Immunostimulatory DNA: sequence-dependent production of potentially harmful or useful cytokines

被引:229
作者
Lipford, GB [1 ]
Sparwasser, T [1 ]
Bauer, M [1 ]
Zimmermann, S [1 ]
Koch, ES [1 ]
Heeg, K [1 ]
Wagner, H [1 ]
机构
[1] Tech Univ Munich, Inst Med Microbiol Immunol & Hyg, D-81675 Munich, Germany
关键词
CpG motif; vaccine adjuvant; cytokine; cytolytic T cell; leishmaniasis;
D O I
10.1002/eji.1830271242
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Certain bacterial immunostimulatory (i.s.) DNA sequences containing unmethylated CpG motifs stimulate antigen-presenting cells (APC) to express a full complement of co-stimulatory molecules and to produce cytokines including interleukin (IL)-12 and tumor necrosis factor (TNF)-alpha. While IL-12 is key to their T helper cell (Th)1-promoting adjuvant activity, secretion of toxic levels of TNF-alpha is harmful in that it promotes toxic shock. Given the beneficial as well as harmful consequences of i.s. DNA, we investigated the possibility of identifying DNA sequences, i.e. CpG oligodeoxynucleotides (ODN) which differentially activate IL-12 versus TNF-alpha cytokine production in APC. Here, we describe an i.s. DNA sequence with these characteristics. While its potential to induce IL-12 is preserved, its ability to trigger TNF-alpha release is strongly curtailed both in vitro and in vivo. I.s. DNA could be segregated into lethal and non-lethal in a mouse toxic shock model. The non-toxic i.s. DNA was useful as an adjuvant, thus allowing cytotoxic T cell responses to the soluble protein ovalbumin and conferring a resistant Th 1 phenotype to BALB/c mice lethally infected with Leishmania major. This i.s. CpG motif may thus be prototypic for a useful immunostimulating DNA sequence that lacks harmful side effects.
引用
收藏
页码:3420 / 3426
页数:7
相关论文
共 29 条
  • [1] Functional diversity of helper T lymphocytes
    Abbas, AK
    Murphy, KM
    Sher, A
    [J]. NATURE, 1996, 383 (6603) : 787 - 793
  • [2] BENLMETSKAYA L, 1997, NAT MED, V3, P414
  • [3] NONMETHYLATED CPG-RICH ISLANDS AT THE HUMAN ALPHA-GLOBIN LOCUS - IMPLICATIONS FOR EVOLUTION OF THE ALPHA-GLOBIN PSEUDOGENE
    BIRD, AP
    TAGGART, MH
    NICHOLLS, RD
    HIGGS, DR
    [J]. EMBO JOURNAL, 1987, 6 (04) : 999 - 1004
  • [4] INDUCTION OF OVALBUMIN-SPECIFIC CYTO-TOXIC T-CELLS BY INVIVO PEPTIDE IMMUNIZATION
    CARBONE, FR
    BEVAN, MJ
    [J]. JOURNAL OF EXPERIMENTAL MEDICINE, 1989, 169 (03) : 603 - 612
  • [5] Origin, maturation and antigen presenting function of dendritic cells
    Cella, M
    Sallusto, F
    Lanzavecchia, A
    [J]. CURRENT OPINION IN IMMUNOLOGY, 1997, 9 (01) : 10 - 16
  • [6] Cowdery J, 1996, J IMMUNOL, V156, P4570
  • [7] Elements of immunity - The instructive role of innate immunity in the acquired immune response
    Fearon, DT
    Locksley, RM
    [J]. SCIENCE, 1996, 272 (5258) : 50 - 54
  • [8] RECOMBINANT INTERLEUKIN-12 CURES MICE INFECTED WITH LEISHMANIA-MAJOR
    HEINZEL, FP
    SCHOENHAUT, DS
    RERKO, RM
    ROSSER, LE
    GATELY, MK
    [J]. JOURNAL OF EXPERIMENTAL MEDICINE, 1993, 177 (05) : 1505 - 1509
  • [9] DEVELOPMENT OF TH1 CD4+ T-CELLS THROUGH IL-12 PRODUCED BY LISTERIA-INDUCED MACROPHAGES
    HSIEH, CS
    MACATONIA, SE
    TRIPP, CS
    WOLF, SF
    OGARRA, A
    MURPHY, KM
    [J]. SCIENCE, 1993, 260 (5107) : 547 - 549
  • [10] THE B7 AND CD28 RECEPTOR FAMILIES
    JUNE, CH
    BLUESTONE, JA
    NADLER, LM
    THOMPSON, CB
    [J]. IMMUNOLOGY TODAY, 1994, 15 (07): : 321 - 331