Abstract
CD4 T-lymphocytes, which orchestrate immune responses, receive a cognitive signal when clonally distributed receptors are occupied by MHC class II bound peptides on antigen-presenting cells. The latter provide costimulatory or accessory signals through macromolecules such as B7.1 and B7.2 which interact with coreceptors on T-cells to regulate outcomes in terms of T-cell activation or specific non-responsiveness. Complementary studies at the chemical level have implicated Schiff base formation between specialised carbonyls and amines, constitutively expressed on antigen-presenting cell and T-cell surfaces, as an essential element in specific T-cell activation. The small xenobiotic Schiff base forming molecule tucaresol, which substitutes for the physiological donor of carbonyl groups to provide a costimulatory signal to CD4 T-helper lymphocytes (Th-cells), has been developed for testing as an immunopotentiatory drug. Tucaresol, which is orally bioavailable and systemically active, enhances CD4 Th-cell and CD8 cytotoxic T-cell responses in vivo and selectively favours a Th1-type profile of cytokine production. In murine models of virus infection and syngeneic tumour growth it has substantial therapeutic activity. Schiff base formation by tucaresol on T-cell surface amines provides a costimulatory signal to the T-cell through a mechanism that activates clofilium-sensitive K+ and Na+ transport. The signalling pathway utilised by tucaresol converges with T-cell receptor signalling at the level of MAP kinase, promoting the tyrosyl phosphorylation of ERK2 by MEK (mitogen-activated protein kinase kinase). The Schiff base forming class of immunopotentiatory drug provides the first orally active, mechanism-based immunopotentiatory agents for therapeutic testing. Tucaresol is currently undergoing pilot phase I/II clinical trials as an immunopotentiator in chronic hepatitis B virus infection, HIV infection and malignant melanoma.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Abbreviations
- APC :
-
Antigen-presenting cell
- IFN :
-
Interferon
- IL :
-
Interleukin
- MAPK :
-
Mitogen-activated protein kinase
- S-NHS-biotin :
-
Sulpho-N-hydroxysuccin-imidobiotin
- TCR :
-
T-cell receptor
- Th-cell :
-
T-helper lymphocyte
References
Hedrick SM, Eidelman FJ (1993) T lymphocyte antigen receptors. In: Paul W (ed) Fundamental immunology, 3rd edn. Raven, New York, pp 383–420
Weiss A (1993) T lymphocyte activation. In: Paul W (ed) Fundamental immunology, 3rd edn. Raven, New York, pp 467–504
Lenschow DJ, Bluestone JA (1993) T cell costimulation and in vivo tolerance. Curr Opin Immunol 5:747–752
Whittington R, Faulds D (1993) Interleukin-2.A review of its pharmacological properties and therapeutic use in patients with cancer. Drugs 46:446–514
Klima N, Pataraca R, Walling J et al (1994) Clinical and immunological changes in AIDS patients following adoptive therapy with activated autologous CD8 T cells and interelukin-2 infusion. AIDS 8:1073–1081
Hendrzak JA, Brunda MJ (1995) Interleukin-12. Biologic activity, therapeutic utility, and role in disease. Lab Invest 72:619–637
Tahara H, Lotze MT (1995) Anti-tumor effects of interleukin 12 (IL-12):applications for the immunotherapy and gene therapy of cancer. Gene Ther 2:96–106
Nabel GJ, Chang AE, Nabel EG et al (1994) Immunotherapy for cancer by direct gene transfer into tumors. Hum Gene Ther 5:57–77
Fenton RT, Sznol M, Luster DG, Taub DD, Longo DL (1994) A phase I trial of B7-transfected or parental lethally irradiated allogeneic melanoma cell lines to induce cell-mediated immunity against tumor associated antigen presented by HLA-A2 or HLA-A1 in patients with stage IV melanoma. NCI protocol T93–0161. BRMP protocol 9401. Hum Gene Ther 5:1385–1399
Rhodes J (1989) Evidence for an intercellular covalent reaction essential in antigen specific T-cell activation. J Immunol 143:1482–1489
Gao X-M, Rhodes J (1990) An essential role for constitutive Schiff base-forming ligands in antigen presentation to murine T cell clones. J Immunol 144:2883–2890
Rhodes J (1990) E-Rosettes provide an analogue for Schiff base formation in specific T cell activation. J Immunol 145:463–469
Rhodes J, Zheng B, Lifely MR (1992) Inhibition of specific T cell activation by monosaccharides is through their reactivity as aldehydes. Immunology 75:629–631
Zheng B, Brett S, Tite JP, Lifely MR, Brodie TA, Rhodes J (1992) Galactose oxidation in the design of immunogenic vaccines. Science 256:1560–1563
Rhodes J, Chen H, Hall SR, Beesley JE, Jenkins DC, Collins P, Zheng B (1995) Therapeutic potentiation of the immune system by costimulatory Schiff base forming drugs. Nature 377:71–75
Thompson CB (1995) Distinct roles for the costimulatory ligands B7–1 and B7–2 in T helper cell differentiation? Cell 81:979–82
Bluestone JA (1995) New perspectives on CD28-B7-mediated T cell costimulation. Immunity 2:555–559
Allison JP (1994) CD28-B7 interactions in T-cell activation. Curr Opin Immunol 6:414–419
Bell GM, Imboden JB (1995) CD2 and the regulation of T cell anergy. J Immunol 155:2805–2807
Shevach EM (1993) Accessory molecules. In: Paul W (ed) Fundamental immunology, 3rd edn. Raven, New York, pp 531–575
August A, Dupont B (1994) CD28 of T lymphocytes associates with phosphatidylinositol 3-kinase. Int Immunol 6:769–777
August AS, Gibson S, Kawakami Y, Kawakami T, Mills GB, Dupont B (1994) CD28 is associated with and induces the immediate tyrosine phosphorylation and activation of the Tec family kinase ITK/EMT in the human Jurkat leukemic T-cell line. Proc Natl Acad Sci USA 91:9347–9350
Li W, Whaley CD, Mondino A, Mueller DL (1996) Blocked signal transduction to the ERK and JNK protein kinases in anergic CD4+ T-cells. Science 271:1272–1276
Fields PE, Gajewski TF, Fitch F (1996) Blocked Ras activation in anergic CD4+ T-cells. Science 271:1276–1278
Seder RA, Paul WE (1994) Acquisition of lymphokine-producing phenotype by CD4+ T-cells. Annu Rev Immunol 12:635–673
Del-Prete G, Maggi E, Romagnani S (1994) Human Th1 and Th2 cells: functional properties, mechanisms of regulation, and role in disease. Lab Invest 70:299–306
Howard M, Miyajima A, Coffman R (1993) T-cell-derived cytokines and their receptors. In: Paul W (ed) Fundamental immunology, 3rd edn. Raven, New York, pp763–800
Thompson CB (1995) Distinct roles for the costimulatory ligands B7–1 and B7–2 in T helper cell differentiation? Cell 81:979–983
Snell EE, Dimari SJ (1970) Schiff base intermediates in enzyme catalysis. In: Boyer PD(ed) The enzymes: kinetics and mechanism, vol 2. Academic. London, pp 335–346
Novogrodsky A, Katchalski E (1973) Induction of lymphocyte transformation by sequential treatment with neuraminidase and galactose oxidase. Proc Nat Acad Sci USA 70:1824–1827
John RA (1995) Pyridoxal phosphate-dependent enzymes. Biochim Biophys Acta 1248:81–96
Fherst A (1984) Covalent catalysis.In: Enzyme structure and mechanism, 2nd edn. Freeman, New York, pp 69–97
Van der Meer RA, Duine JA (1986) Covalently bound pyrroloquinoline quinone is the organic prosthetic group of human placental lysyl oxidase. Biochem J 239:789–791
Stryer L (1988) Excitable membranes and sensory systems. In: Biochemistry, 3rd edn. Freeman, New York, pp 1005–1041
Mukohata Y (1994) Comparative studies on ion pumps of the bacterial rhodopsin family. Biophys Chem 50:191–201
Sasaki J, Brown LS, Chon Y-S, et al. (1995) Conversion of bacteriorhodopsin into a chloride ion pump. Science 269:73–75
Chen H, Rogers M, Rhodes J (1996) Convergence of Schiff base costimulatory signaling and T-cell receptor signaling at the level of MAP kinase ERK2 (manuscript in preparation)
Seger R, Krebs EG (1995) The MAPK signaling cascade. FASEB J 9:726–735
Dudley DT, Pang L, Decker SJ, Bridges AJ, Saltiel AR (1995) A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc Natl Acad Sci USA 92:7686–7689
Greenlaw R, Robinson P, Heaton T, et al (1992) Transfection of HLA-DR-expressing DAP.3 cells with a cDNA clone encoding the glycosyl phosphatidylinositol-linked form of lymphocyte function associated antigen-3: biochemical features and functional consequences. Int Immunol 4:673–80
Hargreaves R, Logiou V, Lechler R (1995) The primary alloresponse of human CD4+ T-cells is dependent on B7 (CD80), augmented by CD58, but realtively unifluenced by CD54 expression. Int Immunol 7:1501–1513
Wyss DF, Choi JS, Maria JL et al (1995) Conformation and function of the N-linked glycan in the adhesion domain of human CD2. Science 269:1273–1278
Malkovsky M, Doré C, Hunt R et al (1983) Enhancement of specific antitumour immunity in mice fed a diet enriched in vitamin A acetate. Proc Natl Acad Sci 80:6322–6326
Malkovsky M, Edwards AJ, Hunt R et al (1983) T-cell mediated enhancement of host-versus-graft reactivity in mice fed a diet enriched with vitamin A acetate. Nature 302:338–340
Malkovsky M, Medawar PB, Thatcher DR et al (1985) Acquired immunological tolerance of foreign cells is impaired by recombinant interleukin 2 or vitamin A acetate. Proc Natl Acad Sci USA 82:536–538
Buck J, Derguini F, Levi E et al (1991) Intracellular signalling by 14-hydroxy-4,14-retro-retinol. Science 254:1645–1656
Derguini F, Nakanishi K, Hämmerling U et al (1994) Intracellular signalling activity of synthetic (14R)-, (14S)-, and (14RS)-14-hydroxy-4,14-retro-retinol. Biochemistry 33:623–628
Meydani SN, Ribaya-Mercado JD, Russell RM et al (1991) Vitamin B6 deficiency impairs interleukin 2 production and lymphocyte proliferation in elerly adults. Am J Clin Nutr 53:1275–1280
Rall C, Meydani SN (1993) Vitamin B6 and immune competence. Nutr Rev 51:217–225
Deeg HJ (1988) Ultraviolet irradiation in transplant biology: manipulation of immunity and immunogenicity. Transplantation 45:845–851
Ullrich SE (1995) Modulation of immunity by ultraviolet radiation: key effects on antigen presentation. J Invest Dermatol 105 [1 Suppl]:30S–36S
Kripke ML (1994) Ultraviolet radiation and immunology: something new under the sun-presidential address. Cancer Res54:6102–6105
Tzianabos AO, Onderdonk AB, Rosner B et al (1993) Structural features of polysaccharides that induce intra-abdominal abscesses. Science 262:416–419
Tzianobos AO, Onderdonk AB, Smith RS et al (1994) Structure-function relationships for polysaccharide-induced intraabdominal abscesses. Infect Immun 62:3590–3593
Edmonds SE, Ellis G, Gaffney K et al (1995) Hypoxia and the rheumatoid joint: immunological and therapeutic implications. Scand J Rheumatol Suppl 101:163–168
Sherman DI, Williams R (1994) Liver damage: mechanisms and management. Br Med Bull 50:124–138
Love RA, Rader JI, Crofford LJ et al (1993) Pathological and immunological effects of ingesting l-tryptophan and 1,1′-ethylidenebis (l-tryptophan) in Lewis rats. J Clin Invest 91:804–811
Driskell WJ, Ashley DL, Grainger J et al (1992) Identification of decomposition products of 1,1′-ethylidenebis [l-tryptophan],a compound associated with eosinophilia-myalgia syndrome. Bull Environ Contam Toxicol 48:679–687
Pol S (1995) Immunotherapy of chronic hepatitis B by anti HBV vaccine. Biomed Pharmacother 49:105–109
Redfield RR, Birx DL (1992) HIV-specific vaccine therapy: concepts, status, and future directions. AIDS Res Hum Retro-viruses 8:1051–1058
Barth A, Hoon DS, Foshag LJ et al (1994) polyvalent melanoma cell vaccine induces delayed-type hypersensitivity and in vitro cellular immune response. Cancer Res 54:3342–3345
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Chen, H., Rhodes, J. Schiff base forming drugs: mechanisms of immune potentiation and therapeutic potential. J Mol Med 74, 497–504 (1996). https://doi.org/10.1007/BF00204975
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00204975