Bacterial CpG DNA activates immune cells to signal infectious danger

Advances in Immunology

Volumn 73, Issue 73, 1999, Pages 329-368

  Wagner, Hermann ^a  

^a TECHNICAL UNIVERSITY OF MUNICH   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

BACTERIAL DNA; CYCLOSPORIN A; OLIGONUCLEOTIDE; VACCINE;

ANTIGEN PRESENTING CELL; B LYMPHOCYTE; CELL ACTIVATION; CELL FUNCTION; DNA SEQUENCE; DRUG EFFECT; ENZYME ACTIVITY; HEMATOPOIESIS; IMMUNOBIOLOGY; IMMUNOCOMPETENT CELL; IMMUNOSUPPRESSIVE TREATMENT; MOUSE; NATURAL KILLER CELL; NONHUMAN; NUCLEIC ACID ANALYSIS; NUCLEOTIDE SEQUENCE; PRIORITY JOURNAL; PROTEIN BINDING; REVIEW; SEQUENCE ANALYSIS; SIGNAL PROCESSING; VACCINATION;

ANIMALS; BACTERIAL INFECTIONS; CPG ISLANDS; DNA, BACTERIAL; HUMANS;

EID: 0032995849     PISSN: 00652776     EISSN: None     Source Type: Book Series    
DOI: 10.1016/s0065-2776(08)60790-7     Document Type: Article

References (218)

1. Abbas, A. K., Murphy, K. M., and Sher, A. (1996). Functional diversity of helper T lymphocytes. Nature (London) 383, 787-793.
2. Aichele, P., Hengartner, IL, Zinkemagel, R. M., and Schulz, M. (1990). Antiviral cytotoxic T cell response induced by in vivo priming with a free synthetic, peptide. J. Exp. Med. 171, 1815-1820.
3. Albert, M. L., Pearce, S. F. A., Francisco, L. M., Sauter, B., Roy, P., Silverstein, R. L., and Bhardwaj, N. (1998). Immature dendritic cells phagocytose apoptotic cells via alphavbetaS and CD36, and cross-present antigens to cytotoxic T lymphocytesJ. Exp. Med. 188,1359-1368.
4. Anitescu, M., Chace, J. IL, Tuetken, R., Yi, A. K., Berg, D. J., Krieg, A. M., and Cowdery, J. S. (1997). Interleukin-10 functions in vitro and in vivo to inhibit bacterial DNA-induced secretion of interleukin-12.J. Interferon Cytokine. Res. 17, 781-788.
5. Dallas, Z. K., Rasmussen, W. L., and Krieg, A. M. (1996). Induction of NK activity in murine and human cells by CpG motifs in oligodeoxynucleotides and bacterial DNA. J. Immiinol 157, 1840-1845.
6. Banchereau, J., and Steinman, R. M. (1998). Dendritic cells and the control of immunity. Nature (London) 392, 245-252.
7. Barker, R. H., Jr., Metelev, V., Rapaport, E., and Zamecnik, P. (1996). Inhibition of Plasmodium falcipamm malaria using antisense oligodeoxynucleotides. Proc. Natl. head. Sei. U.S.A. 93, 514-518.
8. Bast, R. C., and Bast, B. S. (1976). Critical review of previously reported animal studies of tumor immunotherapy with nonspecific immunostimulants. Ann. N.Y. Acad. Sei. 277, 60-93.
9. Bauer, M., Ileeg, K., Wagner, IL, and Lipford, G. B. (1999). DNA activates human immune cells through a CpG sequence dependent manner. Immunology In press.
10. + T cells [see comments]. Nature (London) 372, 691-694.
11. Bendelac, A., and Fearon, D. T. (1997). Innate pathways that control acquired immunity [editorial]. Gurr. Opin. Immiinol. 9, 1-3.
12. Bendelac, A., Rivera, M. N., Park, S. IL, and Roark, J. H. (1997) Mouse GDI-specific NK1 T cells: Development, specificity, and function. Ann. Rev. Immiinol. 15, 535-562.
13. Bendigs, S., Salzer, U., Lipford, G. B., Wagner, IL, and Heeg, K. (1999). CpG-oligodeoxy-nucleotides costimulate primary T cells in the absence of antigen presenting cells. Ettr. J. Immiinol. In press.
14. Benimetskaya, L., Berton, M., Kolbanovsky, A., Benimetsky, S., and Stein, C. A. (1997a). Formation of a G-tetrad and higher order structures correlates with biological activity of the RelA (NF-kappaB p65) 'antisense oligodeoxynucleotide. Nucleic Acids Res. 25,2648-2656.
15. Benimetskaya, L., Loike, J. D., Khaled, Z., Loike, G., Silverstein, S. C., Cao, L., el Khoury, J., Cai, T. Q., and Stein, C. A. (1997b). Mac-1 (CDllb/CD18) is an oligodeoxynucleotide-binding protein [see comments]. Nature Med. 3, 414-420.
16. Bennett, R. M., Gabor, G. T., and Merritt, M. M. (1985). DNA binding to human leukocytes. Evidence for a receptor-mediated association, intemalization, and degradation of DNA. J. Clin. Invest. 76, 2182-2190.
17. Bevan, M. J. (1995). Antigen presentation to cytoto.xic T lymphocytes in cico. J. Exp. Med. 182, 639-641.
18. Bird, A. P. (1980). DNA methylation and the frequency of CpG in animal DNA. Nucleic Acids Res. 8, 1499-1504.
19. Bird, A. P., (1993). Functions for DNA methylation in vertebrates. Cold Spring Harb. Symp. Quant. Biol. 58, 281-285.
20. Bird, A. P., Taggart, M. IL, Nicholls, R. D., and Higgs, D. R. (1987). Non-methylated CpG-rich islands at the human alpha-globin locus: Implications for evolution of the alpha-globin pseudogene. EMBO J. 6, 999-1004.
21. Branch, A. D. (1998). A good antisense molecule is hard to find. Trends Biochem. Sei. 23, 45-50.
22. Branda, R. F., Moore, A. L., Mathews, L., McCormack, J. J., and Zon, G. (1993). Immune stimulation by an antisense oligomer complementary to die rev gene of HIV-1. Biochem. Pliannacol. 45, 2037-2043.
23. Branda, R. F., Moore, A. L., Hong, R., McCormack, J. J., Zon, G., and Cunningham-Rundles, C. (1996a). B-cell proliferation and differentiation in common variable immunodeficiency patients produced by an antisense oligomer to the rev gene of HIV-1. Clin. Immtinol. Immunopatliol. 79, 115-121.
24. Branda, R. F., Moore, A. L., Lafayette, A. R., Mathews, L., Hong, R., Zon, G., Brown, T., and McCormack, J. J. (1996b). Amplification of antibody production by phosphorothioate oligodeoxynucleotides. J. Lab. Clin. Med. 128, 329-338.
25. Bretscher, P., and Cohn, M. (1970). A theory of self-nonself discrimination. Science 169, 1042-1049.
26. + T cells. J. Exp. Med. 178, 1655-1663.
27. Brossart, P., and Bevan, M. J. (1997). Presentation of exogenous protein antigens on major histocompatibility complex class I molecules by dendritic cells: Pathway of presentation and regulation by cytokines. Blood 90, 1594-1599.
28. Burge, C., Campbell, A.M., and Karlin, S. (1992). Over- and under-representation of short oligonucleotides in DNA sequences. Proc. Natl. Acad. Sei. U.S.A. 89, 1358T1362.
29. Gastier, Y., Cheinla, E., Nierat, J., Heudes, D., Vasseur, M. A., Rajnoch, C., Bruneval, P., Carpentier, A., and Fabiani, J.N. (1998). The activity of c-myb antisense oligonucleotide to prevent intimai hyperplasia is nonspecific. J. Cardiovasc. Surg. (Torino) 39, 1-7.
30. Cella, M., Engering, A., Pinet, V., Pieters, J., and Lanzavecchia, A. (1997). Inflammatory stimuli induce accumulation of MHC class II complexes on dendritic cells [see comments]. Nature (London) 388, 782-787.
31. Chace, J. II., Hooker, N. A., Mildenstein, K. L., Krieg, A. M., and Cowdery, J. S. (1997). Bacterial DNA-induced NK cell IFN-gamma production is dependent on macrophage secretion of IL-12. Clin. Immunol. Immunopatliol. 84, 185-193.
32. Chu, R. S., Targoni, O. S., Krieg, A. M., Lehmann, P. V., and Harding, C. V. (1997). CpG oligodeoxynucleotides act as adjuvants that switch on T helper 1 (Th 1) immunity, y. Exp. Med. 186, 1623-1631.
33. Clipstone, N. A., and Crabtree, G. R. (1992). Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation. Nature (London) 357, 695-697.
34. Condon, C., Watkins, S. C., Celluzzi, C. M., Thompson, K., and Falo, L. D., (1996). DNA-based immunization by in vico transfection of dendritic cells. Nature, Med. 2,1122-1128.
35. Coulondre, C., Miller, J. H., Farabaugh, P. J., and Gilbert, W. (1978). Molecular basis of base substitution hotspots in Eschericliia coli. Nature (London) 274, 775-780.
36. Cousens, L. P., Orange, J. S., Su, II. C., and Biron, C. A. (1997). Interferon-alpha/beta inhibition of interleukin 12 and interferon-gamma production in vitro and endogenously during viral infection. Proc. Natl. Acad. Sei. U.S.A. 94, 634-639.
37. Cowdery, J. S., Chace, J. IL, Yi, A. K., and Krieg, A. M. (1996). Bacterial DNA induces NK cells to produce IFN-gamma tn vico and increases the toxicity of lipopolysaccharides. J. Immunol. 156, 4570-4575.
38. Crooke, R. M., Crooke, S. T., Graham, M. J., and Cooke, M. E. (1996). Effect of antisense oligonucleotides on cytokine release from human keratinocytes in an in vitro model of skin. Toxicol. Appl. Phannacol. 140, 85-93.
39. Davis, II. L., Weeranta, R., Waldschmidt, T. J., Tygrett, L., Schorr, J., and Krieg, A. M. (1998). CpG DNA is a potent enhancer of specific immunity in mice immunized with recombinant hepatitis B surface antigen. J. Immunol. 160, 870-876.
40. Delgado, S., Gomez, M., Bird, A., and Antequera, F. (1998). Initiation of DNA replication at CpG islands in mammalian chromosomes. EMBO }. 17, 2426-2435.
41. Dempsey, P. W., Allison, M. E., Akkaraju, S., Goodnow, C. C., and Fearon, D. T. (1996). C3d of complement as a molecular adjuvant: Bridging innate and acquired immunity. Science 271, 348-350.
42. De Smedt, T., Pajak, B., Muraille, E., Lespagnard, L., Heinen, E., De Baetselier, P., Urbain, J., Leo, O., and Moser, M. (1996). Regulation of dendritic cell numbers and maturation by lipopolysaccharide in vivo. J. Exp. Med. 184, 1413-1424.
43. Doerfler, W. (1991). Patterns of DNA methylation-evolutionary vestiges of foreign DNA inactivation as a host defense mechanism. A proposal. Biol. Chcm. lloppe Setjler 372, 557-564.
44. Donnelly, J. J., Ulmer, J. B., Shiver, J. W., and Liu, M. A. (1997). DNA vaccines. Annu. Rev. Immunol. 15, 617-648.
45. Emlen, W., Pisetsky,. D. S., and Taylor, R. P. (19S6). Antibodies to DNA. A perspective. Arthritis Rlieum. 29, 1417-1426.
46. Erb, K. J., Hollow-ay, J. W., Sobeck, A., Moll, IL, and Le Gros, G. (1998). Infection of mice with Mycobacteritim totis-Bacillus Calmette-Guerin (BCG) suppresses allergen-induced airway eosinophilia. J. Exp. Mcd. 187, 561-569.
47. Fearon, D. T. (1997). Seeking wisdom in innate immunity [news; comment]. Nature (London) 388, 323-324.
48. Fearon, D. T., and Locksley, R. M. (1996). The instructive role of innate immunity in the acquired immune response. Science 272, 50-53.
49. Fisher, T. L., Terhorst, T., Cao, X., and Wagner, R. W. (1993). Intracellular disposition and metabolism of fluorescently-labeled unmodified and modified oligonucleotides microinjected into mammalian cells. Nucleic Acids Res. 21, 3857-3S65.
50. Fornace, A. J. Jr., Alamo, I. Jr., and Hollander, M. C. (19S8). DNA damage-inducible transcripts in mammalian cells. Proc. Natl. Acad. Sei. U.S.A. 85, 8SOO-8S04.
51. Fox, R. I. (1993). Mechanism of action of hydroxychloroquine as an antirheumatic drug. Semin. Arthritis Rlieum. 23, 82-91.
52. Freimark, B. D., Blezinger, II. F., Florack, V. J., Nordstrom, J. L., Long, S. D., Deshpande, D. S., Nochumson, S., and Petrak, K. L. (1998). Cationic lipids enhance cytokine and cell influx levels in the lung following administration of plasmid: Cationic lipid complexes. J. Immunol. 160, 4580-4586.
53. Fynan, E. F., Webster, R. G., Fuller, D. H., Haynes, J. R., Santoro, J. C., and Robinson, H. L. (1993). DNA vaccines: Protective immunizations by parenteral, mucosal, and genegun inoculations. Proc. Natl. Acad. Sei. U.S.A. 90, 11478-11482.
54. Geliert, M. (1997). Recent advances in understanding V(D)J recombination Ado. Immunol. 64, 39-64.
55. Germain, R. N., and Margulies, D. H. (1993). The biochemistry and cell biology of antigen processing and presentation. Ami. Rev. Immunol. 11, 403-450.
56. Gluck, R., Mischler, R., Brantschen, S., Just, M., Althaus, B., and Cryz, S. J. (1992).
57. Immunopotentiating reconstituted influenza virus virosome vaccine delivery system for immunization against hepatitis A. J. Clin. Incest. 90, 2491-2495.
58. Green, D. R., and Scott, D. \V. (1994). Activation-induced apoptosis in lymphocytes. Ctirr. Opin. Immunol. 6, 476-487.
59. Guvakova, M. A., Yakubov, L. A., Vlodavsky, I., Tonkinson, J. L., and Stein, C. A. (1995).
60. Phosphorothioate oligodeoxynucleotides bind to basic fibroblast growth factor, inhibit its binding to cell surface receptors, and remove it from low affinity binding sites on extracellular matrix. J. Biol. Chem. 270, 2620-2627.
61. Hacker, H., Mischak, H., Miethke, T., Liptay, S., Schmid, R., Spanvasser, T., Heeg, K., Lipford, G. B., and Wagner, H. (1998). CpG-DNA-specific activation of antigen-presenting cells requires stress kinase activity and is preceded by non-specific endocytosis and endosomal maturation. EMBO ]. 17, 6230-6240.
62. Halpern, M. D., and Pisetsky, D. S. (1995). In vitro inhibition of murine IFN gamma production by phosphorothioate deoxyguanosine oligomers. Immunopharmacologtj 29, 47-52.
63. Halpern, M. D., Kurlander, R. J., and Pisetsky, D. S. (1996). Bacterial DNA induces murine interferon-gamma production by stimulation of interleukin-12 and tumor necrosis factor-alpha. Cell Immunol. 167, 72-78.
64. Han, J., Lee, J. D., Bibbs, L., and Ulevitch, R. J. ( 1994). A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science 265, 808-811.
65. Hartmann, G., Krug, A., Waller-Fontaine, K., and Endres, S. (1996). Oligodeoxynucleotides enhance lipopolysaccharide-stimulated synthesis of tumor necrosis factor: Dependence on phosphorothioate modification and reversal by beparin. Mol. Med. 2, 429-438.
66. + alpha beta T cells with intermediate TCR induced in the liver of mice by IL-12. J. Immunol. 154, 4333-4340.
67. Hertl, M., Neckers, L. M., and Katz, S. I. (1995). Inhibition of interferon-gamma-induced intercellular adhesion molecule-1 expression on human keratinocytes by phosphorothioate antisense oligodeoxynucleotides is the consequence of antisense-specific and antisensenon-specific effects.J. Invest. Dermatol. 104, 813-818.
68. Hibi, M., Lin, A., Smeal, T., Minden, A., and Karin, M. (1993). Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain. Genes Dev. 7, 2135-2148.
69. Jakob, T., Walker, P. S., Krieg, A. M., Udey, M. C., and Vogel, J. C. (1998). Activation of cutaneous dendritic cells by CpG-containing oligodeoxynucleotides: A role for dendritic cells in the augmentation of Thl responses by immunostimulatory DNA. J. Immunol. 161, 3042-3049.
70. Janeway, C. A. (1989). Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb. Symp. Quant. Biol. 54, 1-13.
71. Jondal, M., Schirmbeck, R., and Reimann, J. (1996). MHC class I-restricted CTL responses to exogenous antigens. Immunity 5, 295-302.
72. Jones, P. A., Rideout, W. M., 3d, Shen, J. C., Spruck, C. II., and Tsai, Y. C. (1992). Methylation, mutation and cancer. Bioessays 14, 33-36.
73. Kaminski, M. S., Kitamura, K., Maloney, D. G., Campbell, M. J., and Levy, R. (1986). Importance of antibody isotype in monoclonal anti-idiotype therapy of a murine B cell lymphoma. A study of hybridoma class switch variants.J. Immunol. 136, 1123-1130.
74. Karin, M. (1995). The regulation of AP-1 activity by mitogen-activated protein kinases. J. Biol. Chem. 270, 16483-16486.
75. Karlin, S., Doerfler, W., and Cardon, L. R. (1994). Why is CpG suppressed in the genomes of virtually all small eukaryotic viruses but not in those of large eukaryotic viruses? J. Virol 68, 2889-2897.
76. Karounous, D. G., Grudier, J. P., and Pisetsky, D. S. (1968). Spontaneous expression of antobodies to DNA of various species origin in sera of normal subjects and patients with systemic lupus erythematosus. J. Immunol. 140, 451-459.
77. Kimura, Y., Sonehara, K., Kuramoto, E., Makino, T., Yamamoto, S., Yamamoto, T., Kataoka, T., and Tokunaga, T. (1994). Binding of oligoguanylate to scavenger receptors is required for oligonucleotides to augment NK cell activity and induce IFN. J. Biocliem. (Tokyo) 116, 991-994.
78. Kline, J. N., Waldschmidt, T. J., Businga, T. R., Lemish, J. E., Weinstock, J. V., Thorne, P. S., and Krieg, A. M. (1998). Modulation of airway inflammation by CpG oligodeoxynucleotides in a murine model of asthma. J. Immunol. 160, 2555-2559.
79. Klinman, D. M., Yi, A. K., Beaucage, S. L., Conover, J., and Krieg, A. M. (1996). CpG motifs present in bacteria DNA rapidly induce lymphocytes to secrete interleukin 6, interleukin 12, and Interferon gamma. Proc. Natl. Acad. Sei. U.S.A. 93, 2879-2883.
80. Klinman, D. M., Yamshchikov, G., and Ishigatsubo, Y. (1997). Contribution of CpG motifs to the immunogenicity of DNA vaccines. J. Immunol. 158, 3635-3639.
81. Krieg, A. M. (1996). An innate immune defense mechanism based on the recognition of CpG motifs in microbial DNAJ. Lab. Clin. Med. 128, 128-133.
82. Krieg, A. M., Cause, W. C., Gourley, M. F., and Steinberg, A. D. (19S9). A role for endogenous retroviral sequences in the regulation of lymphocyte activation. J. Immunol. 143, 2448-2451.
83. Krieg, A. M., Yi, A. K., Maison, S., Waldschmidt, T. J., Bishop, G. A., Teasdale, R., Koretzky, G. A., and Klinman, D. M. (1995). CpG motifs in bacterial DNA trigger direct B-C cell activation. Nature (London) 374, 546-549.
84. Krieg, A. M., Maison, S., and Fisher, E. (1996). Oligodeoxynucleotide modificalions détermine thé magnitude of B cell stimulation by CpG motifs. Antisense Nucleic Acid Drug Dev. 6, 133-139.
85. Krieg, A. M., Love-Homan, L., Yi, A. K., and Harty, J. T. (1998a). CpG DNA induces sustained IL-12 expression in vivo and resistance to Listeria monocytogenes challenge. J. Immunol. 161, 2428-2434.
86. Krieg, A. M., Wu, T., Weeratna, R., Efler, S. M., Love-Homan, L., Yang, L., Yi, A. K., Short, D., and Davis, H. L. (1998b). Séquence motifs in adenoviral DNA block immune activalion by slimulatory CpG motifs. Proc. Natl. Acad. Sei. U.S.A. 95, 12631-12636.
87. Krieg, A. M., Yi, A. K., Schorr, J., and Davis, H. L. (1998e). The role of CpG dinucleotides in DNA vaccines. Trends Microbiol. 6, 23-27.
88. Krieger, M. (1992). Molecular flypaper and atherosclerosis: Structure of the macrophage scavenger receptor. Trends. Biocliem. Sei. 17, 141-146.
89. Kyriakis, J. M., and Avruch, J. (1996). Sounding the alarm: Protein kinase cascades activated by stress and inflammation. J. Biol Chcm. 271, 24313-24316.
90. Kyriakis, J. M., Banerjee, P., Nikolakaki, E., Dai, T., Rubie, E. A., Ahmad, M. F., Avruch, J., and Woodgett, J. R. (1994). The stress-activated protein kinase subfamily of c-Jun kinases. Nature (London) 369, 156-160.
91. Lafferty, K. J., and Woolnough, J. (1977). The origin and mechanism of the allograft reaction. Immunol. Rev. 35, 231-262.
92. Lang, R., Hühner, L., Lipford, G. B., Wagner, H., and Heeg, K. (1999). G-Rich oligodeoxy-nucleotides induce proliferation of bone marrow cells. Submitted.
93. Lapatschek, M. S., Gilbert, R., Wagner, H., and Miethke, T. (1998). Activation of macrophages and B-lymphocytes by an oligodeo.xynucleotide derived from an acutely pathogenic simian immunodeficiency virus. Antiscnse Nucleic Acid Drug Dev. 8, 357-370.
94. Leclerc, C., Deriaud, E., Rojas, M., and Whalen, R. G. (1997). The preferential induction of aThl immune response by DNA-based immunization is mediated by the immunostimulatory effect of plasmid DNA. Cell Immunol. 179, 97-106.
95. Lee, F. S., Hagler, J., Chen, Z. J., and Maniatis, T. (1997). Activation of the IkappaB alpha kinase complex by MEKK1, a kinase of the JNK pathway. Cell 88, 213-222.
96. Lehner, P. J., and Cresswell, P. (1996). Processing and delivery of peptides presented by MHC class I molecules. Curr. Opin. Immunol. 8, 59-67.
97. Lenschow, D. J., Walunas, T. L., and Bluestone, J. A. (1996). CD28/B7 system of T cell costimulation. Anna. Rev. Immunol. 14, 233-258.
98. Li, E., Beard, C., and Jaenisch, R. (1993). Role for DNA methylation in genomic imprinting [see comments]. Nature 366, 362-365.
99. Liang, II., Nishioka, Y., Reich, C. F., Pisetsky, D. S., and Lipsky, P. E. (1996). Activation of human Bcellsbyphosphorothioateoligodeoxynucleotides.J. Clin. Invest. 98,1119-1129.
100. Lipford, G. B., Bauer, M., Blank, C., Reiter, R., Wagner, H., and Heeg, K. (1997a). CpG-containing synthetic oligonucleotides promote B and cytotoxic T cell responses to protein antigen: A new class of vaccine adjuvants. Eur. J. Immunol. 27, 2340-2344.
101. Lipford, G. B., Sparwasser, T., Bauer, M., Zimmerman, S., Koch, E. S., Heeg, K., and Wagner, H. (1997b). Immunostimulatory DNA: Sequence-dependent production of potentially harmful or useful cytokines. Eur. J. Immunol. 27, 3420-3426.
102. Lipford, G. B., Heeg, K., and Wagner, H. (1998). Bacterial DNA as immune cell activator. Trends Microbiol. 6, 496-500.
103. Lipford, G. B., Bendigs, S., Wagner, H., and Heeg, K. (1999a). Bacterial CpG-DNA mediated T cell co-stimulation: Sequence dependence but independence of APCs. Submitted.
104. Lipford, G. B., Sparwasser, T., Zimmermann, S., Heeg, K., and Wagner, H. (1999b). Bacterial CpG-DNA primes draining lymphnodes for protective Thl cell responsiveness. Submitted.
105. Locksley, R. M., and Louis, J. A. (1992). Immunology of leishmaniasis. Curr. Opin. Immunol. 4, 413-418.
106. Loke, S. L., Stein, C. A., Zhang, X. IL, Mon, K., Nakanishi, M., Subasinghe, C., Cohen, J. S., and Neckers, L. M. (1989). Characterization of oligonucleotide transport into living cells. Troc. Natl. Acad. Sei. U.S.A. 86, 3474-3478.
107. Macfarlane, D. E., Manzel, L., and Krieg, A. M. (1997). Unmethylated CpG-containing oligodeoxynucleotides inhibit apoptosis in WEHI 231 B lymphocytes induced by several agents: Evidence for blockade of apoptosis at a distal signalling step. Immunology 91, 586-593.
108. Macfarlane, D. E., and Manzel, L. (1998). Antagonism of immunostimulatory CpG-oligodeo.xynucleotides by quinacrine, chloroquine, and structurally related compounds. J. Immunol. 160, 1122-1131.
109. Maloney, D. G., Grillo-Lopez, A. J., Bodkin, D. J., White, G. A., Liles, T. M., Royston, I., Yarns, G., Rosenberg, J., and Levy, R. (1997). IDEC-C2B8: Results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin's lymphoma. J. Clin. Oncol. 15, 3266-3274.
110. + T lymphocytes. J. Immiinol. 155, 259-265.
111. Manickan, E., Karem, K. L., and Rouse, B. T. (1997). DNA vaccines-A modem gimmick or a boon to vaccinology? Crit. Rev. Immnnol. 17, 139-154.
112. Matzinger, P. (1994). Tolerance, danger, and the extended family. Annn. Rev. Immnnol. 12, 991-1045.
113. McCluskie, M. ]., and Davis, H. L. (1998). CpG DNA is a potent enhancer of systemic and mucosal immune response against hepatitis B surface antigen with intranasal administration to mice. J. Immnnol. 161, 4463-4466.
114. Mclntyre, K. W., Lombard-Gillooly, K., Ferez, J. R., Kunsch, C., Sarmiento, U. M., Larigan, J. D., Landreth, K. T., and Narayanan, R. (1993). A sense phosphorothioate oligonucleotide directed to the initiation codon of transcription factor NF-kappa B p65 causes sequence-specific immune stimulation. Antiseiise Res. Dcv. 3, 309-322.
115. Medzhitov, R., and Janeway, C. A. (1996). On the semantics of immune recognition. Res. Immwiol 147, 208-214.
116. Medzhitov, R., and Janeway, C. A. (1997). Innate immunity: Impact on the adaptive immune response. Curr. Opln. Immunol. 9, 4-9.
117. Meehan, R. R., Lewis, J. D., McKay, S., Kleiner, E. L., and Bird, A. P. (19S9). Identification of a mammalian protein that binds specifically to DNA containing methylated CpGs. Cell 58, 499-507.
118. Messina, J. P., Gilkeson, G. S., and Pisetsky, D. S. (1991). Stimulation of in vitro murine lymphocyte proliferation by bacterial DNA.J. Immnnol. 147, 1759-1764.
119. Messina, J. P., Gilkeson, G. S., and Pisetsky, D. S. (1993). The influence of DNA structure on the in vitro stimulation of murine lymphocytes by natural and synthetic polynucleotide antigens. Cell Immnnol. 147, 148-157.
120. Milligan, J. F., Matteucci, M. D., and Martin, J. C. (1993). Current concepts in antisense drug design. J. Mcd. Chem. 36, 1923-37.
121. Mojcik, C. F., Gourley, M. F., Klinman, D. M., Krieg, A. M., Gmelig-Meyling, F., and Steinberg, A. D. (1993). Administration of a phosphorothioate oligonucleotide antisense to murine endogenous retroviral MCF env causes immune effects i;i vivo in a sequence-specific manner. Clin. Immnnol. Immnnopathol. 67, 130-136.
122. Moldoveanu, Z., Love-Homan, L., Huang, W. Q., and Krieg, A. M. (1998). CpG DNA, a novel immune enhancer for systemic and mucosal immunization with influenza virus. Vaccine 16, 1216-1224.
123. Monteith, D. K., Henry, S. P., Howard, R. B., Floumoy, S., Levin, A., Bennett, C. F., and Crooke, S. T. (1997). Immune stimulation - A class effect of phosphorothioate oligodeoxynucleotides in rodents. Anticancer Drug Design 12, 421-432.
124. Mosmann, T. R., and Coffman, R. L. (1989). Till and TH2 cells: Different patterns of lymphokine secretion lead to different functional propeties. Annu. Rev. Immnnol. 7, 145-173.
125. Nan, X., Campoy, F. J., and Bird, A. (1997). MeCP2 is a transcriptional repressor with abundant binding sites in genomic chromatin. Cell 88, 471-481.
126. Paglia, P., Chiodoni, C., Rodolfo, M., and Colombo, M. P. (1996). Murine dendritic cells loaded in vitro with soluble protein prime cytotoxic T lymphocytes against tumor antigen in vivo [see comments].J. E\p. Med. 183, 317-322.
127. Parillo, J. E. (1993). Pathogenetic mechanisms of septic shock. N. EngJ. J. Med. 328,1471-1477.
128. Pearson, A. M., Rich, A., and Krieger, M. (1993). Polynucleotide binding to macrophage scavenger receptors depends on the formation of base-quartet-stabilized four-stranded helices. J. biol. Chem. 268, 3546-3554.
129. Perez, J. R., Li, Y., Stein, C. A., Majumder, S., van Oorschot, A., and Narayanan, R. (1994). Sequence-independent induction of Spl transcription factor activity by phosphorothioate oligodeoxynucleotides. Proc. Natl. Acad. Sei. U. S. A. 91, 5957-5961.
130. Pisetsky, D. S. (1996). Immune activation by bacterial DNA: A new genetic code. Immunity 5, 303-310.
131. Pisetsky, D. S., and Reich, C. F. (1994). Stimulation of murine lymphocyte proliferation by a phosphorothioate oligonucleotide with antisense activity for herpes simplex virus. Life Sei. 54, 101-107.
132. Pisetsky, D. S., Grudier, J. P., and Gilkeson, G. S. (1990). A role for immunogenic DNA in the pathogenesis of systemic lupus erythematosus. Arthritis Rlieiim. 33, 153-159.
133. Plescia, O. J., Palczuk, N. C., Cora-Figueroa, E., Mukherjee, A., and Braun, W. (1965). Production of antibodies to soluble RNA (sRNA). Proc. Natl. Acad. Sei. U.S.A. 54,1281-1285.
134. Porter, K. R., Kochel, T. J., Wu, S. J., Raviprakash, K., Phillips, I., and Hayes, C. G. (1998). Protective efficacy of a dengue 2 DNA vaccine in mice and the effect of CpG immunostimulatory motifs on antibody responses. Arch. Viral. 143, 997-1003.
135. Prestridge, D. S., and Burks, C. (1993). The density of transcriptional elements in promoter and non-promoter sequences. Human Mol. Genet. 2, 1449-1453.
136. Ramanathan, M., Lantz, M., MacGregor, R. D., Garovoy, M. R., and Hunt, C. A. (1994). Characterization of the oligodeoxynucleotide-mediated inhibition of interferon-gamma-induced major histocompatibility complex class I and intercellular adhesion molecule-1. / Biol. Chem. 269, 24564-24574.
137. Ramasamy, R., Kanagaratnain, R., Misiura, K., Rebowski, G., Amerakoon, R., and Stec, W. J. (1996). Anti-sense oligodeoxynucleoside phosphorothioates nonspecifically inhibit invasion of red blood cells by malaria parasites. Biochcm. BiopJiys. Res. Commun. 218, 930-933.
138. Ray, A., Sassone-Corsi, P., and Schgal, P. B. (1989). A multiple cytoldne- and second messenger-responsive element in the enhancer of the human interleukin-6 gene: Similarities with c-fos gene regulation. Mol. Cell Biol. 9, 5537-5547.
139. Raz, E., Carson, D. A., Parker, S. E., Parr, T. B., Abai, A. M., Aichinger, G., Gromkowski, S.U., Singh, M., Lew, D., and Yankauckas; M. A. (1994). Intradermal gene immunization: The possible role of DNA uptake in the induction of cellular immunity to viruses. Proc. Natl. Acad. Sei. U.S.A. 91, 9519-9523.
140. Raz, E., Tighe, IL, Sato, Y., Corr, M., Dudler, }. A., Roman, M., Swain, S. L., Spiegelberg, IL L., and Carson, D. A. (1996). Preferential induction of a Thl immune response and inhibition of specific IgE antibody formation by plasmid DNA immunization. Proc. Natl. Acad. Sei. U.S.A. 93, 5141-5145.
141. Redford, T. W., Yi, A. K., Ward, C. T., and Krieg, A. M. (1998). Cyclosporin A enhances IL-12 production by CpG motifs in bacterial DNA and synthetic oligodeoxynucleotides. J. Immnnol. 161, 3930-3935.
142. Rietschel, E. T., and Wagner, IL, eds (1996). "Pathology of Septic Shock." Springer-Verlag, Berlin and New York.
143. Rock, K. L. (1996). A new foreign policy: MHC class I molecules monitor the outside world. Immnnol. Today 17, 131-137.
144. Roman, M., Martin-Orozco, E., Goodman, J. S., Nguyen, M. D., Sato, Y., Ronaghy, A., Kornbluth, R. S., Richman, D. D., Carson, D. A., and Raz, E. (1997). Immunostimulatory DNA sequences function as T helper-1-promoting adjuvants. Nature Med. 3, 849-854.
145. Saijo, Y., Uchiyama, B., Abe, T., Satoh, K., and Nukiwa, T. (1997). Contiguous four-guanosine sequence in c-mijc antisense phosphorothioate oligonucleotides inhibits cell growth on human lung cancer cells: Possible involvement of cell adhesion inhibition.//). J. Cancer Res. 88, 26-33.
146. Sasaki, T., Horiuchi, S., Yamazaki, M., and Yui, S. (1996). Stimulation of macrophage DNA synthesis by polyanionic substances through binding to the macrophage scavenger receptor. Biol. Phann. Bull. 19, 449-455.
147. Sato, Y., Roman, M., Tighe, H., Lee, D., Corr, M., Nguyen, M. D., Silverman, G. J., Lotz, M., Carson, D. A., and Raz, E. (1996). Immunostimulatory DNA sequences necessary for effective intradermal gene immunization. Science 273, 352-354.
148. Schubbert, R., Lettmann, C., and Doerfler, W. (1994). Ingested foreign (phage M13) DNA survives transiently in the gastrointestinal tract and enters the bloodstream of mice. Mol. Gen. Genet. 242, 495-504.
149. Schubbert, R., Renz, D., Schmilz, B., and Doerfler, W. (1997). Foreign (M13) DNA ingested by mice reaches peripheral leukocytes, spleen, and liver via the intestinal wall mucosa and can be covalently linked to mouse DNA. Proc. Natl. Acad. Sei. U.S.A. 94, 961-966.
150. Schuler, G., Thurner, B., and Romani, N. (1997). Dendritic cells: From ignored cells to major players in T-cell-mediated immunity. Int. Arch. Allergy Immtinol. 112, 317-322.
151. Schwartz, D. A., Quinn, T. J., Thome, P. S., Sayeed, S., Yi, A. K., and Krieg, A. M. (1997). CpG motifs in bacterial DNA cause inflammation in the lower respiratory tract. J. Clin. Invest. 100, 68-73.
152. Segal, B. M., Klinman, D. M., and Shevach, E. M., (1997). Microbial products induce autoimmune disease by an IL-12-dependent pathway.J. Immunol. 158, 5087-5090.
153. Sen, G. C., and Lengyel, P. (1992). The interferon system. A bird's eye view of its biochemistry. J. Biol. Chem. 267, 5017-5020.
154. Shimada, S., Yano, O., Inoue, H., Kuramoto, E., Fukuda, T., Yamamoto, H., Kataoka, T., and Tokunaga, T. (1985). Antitumor activity of the DNA fraction from Mycobacterium bovis BCG. II. Effects on various syngeneic mouse tumors. J. Natl. Cancer Inst. 74, 681-688.
155. Shimada, S., Yano, O., and Tokunaga, T. (1986). In vivo augmentation of natural killer cell activity with a deoxyribonucleic acid fraction of BCG. Jpn. J. Cancer Res. 77, 808-816.
156. Shirakvva, T., Enomoto, T., Shimazu, S., and Hopkin, J. M. (1997). The inverse association between tuberculin responses and atopic disorder [see comments]. Science 275, 77-79.
157. Sonehara, K., Saito, H., Kuramoto, E., Yamamoto, S., Yamamoto, T., and Tokunaga, T. (1996). Hexamer palindromic oligonucleotides with 5′-CG-3′ motif(s) induce production of interferon. J. Interferon Ctjtokine Res. 16, 799-803.
158. Sousa, C. R., Hieny, S., Scharton-Kersten, T., Jankovic, D., Charest, IL, Germain, R. N., and Slier, A. (1997). In vivo microbial stimulation induces rapid CD40 ligand-independent production of interleukin 12 by dendritic cells and their redistribution to -T cell areas [see comments].J. Exp. Med. 186, 1819-1829.
159. Sparwasser, T., Miethke, T., Lipford, G., Borschert, K., Hacker, H., Heeg, K., and Wagner, II. (1997a). Bacterial DNA causes septic shock. Nature (London) 386, 336-337.
160. Sparwasser, T., Miethke, T., Lipford, G., Erdmann, A., Hacker, H., Heeg, K., and Wagner, H. (1997b). Macrophages sense pathogens via DNA motifs: Induction of tumor necrosis factor-alpha-mediated shock. Eur. ]. Immunol. 27, 1671-1679.
161. Sparwasser, T., Koch, E. S., Vabulas, R. M., Heeg, K., Lipford, G. B., EUwart, J. W., and Wagner, H. (1998). Bacterial DNA and immunostimulatory CpG oligonucleotides trigger maturation and activation of murine dendritic cells. Eur. J. Immunol. 28, 2045-2054.
162. Sparwasser, T., Hühner, L., Koch, E. S., Luz, A., Lipford, G. B., and Wagner, II. (1999a). Immunostimulatory CpG-oligonucleotides cause extramedullary murine hemotopoiesis. ]. Immwiol. 162, 2368-2374.
163. Spanvasser, T., Vabulas, M., Lipford, G., and Wagner, H. (1999b). Bacterial CpG-DNA driven transient lymphadenopathy is associated with T and B cell influx, chemokine production and sustained propensity for Thl immune reactivity. Submitted.
164. Staber, F. G., and Metcalf, D. (1980). Cellular and molecular basis of the increased splenic hemopoiesis in mice treated with bacterial cell wall components. Proc. Natl. Acad. Sei. U. S. A. 77, 4322-4325.
165. Stacey, K. J., Sweet, M. J., and Hume, D. A. (1996). Macrophages ingest and are activated by bacterial DNAJ. linmunol. 157, 2116-2122.
166. Stames, C. O. (1992). Coly's toxins in perspective. Nature (London) 357, 11-12.
167. Stein, C. A. (1995). Does antisense exist? Nature Med. 1, 1119-1121.
168. Stein, C. A. (1996). Phosphorothioate antisense oligodeoxynucleotides: Questions of specificity. Trends Biotechnol. 14, 147-149.
169. Stein, C. A., and Cheng, Y. C. (1993). Antisense oligonucleotides as therapeutic agents - is the bullet really magical? Science 261, 1004-1012.
170. Stein, C. A., and Cohen, J. S. (1988). Oligodeoxynucleotides as inhibitors of gene expression: A review. Cancer Res. 48, 2659-2668.
171. Stein, C. A., Tonkinson, J. L., Zhang, L. M., Yakubov, L., Gervasoni, J., Taub, R., and Rotenberg, S. A. (1993) Dynamics of the internalization of phosphodiester oligodeoxynucleotides in HL60 cells. Biochemistry 32, 4855-4861.
172. Steinman, R. M., Pack, M., and Inaba, K. (1997). Dendritic cells in the T-cell areas of lymphoid organs. Immunol. Rev. 156, 25-37.
173. Stenger, S., Donhauser, N., Thuring, IL, Rollinghoff, M., and Bogdan, C. (1996). Reactivation of latent leishmaniasis by inhibition of inducible nitric oxide synthase. J. Exp. Med. 183, 1501-1514.
174. + T cells: Implications for tumor immunotherapy. Immunity 4, 555-564.
175. Sun, S., Beard, C., Jaenisch, R., Jones, P., and Sprent, J. (1997). Mitogenicity of DNA from different organisms for murine B cells./ Immunol. 159, 3119-3125.
176. Sun, S., Kishimoto, IL, and Sprent, J. (1998). DNA as an adjuvant: Capacity of insect DNA and synthetic oligodeoxynucleotides to augment T cell responses to specific antigen. J. Exp. Med. 187, 1145-1150.
177. Sweet, M. J., Stacey, K. J., Kakuda, D. K., Markovich, D., and Hume, D. A. (1998). IFN-gamma primes macrophage responses to bacterial DNA.J. Interferon Cytokine Res. 18, 263-271.
178. Takekawa, M., and Saito, H. (1998). A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK. Cell 95,521-530.
179. Tanaka, T., Chu, C. C., and Paul, W. E. (1992). An antisense oligonucleotide complementary to a sequence in I gamma 2b increases gamma 2b germline transcripts, stimulates B cell DNA synthesis, and inhibits immunoglobulin secretion. J. Exp. Med. 175, 597-607.
180. Tang, D. C., DeVit, M., and Johnston, S. A. (1992). Genetic immunization is a simple method for eliciting an immune response. Nature (London) 356, 152-154.
181. Terada, K., Okuhara, E., and Kawarada, Y. (1991). Antigen DNA isolated from immune complexes in plasma of patients with systemic lupus erythematosus hybridizes with the Escliericliia coli lac Z gene. Clin. Exp. Immunol. 85, 66-69.
182. Terry, W. D., and Yamamura, Y. (1979). "Immunobiology and Immunotherapy of Cancer: Developments in Immunology." Elsevier/North-Holland, Amsterdam.
183. Thompson, C. B. (1995). New insights into V(D)J recombination and its role in the evolution of the immune system. Immunity 3, 531-539.
184. Tokunaga, T., Yamamoto, IL, Shimada, S., Abe, H., Fukuda, T., Fujisawa, Y., Furutani, Y., Yano, O., Kataoka, T., and Sudo, T. (1984). Antitumor activity of deoxyribonucleic acid fraction from Mycobacteriiim bovis BCG. I. Isolation, physicochemical characterization, and antitumor activity. ]. Natl. Cancer Inst. 72, 955-962.
185. Tokunaga, T., Yano, O., Kuramoto, E., Kimura, Y., Yamamoto, T., Kataoka, T., and Yamamoto, S. ( 1992) Synthetic oligonucleotides with particular base sequences from the cDNA encoding proteins of Mycobacterium bods BCG induce interferons and activate natural killer cells. Microbiol. Immunol. 36, 55-66.
186. Tonkinson, J. L., and Stein, C. A. (1994). Patterns of intracellular compartmentalization, trafficking and acidification of 5′-fluorescein labeled phosphodiester and phosphorothioate oligodeoxynucleotides in HL60 cells. Nucleic Acids Res. 22, 4268-4275.
187. Tough, D. F., Borrow, P., and Sprent, J. (1996). Induction of bystander T cell proliferation by viruses and type I interferon in tiuo [see comments]. Science 272, 1947-1950.
188. Tough, D. F., Sun, S., and Sprent, J. (1997). T cell stimulation in vivo by lipopolysaccharide (LPS). J. Exp. Meil. 185, 20S9-2094.
189. Trinchieri, G. (1998). Interleukin-12; A cytokine at the interface of inflammation and immunity. Adv. Immunol. 70, 83-243.
190. Tsubata, T., Wu, J., and Honjo, T. (1993). B-cell apoptosis induced by antigen receptor crosslinking is blocked by a T-cell signal through CD40. Nature (London) 364, 645-648.
191. Ulevitch, B. J., and Tobias, P. S., (1995). Beceptor-dependent mechanisms of cell stimulation by bacterial endotoxin. Annu. Rev. Immunol. 13, 437-457.
192. Unanue, E. B. (1997). Inter-relationship among macrophages, natural killer cells and neutrophils in early stages of Listeria resistance. Curr. Opin. Immunol. 9, 35-43.
193. Vaerman, J. L., Moureau, P., Deldime, F., Lewalle, P., Lammineur, C., Morschhauser, F., and Martial, P. (1997). Antisense oligodeoxyribonucleotides suppress hématologie cell growth through stepwise release of deoxyribonucleotides. Blood 90, 331-339.
194. Vieillard, V., Cremer, L, Lauret, E., Bozenbaum, W., Debre, P., Autran, B., and De Maeyer, E. (1997). Interferon beta transduction of peripheral blood lymphocytes from IIIV-infected donors increases Thl-type cytokine production and improves the proliferative response to recall antigens. Proc. Natl. Acad. Sei. U.S.A. 94, 11595-11600.
195. von Mutius, E., Fritzsch, C., Weiland, S. K., Boll, G., and Magnussen, IL (1992). Prevalence of asthma and allergic disorders among children in united Germany: A descriptive comparison. BMJ 305, 1395-1399.
196. Wagner, B. (1994). Gene inhibition using antisense oligodeoxynucleotides. Nature (London) 372,333-335.
197. Weeratna, B., Brazolot Millan, C. L., Krieg, A. M., and Davis, IL L. (1998). Reduction of antigen expression from DNA vaccines by coadministered oligodeoxynucleotides. Antisense Nucleic Acid Drug Deo. 8, 351-356.
198. Weiner, G. J., Liu, IL M., Wooldridge, J. E., Dahle, C. E., and Kreig, A. M. (1997). Immunostimulatoty oligodeoxynucleotides containing the CpG motif are effective as immune adjuvants in tumor antigen immunization. Proc. Natl.Acad. Sei. U.S.A. 94,10833-10837.
199. White, J. B., Gordon-Smith, E. C., and Butherford, T. B. (1996). Phosphorothioate-capped antisense oligonucleotides to Bas GAP inhibit cell proliferation and trigger apoptosis but fail to downregulate GAP gene expression. Biochem. Biopliys. Res. Commun. 227, 118-124.
200. Williamson, J. B., Baghuraman, M. K., and Cech, T. B. (19S9) Monovalent cation-induced stmcture of telomeric DNA: The G-quarter model. Cell 59, 871-880.
201. Wooldridge, J. E., Dallas, Z., Krieg, A. M., and Weiner, G. J. (1997). Immunostimulatory oligodeoxynucleotides containing CpG motifs enhance the efficacy of monoclonal antibody therapy of lymphoina. Blood 89, 2994-299S.
202. Yamamoto, S., Yamamoto, T., Kataoka, T., Kuramoto, E., Yano, O., and Tokunaga, T. (1992a). Unique palindromic sequences in synthetic oligonucleotides are required to induce IFN and augment IFN-mediated natural killer activity. J. Immtinol. 148, 4072-4076.
203. Yamamoto, S., Yamamoto, T., Shimada, S., Kuramoto, E., Yano, O., Kataoka, T., and Tokunaga, T. (1992b). DNA from bacteria, but not from vertebrates, induces interferons, activates natural killer cells and inhibits tumor growth. Microbiol. Immunol. 36, 983-997.
204. Yamamoto, T., Yamamoto, S., Kataoka, T., Komuro, K., Kohase, M., and Tokunaga, T. (1994a). Synthetic oligonucleotides with certain palindromes stimulate Interferon production of human peripheral blood lymphocytes in vitro. Jpn. ]. Cancer Res. 85, 775-779.
205. Yamamoto, T., Yamamoto, S., Kataoka, T., and Tokunaga, T. (1994b). Lipofection of synthetic oligodeoxyribonucleotide having a palindromic sequence of AACGTT to murine splenocytes enhances interferon production and natural killer activity. Microbiol. Immunol. 38, 831-836.
206. Yang, R. B., Mark, M. R., Gray, A., Huang, A., Xie, M. IL, Zhang, M., Goddard, A., Wood, W. I., Gurney, A. L., and Godowski, P. J. (1998). Toll-like receptor-2 mediates lipopolysaccharide-induced cellular signalling [see comments]. Nature (London) 395, 284-288.
207. Yi, A. K., and Krieg, A. M. (199Sa). CpG DNA rescue from anti-IgM-induced WEHI-231 B lymphoina apoptosis via modulation of I kappa B alpha and I kappa B beta and sustained activation of nuclear factor-kappa B/c-Rel. J. Immunol. 160, 1240-1245.
208. Yi, A. K., and Krieg, A. M. (1998b). Rapid induction of mitogen-activated protein kinases by immune stimulatory CpG DNA. J. Immunol. 161, 4493-4497.
209. Yi, A. K., Chace, J. IL, Cowdery, J. S., and Krieg, A. M. (1996a). IFN-gamma promotes IL-6 and IgM secretion in response to CpG motifs in bacterial DNA and oligodeoxynucleotides. J. Immunol. 156, 558-564.
210. Yi, A. K., Hombeck, P., Lafrenz, D. E., and Krieg, A. M. (1996b). CpG DNA rescue of murine B lymphoma cells from anti-IgM-induced growth arrest and programmed cell death is associated \\ith increased expression of c-myc and bcI-xL. J. Immtinol. 157,4918-4925.
211. Yi, A. K., Klinman, D. M., Martin, T. L.,.Matson, S., and Krieg, A. M. (1996c). Rapid immune activation by CpG motifs in bacterial DNA. Systemic induction of IL-6 transcription through an antioxidant-sensitive pathway. J. Immunol. 157, 5394-5402.
212. Yi, A. K., Chang, M., Peckham, D. W., Krieg, A. M., and Ashman, R. F. (1998a). CpG oligodeoxyribonucleotides rescue mature spleen B cells from spontaneous apoptosis and promote cell cycle entry. J. Immunol. 160, 589S-5906.
213. Yi, A. K., Tuetken, R., Redford, T., Waldschmidt, M., Kirsch, J., and Krieg, A. M. (199Sb) CpG motifs in bacterial DNA activate leukocytes through the pH-dependent generation of reactive oxygen species. J. Immnnol. 160,4755-4761.
214. Yoshimori, T., Yamamoto, A., Moriyama, Y., Futai, M., and Tashiro, Y. (1991). Bafilomycin Al, a specific inhibitor of vacuolar-type H(+)-ATPase, inhibits acidification and protein degradation in lysosomes of cultured cells. J. Biol. Chem. 266, 17707-17712.
215. Zbar, B., Bernstein, I. D., and Rapp, H. J. (1971). Suppression of tumor growth at the site of infection with living Bacillus Calmette-Guerin.J. Natl. Cancer Inst. 46, 831-839.
216. Zbar, B., Ribi, E., Meyer, T., Azuma, L, and Rapp, H. J. (1974). Immunotherapy of cancer: Regression of established intradermal tumors after intralesional injection of mycobacterial il walls attached to oil droplets. J. Natl. Cancer Inst. 52, 1571-1577.
217. Zhang, X., Sun, S., Hwang, I., Tough, D. F., and Sprent, J. (1998). Potent and selective stimulation of memory-phenotype CD8+ T cells in cico by IL-15. Immunity 8, 591-599.
218. Zimmermann, S., Egeter, O., Hausmann, S., Lipford, G. B., Rocken, M., Wagner, H., and Heeg, K. (1998). CpG oligodeoxynucleotides trigger protective and curative Th. 1 responses in lethal murine leishmaniasis. J. Immunol. 160, 3627-3630.