima, A.A.F., 1987, Sorbitol, phosphoinositides, and sodium-potassium-ATPase in the pathogenesis of diabetic complications, N. Engl. J. Med. 316:599–606.

    Article  PubMed  CAS  Google Scholar 

  • Griffioen, A. W., Toebes, E. A. H., Zegers, B. J. M., and Rijkers, G. T., 1992, Role of CR2 in the human adult and neonatal in vitro antibody response to type 4 pneumococcal Polysaccharide, Cell. Immunol. 143:11–22.

    Article  PubMed  CAS  Google Scholar 

  • Grupp, S. A., Snow, E. C., and Harmony, J. A. K., 1987, The phosphatidylinositol response is an early event in the physiologically relevant activation of antigen-specific B lymphocytes, Cell. Immunol. 109:181–191.

    Article  PubMed  Google Scholar 

  • Jin, A., Mhaskar, S., Jolley, W. B., Robins, R. K., and Ojo-Amaize, E. A., 1990, A novel guanosine analogue, 7-thia-8-oxoguanosine, enhances macrophage and lymphocyte antibody-dependent cell mediated cytotoxicity, Cell. Immunol. 126:414–419.

    Article  PubMed  CAS  Google Scholar 

  • Koo, G. C., Jewell, M. E., Manyak, C. L., Sigal, N. H., and Wicker, L. S., 1988, Activation of murine natural killer cells and macrophages by 8-bromoguanosine, J. Immunol. 140:3249–3252.

    PubMed  CAS  Google Scholar 

  • Mond, J. J., Feuerstein, N., Finkelman, F. D., Huang, F., Huang, K.-P., and Dennis, G., 1987, B-lymphocyte activation mediated by anti-immunoglobulin antibody in the absence of protein kinase C, Proc. Natl. Acad. Sci. USA 84:8588–8592.

    Article  PubMed  CAS  Google Scholar 

  • Mond, J. J., Hunter, K., Kenny, J. J., Finkelman, F., and Witherspoon, K., 1989, 8-Mercaptoguanosine-mediated enhancement of in vivo IgG1, IgG2 and IgG3 antibody responses to Polysaccharide antigens in normal and xid mice, Immunopharmacology 18:205–212.

    Article  PubMed  CAS  Google Scholar 

  • Phillips, N. E., and Campbell, P. A., 1982, IgG subclass distribution of anti-sheep red blood cell plaqueforming cells in mice with the CBA/N defect, J. Immunol. 128:2319–2321.

    PubMed  CAS  Google Scholar 

  • Physicians Desk Reference, 1994, 48th ed., Medical Economics Data, Montvale, NJ, pp. 1534-1537.

    Google Scholar 

  • Pope, B. L., Chourmouzis, E., Capetola, R. J., and Lau, C. Y., 1992a, Activation of NK cells by loxoribine, Int. J. Immunopharmacol. 14:1375–1382.

    Article  PubMed  CAS  Google Scholar 

  • Pope, B. L., Chourmouzis, E., Sigindere, J., and MacIntyre, J. P., 1992b, In vivo activation of natural killer cells and priming of IL-2 responsive cytolytic cells by loxoribine (7-allyl-8-oxoguanosine), Cell. Immunol. 147:302–312.

    Article  Google Scholar 

  • Pope, B. L., Chourmouzis, E., Victorino, L., Maclntyre, J. P., Capetola, R. J., and Lau, C. Y., 1993, Loxoribine (7-allyl-8-oxoguanosine) activates natural killer cells and primes cytolytic precursor cells for activation by IL-2, J. Immunol. 151:3007–3017.

    PubMed  CAS  Google Scholar 

  • Pope, B. L., Sigindere, J., Chourmouzis, E., Maclntyre, P., and Goodman, M. G., 1994a, 7-Allyl-8-oxoguanosine (loxoribine) inhibits the metastasis of B16 melanoma cells and has adjuvant activity in mice immunized with a B16 tumor vaccine, Cancer Immunol. Immunother. 38:83–91.

    Article  PubMed  CAS  Google Scholar 

  • Pope, B. L., Chourmouzis, E., Maclntyre, J. P., Lee, S., and Goodman, M. G., 1994b, Murine strain variation in the natural killer cell and proliferative responses to the immunostimulatory compound 7-allyl-8-oxoguanosine: Role of cytokines, Cell. Immunol. 159:194–210.

    Article  PubMed  CAS  Google Scholar 

  • Quintans, J., and Kaplan, R. B., 1978, Failure of CBA/N mice to respond to thymus-dependent and thymus-independent phosphorylcholine antigens, Cell. Immunol. 38:294–301.

    Article  PubMed  CAS  Google Scholar 

  • Ransom, J. T., Chen, M., Sandoval, V. M., Pasternak, J. A., Digiusto, D., and Cambier, J. C., 1988, Increased plasma membrane permeability to Ca2+ in anti-Ig-stimulated B lymphocytes is dependent on activation of phosphoinositide hydrolysis, J. Immunol. 140:3150–3155.

    PubMed  CAS  Google Scholar 

  • Rijkers, G. T., Dollekamp, I., and Zegers, B. J. M., 1988, 8-Mercaptoguanosine overcomes unresponsiveness of human neonatal B cells to Polysaccharide antigens, J. Immunol. 141:2313–2316.

    PubMed  CAS  Google Scholar 

  • Rizkalla, B. H., Robins, R. K., and Broom, A. D., 1969, Purine nucleosides. XXVII. The synthesis of 1-and 7-methyl-8-oxoguanosine and related nucleosides, Biochim. Biophys. Acta 195:285–293.

    Article  PubMed  CAS  Google Scholar 

  • Rollins-Smith, L. A., and Lawton, A. R., 1988, Regulation of B cell differentiation: Anti-μ antibodies have opposite effects on differentiation stimulated by bacterial lipopolysaccharide and 8-mercaptoguanosine, J. Mol. Cell. Immunol. 4:9–19.

    PubMed  CAS  Google Scholar 

  • Scheuer, W. V., Goodman, M. G., Parks, D. E., and Weigle, W. O., 1985a, Enhancement of the in vivo antibody response by an 8-derivatized guanine nucleoside, Cell. Immunol. 91:294–300.

    Article  PubMed  CAS  Google Scholar 

  • Scheuer, W. V., Goodman, M. G., Parks, D. E., and Weigle, W. O., 1985b, Active transformation of tolerogenic to immunogenic signals in T and B cells by 8-bromoguanosine, J. Immunol. 135:2962–2966.

    PubMed  CAS  Google Scholar 

  • Sharma, B. S., Balazs, L., Jin, A., Wang, J. C.-J., Jolley, W. B., and Robins, R. K., 1991, Potentiation of the efficacy of murine L1210 leukemia vaccine by a novel immunostimulator 7-thia-8-oxoguanosine: Increased survival after immunization with vaccine plus 7-thia-8-oxoguanosine, Cancer Immunol. Immunother. 33:109–114.

    Article  PubMed  CAS  Google Scholar 

  • Stein, K. E., Zopf, D. A., Miller, C. B., Johnson, B. M., Mongini, P. K. A., Ahmed, A., and Paul, W. E., 1983, Immune response to a thymus-dependent form of B512 dextran requires the presence of Lyb-5+ lymphocytes, J. Exp. Med. 157:657–666.

    Article  PubMed  CAS  Google Scholar 

  • Strauss, P. R., Sheehan, J. M., and Kashket, E. R., 1976, Membrane transport by murine lymphocytes. I. A rapid sampling technique as applied to the adenosine and thymidine systems, J. Exp. Med. 144:1009–1021.

    Article  PubMed  CAS  Google Scholar 

  • Watson, J., 1975, Cyclic nucleotides as intracellular mediators of B cell activation, Transplant Rev. 23:223.

    PubMed  CAS  Google Scholar 

  • Watson, J., Epstein, R., and Cohn, M., 1973, Cyclic nucleotides as intracellular mediators of the expression of antigen-sensitive cells, Nature 246:405–408.

    Article  PubMed  CAS  Google Scholar 

  • Weber, T. H., and Goldberg, M. L., 1976, Effect of leukoagglutinating phytohemagglutinin on cAMP and cGMP levels in lymphocytes, Exp. Cell Res. 97:432–440.

    Article  PubMed  CAS  Google Scholar 

  • Wedner, H. J., Dankner, R., and Parker, C. W., 1975, Cyclic GMP and lectin-induced lymphocyte activation, J. Immunol. 115:1682–1688.

    PubMed  CAS  Google Scholar 

  • Weinstein, Y., Chambers, D. A., Bourne, H. R., and Melmon, K. L., 1974, Cyclic GMP stimulated lymphocyte nucleic acid synthesis, Nature 251:352–355.

    Article  PubMed  CAS  Google Scholar 

  • Weinstein, Y., Segal, S., and Melmon, K. L., 1975, Specific mitogenic activity of 8-Br-guanosine 3′,5′-monophosphate (Br-cyclic GMP) on B lymphocytes, J. Immunol. 115:112–118.

    PubMed  CAS  Google Scholar 

  • Wicker, L. S., Boltz, R. C., Jr., Nichols, E. A., Miller, B. J., Sigal, N. H., and Peterson, L. B., 1987, Large, activated B cells are the primary B-cell target of 8-bromoguanosine and 8-mercaptoguanosine, Cell. Immunol. 106:318–329.

    Article  PubMed  CAS  Google Scholar 

  • Wicker, L. S., Boltz, R. C., Jr., Matt, V., Nichols, E. A., Peterson, L. B., and Sigal, N. H., 1990, Suppression of B cell activation by cyclosporin A, FK506 and rapamycin, Eur. J. Immunol. 20:2277–2283.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Immunology, The Scripps Research Institute, La Jolla, California, 92037, USA

    Michael G. Goodman

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  1. Michael G. Goodman
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  1. Genentech, Inc., South San Francisco, California, USA

    Michael F. Powell

  2. Vaxcel, Inc., Norcross, Georgia, USA

    Mark J. Newman

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Goodman, M.G. (1995). A New Approach to Vaccine Adjuvants. In: Powell, M.F., Newman, M.J. (eds) Vaccine Design. Pharmaceutical Biotechnology, vol 6. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-1823-5_25

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  • DOI: https://doi.org/10.1007/978-1-4615-1823-5_25

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