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The Journal of Immunology, 1998, 160: 3627-3630.
Copyright © 1998 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: CpG Oligodeoxynucleotides Trigger Protective and Curative Th1 Responses in Lethal Murine Leishmaniasis

Stefan Zimmermann*, Oliver Egeter{dagger}, Susanne Hausmann*, Grayson B. Lipford*, Martin Röcken{dagger}, Hermann Wagner* and Klaus Heeg2,*

* Institute of Medical Microbiology, Immunology and Hygiene, Technische Universität München and {dagger} Department of Dermatology, Ludwig Maximilians Universität München, München, Germany


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
Synthetic oligodeoxynucleotides containing CpG dinucleotides (CpG-ODN) mimic the immunostimulatory qualities of bacterial DNA. We asked whether immunostimulation by CpG-ODN predisposes for a commitment toward a Th1 vs a Th2 response in Leishmania major infection, a model for a lethal Th2-driven disease, in BALB/c mice. CpG-ODN induced Th1 effector T cells in vitro and conveyed protective immunity to disease-prone BALB/c mice in vivo. Conversion to a Th1-driven resistant phenotype was associated with IL-12 production and maintained the expression of IL-12R ß2-chains. Most strikingly, CpG-ODN were even curative when given as late as 20 days after lethal L. major infection, indicating that CpG-ODN revert an established Th2 response. These findings imply an important role of bacterial DNA and CpG-ODN in the instruction of adaptive immune responses. They also point to the therapeutic potential of CpG-ODN in redirecting curative Th1 responses in Th2-driven disorders.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
Uptake of bacterial DNA that is rich in unmethylated CpG motifs causes brisk activation of immune cells (1, 2, 3, 4, 5). Certain synthetic oligodeoxynucleotides (ODN)3 displaying unmethylated CpG motifs in a given base context mimic the immunostimulatory effects of bacterial DNA (1, 6) and activate APCs to up-regulate the expression of the membrane proteins B7-1 and B7-2 (7) and secrete cytokines such as TNF, IL-1, IL-6, and high concentrations of IL-12 (4, 8, 9). In vivo, the injection of CpG-containing ODN (CpG-ODN) together with Ag skewed Ag-specific IgG-isotypes toward IgG2a and promoted the induction of Ag-specific CD8+ cytolytic T cells (7), suggesting that CpG-ODN might favor Th1 development (7, 10). Therefore, we tested the capacity of CpG-ODN to instruct a Th1-mediated adaptive response and to prevent and treat infection with Leishmania major, a lethal Th2-mediated disease, in BALB/c mice (11, 12, 13).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Animals and infection

We purchased 8- to 10-week-old female BALB/c mice from Harlan Winkelmann (Borchen, Germany). L. major promastigotes (strain MHOM/IL/81/FE/BNI; a kind gift from Dr. W. Solbach, University of Lübeck, Lübeck, Germany) were grown in Click/RPMI 1640 supplemented with 10% FCS on Novy-Nicolle-MacNeal agar and washed twice in PBS before infection. Promastigotes (2 x 105 or 2 x 106) were injected into the right hind footpad of BALB/c mice. The swelling of the footpad was measured weekly with a metric caliper, and the uninfected footpad served as an internal control. The percent increase of footpad swelling was calculated from both values.

Media, mAbs, and reagents

Cells were cultured in Click/RPMI 1640 supplemented with 10% FCS (Biochrom, Berlin, Germany). Phosphothioate-modified CpG-ODN were custom synthesized by MWG (Munich, Germany). The sequence used here was 5'-TCC ATG ACG TTC CTG ATG CT-3'. (the bold letters indicate the proposed active motif). As a control, an ODN with an inverted CG motif was used (5'-TCC ATG AGC TTC CTG ATC CT-3'). IgG-subtype-specific mAbs were purchased from PharMingen (Hamburg, Germany). Staphylococcal enterotoxin B (SEB) came from Toxin Technologies (Sarasota, FL). L-N6-(1-iminoethyl)-lysine (NIL) was purchased from Alexis (Läufelfingen, Switzerland).

Animal treatment

CpG-ODN were injected in quantities of 40 µl per footpad or in 200 µl i.p. L. major Ag (LmAg) was prepared as described previously (14). NIL was diluted in the drinking water at 4.5 mM and given ad libidum.

In vitro cell culture

CD4+ lymphocytes (>95% pure) from BALB/c mice were negatively selected using Biotex T cell columns (TEBU, Frankfurt, Germany). Cells (3 x 104) were stimulated in 96-well flat-bottom tissue culture plates with 10 µg/ml SEB, 5 x 105 T cell-depleted and irradiated (30 Gy) spleen cells (APCs), 5 U/ml rIL-2, and anti-IL-4 mAb (clone 11B11) (10 µg/ml) or CpG-ODN as described previously (15). After 3 days, cells were transferred into 24-well tissue culture plates and expanded with fresh medium containing 50 U/ml rIL-2. On day 10, cells were washed twice and restimulated with SEB. The 24-h culture supernatant was analyzed for IFN-{gamma} content using an ELISA and analyzed for IL-4 using IL-4-responsive CT4.S cells (a kind gift from Dr. W. Paul) (National Institutes of Health, Bethesda, MD). To restimulate lymphocytes from L. major-infected mice, 5 x 105 nonadherent lymph node cells (LNCs) were incubated with LmAg (equivalent to 2 x 105 parasites) and syngeneic APCs (5 x 104 cells, 15 Gy-irradiated) in 200 µl. After 48 h, the supernatant was analyzed for IL-4 and IFN-{gamma} content by ELISA.

PCR analysis

Total RNA was isolated from spleen and lymph nodes using the RNeasy total RNA extraction kit (Qiagen, Hilden, Germany), and 2 µg of RNA were reverse transcribed (Life Technologies, Eggenstein, Germany). IL-12Rß2 primers (sense: 5'-CAT CGC TAT CAT CAC GGT GG-3', position 2079–2098; antisense: 5'-AGT AGC CTT GGA ATC CTT GGC 3', position 2383–2363) and ß-actin primers (sense: 5'-GAT GAC GAT ATC GCT GCG CTG-3', position 84–104; antisense: 5'-GTA CGA CCA GAG GCA TAC AGG-3', position 523–503) were synthesized as phosphodiesters by MWG. PCR reaction products were separated on a 2% agarose gel and documented with Stratagene Eagle Eye System (La Jolla, CA).

IgG subtype ELISA and cytokine assays

Microtiter plates were coated with 10 µg/ml soluble LmAg (16) and then blocked with BSA. Serum samples were diluted twofold in PBS. IgG subtypes were detected with alkaline phosphatase-labeled subtype-specific mAb. Sera were titrated to background levels, from which the end-point titer was calculated. IL-12 p40 content was detected in sera using a commercially available ELISA (PharMingen).


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
To investigate the capability of CpG-ODN in promoting Th1 development in vitro, freshly isolated murine CD4+ T cells were stimulated with SEB, syngeneic APCs (15), and various concentrations of CpG-ODN. As shown in Figure 1Go, CD4+ T cells stimulated under these conditions developed a Th phenotype, producing IL-4 and low amounts of IFN-{gamma} (15). As expected, stimulation of T cells in the presence of neutralizing anti-IL-4 mAb abolished IL-4 production and slightly enhanced IFN-{gamma} secretion. The addition of CpG-ODN promoted dose-dependent, strong IFN-{gamma} production, while IL-4 secretion was reduced.



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  		FIGURE 1. Induction of Th1 development by CpG-ODN in vitro. CD4+ T cells were stimulated with SEB, rIL-2, and the additives indicated. After 3 days, the cultures were extensively washed, replated, and expanded further with rIL-2. On day 10, the cells were washed and restimulated again. The 24-h supernatants were tested for IFN-{gamma} by ELISA or for IL-4 content by bioassay.

 
The fact that CpG-ODN promote Th1 development in vitro (Fig. 1Go) prompted us to evaluate effect of CpG-ODN in a Th2-driven disease model, i.e., BALB/c mice infected with L. major (11, 12). As shown in Figure 2Go, untreated BALB/c mice developed severe leishmaniasis and had to be killed after 8 wk, while CpG-treated mice developed resistance (Fig. 2Go). An initial increase in footpad thickness was followed by a decline of lesions, which then remained stable for at least 16 wk postinfection (Fig. 2Go). Control ODN without the active CG motif failed to influence the course of infection (data not shown). Reinfection of ODN-treated mice after 10 wk resulted in only a slight and transient increase in footpad thickness (Fig. 2Go).



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  		FIGURE 2. Course of infection with L. major in CpG-ODN-treated BALB/c mice. BALB/c mice were injected with 2 x 106 L. major promastigotes into the right footpad. A total dose of 10 nmol CpG-ODN were given 2 h before and 10 h after infection (5 nmol i.p. and 5 nmol at the site of infection). The mean percent increase (plus SD) of footpad thickness is given (six mice per group). Filled squares indicate the CpG-ODN-treated group, and open circles indicate the untreated control group. After 10 wk, the CpG-ODN-treated mice were reinfected with L. major. After 16 wk, one-half of the mice were treated for 2 wk with L-NIL in the drinking water (open squares).

 
Nitric oxide (NO) generated by the inducible NO synthase is crucial for the control of L. major persisting in resistant mice (17). Inhibition of inducible NO synthase by L-N6-iminoethyl-lysine (L-NIL) leads to reactivation of the cutaneous lesions (18). To investigate whether CpG-ODN-treated BALB/c mice also control the infection by a NO-dependent mechanism, we administered L-NIL to L. major-infected BALB/c mice at 16 wk after reinfection (Fig. 2Go). Within 2 wk, the footpad thickness increased. The infection was under control again after L-NIL was withdrawn (Fig. 2Go). Thus CpG-ODN-treated BALB/c mice control L. major infection similar to resistant C57BL/6 mice.

To directly demonstrate that CpG-ODN induce Leishmania-specific Th1 development, we analyzed the L. major-specific T cell responses in vivo and in vitro. LNCs from ODN-treated BALB/c mice produced high amounts of IFN-{gamma} but no IL-4 upon stimulation with LmAg in vitro (Fig. 3Go, A and B). In contrast, LNCs from untreated BALB/c mice produced high amounts of IL-4 but no IFN-{gamma} (Fig. 3Go, A and B). In addition, the IgG isotype pattern of L. major-specific Abs was typical for a Th1 response in CpG-ODN-treated BALB/c mice (Fig. 3GoC). IgG1 was reduced, while IgG2a and IgG2b was markedly enhanced. To obtain direct evidence for Th1 development in vivo, we determined IL-12Rß2 mRNA expression on isolated LNCs and spleen cells 10 days postinfection; this expression is known to be abolished in Th2 cells (19). Following CpG-ODN treatment, IL-12Rß2 mRNA expression in lymphocytes from L. major-infected BALB/c mice was similar to that observed in resistant C57BL/6 mice (Fig. 3GoD). In contrast, IL-12Rß2 mRNA was not detectable in untreated BALB/c mice (Fig. 3GoD). Th1 development may be explained by the ability of CpG-ODN to antagonize L. major-mediated suppression of IL-12 production (20, 21). To directly support this hypothesis, we determined IL-12 serum levels in L. major-infected BALB/c mice. CpG-ODN-treated mice had 10-fold higher serum levels of IL-12 than L. major-infected control mice 16 h postinfection (data not shown). Thus CpG-ODN directed the anti-L. major immune response toward a Th1 phenotype.



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  		FIGURE 3. Induction of the Th1 phenotype in L. major-infected mice by CpG-ODN. BALB/c mice were infected with 2 x 106 L. major promastigotes into the right footpad (three mice per group). One group was treated with CpG-ODN 2 h before and 10 h after infection as detailed in Figure 2Go. After 6 wk, mice were sacrificed, and blood serum and LNCs were recovered (gray bars, ODN-treated mice; hatched bars, control mice). In A and B, lymphocytes from the draining lymph nodes were restimulated in vitro with LmAg for 48 h. Thereafter, the IL-4 and IFN-{gamma} content of the culture supernatants was analyzed by ELISA. In C, the serum was analyzed for L. major-specific Abs of the IgG1, IgG2a, and IgG2b isotype. In D, total mRNA of draining LNCs and spleen cells was isolated (day 10 after infection) and analyzed by PCR for the expression of IL-12Rß2 transcripts (upper panel). The internal housekeeping gene ß-actin served as a control (lower panel).

 
While Th2 development can be prevented by either anti-IL-4 (13, 22) or IL-12 (23, 24) in the first days after infection, established Th2 responses are not susceptible to these regulatory mechanisms. Treatment with anti-IL-4 or IL-12 following infection with L. major is effective only within the first 3 days; at later time points, even multiple injections of IL-12 fail to influence the course of infection (25). Since CpG-ODN effectively stimulate NK cells to produce IFN-{gamma} (26), and since there is evidence that IFN-{gamma} can redirect Th2 responses in vitro and in vivo (27, 28), we tested the curative effect of CpG-ODN in L. major-infected BALB/c mice. Single injections of CpG-ODN were curative when given during the first 8 days of infection but failed when given later (data not shown). Because multiple combined injections of IL-12 plus the anti-leishmanial drug pentostam are capable of curing 85% of diseased animals at 3 wk postinfection (25), we subsequently evaluated multiple CpG-ODN applications during the late phase of infection. BALB/c mice were infected with L. major and then treated with three consecutive doses of CpG-ODN starting on day 15 or 20 postinfection (Fig. 4GoA). This regimen reduced the lesion size, and five of six mice ultimately controlled the infection (Fig. 4GoA). Reinfection of mice after 16 wk resulted in only a slight and transient increase in footpad thickness (Fig. 4GoA). The administration of L-NIL led to an exacerbation of the lesions; however, these lesions disappeared again after the withdrawal of L-NIL (Fig. 4GoA). Hence ODN-cured mice control infection by a NO-dependent mechanism (Fig. 4GoA). To obtain additional evidence for Th1 development in ODN-cured mice, we determined IL-12Rß2 mRNA expression and cytokine production profiles. Lymphocytes from ODN-cured mice produced high amounts of IFN-{gamma} (Fig. 4GoC) but little IL-4 (Fig. 4GoB) upon restimulation with LmAg in vitro. In addition, they expressed IL-12Rß2 mRNA similar to resistant C57BL/6 mice (Fig. 4GoD). In contrast, normal BALB/c mice only showed weak expression (Fig. 4GoD). Thus, CpG-ODN therapy in BALB/c mice not only prevents the development of Th2 responses causing lethal leishmaniasis but also reverts an already established Th2 polarization toward a protective Th1 response.



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  		FIGURE 4. Cure of established murine leishmaniasis by CpG-ODN. A, Mice were infected with 2 x 105 parasites and received three injections (5 nmol i.p. and 5 nmol at the site of infection) of CpG-ODN every 5 days starting at day 15 (triangles) or day 20 (squares) (cure of infection was observed in five of six mice). Open circles indicate the untreated control group. After 16 wk, the ODN-treated mice were reinfected with L. major. After 25 wk, the drinking water of half of the ODN-treated (day 15) mice was supplemented with L-NIL for 2 wk (shaded triangles). B, C, and D, Mice were challenged with LmAg at 6 wk after reinfection, and lymphocytes from the draining lymph nodes were recovered 4 days later (gray bars, ODN-treated mice; hatched bars, control mice). In B and C, the nonadherent fraction was restimulated in vivo with LmAg, and the supernatants were analyzed for IL-4 (b) or IFN-{gamma} content by ELISA 48 h later. Infected BALB/c mice that were restimulated 6 wk after infection served as a control (hatched bars). In D, the expression of IL-12Rß2 mRNA was analyzed as detailed in Figure 3Go (upper panel, IL-12ß2 transcripts; lower panel, ß-actin).

 
As CD4+ T cells in L. major-infected BALB/c mice lose IL-12Rß2 expression and consequently lose IL-12 responsiveness within the first 3 days of infection (21), it is likely that the protective and curative effects of CpG-ODN are mediated by different pathways. During the early phases of L. major infection, CpG-ODN-induced IL-12 production in APCs may be sufficient to shift Ag-reactive CD4+ T cells toward Th1 responsiveness. In late phase disease, additional effects of CpG-ODN might be operational. IFN-{gamma} has been shown to restore IL-12 responsiveness in Th2 cells (28). In addition, successful therapy of leishmaniasis with IFN-{gamma} and pentostam depended upon continued endogenous IL-12 production (29). Thus, during late infection, the curative effect of CpG-ODN may depend upon the ability of CpG-ODN to restore IL-12 responsiveness by promoting IFN-{gamma} production in NK cells (26) and in Ag-reactive T cells (Fig. 1Go); this effect may also depend upon the capacity of CpG-ODN to trigger endogenous IL-12 production.

In summary, our findings indicate that CpG-ODN influence the course of Th1 vs Th2 development in vitro and in vivo. By the same token, the data reveal a therapeutic potential of CpG-ODN in shifting an established Th2-driven disease toward a protective Th1 response. The capacity of CpG-ODN to promote and redirect Th1 development may have a price if potentially autoreactive T cells become activated (30) or if overshooting cytokine release leads to conditions for septic shock (4, 5). Recent results indicate the possibility of segregating "dangerous" ODN, which preferentially induce TNF-{alpha} from potentially curative ODN that trigger IL-12 (9). Understanding the molecular action of ODN will continue to promote progress in engineering therapeutically useful ODN in the treatment of Th2-driven disease.


   Footnotes
 
1 This work was supported by grants from the Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie, Sonderforschungsbereich 322 and 217, and the Wilhelm-Sander Stiftung. Back

2 Address correspondence and reprint requests to Dr. Klaus Heeg, Institute of Medical Microbiology, Immunology and Hygiene, Technische Universität München, Trogerstraße 32, D-81675 München, Germany. E-mail address: Back

3 Abbreviations used in this paper: ODN, oligodeoxynucleotides; CpG-ODN, CpG-containing oligodeoxynucleotides; LNC, lymph node cell; NO, nitric oxide. Back

Received for publication October 29, 1997. Accepted for publication February 5, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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R. B. Anderson, G. J. Cianciolo, M. N. Kennedy, and S. V. Pizzo
{alpha}2-Macroglobulin binds CpG oligodeoxynucleotides and enhances their immunostimulatory properties by a receptor-dependent mechanism
J. Leukoc. Biol., February 1, 2008; 83(2): 381 - 392.
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A. C. Hsu and P. Scott
Leishmania mexicana Infection Induces Impaired Lymph Node Expansion and Th1 Cell Differentiation Despite Normal T Cell Proliferation
J. Immunol., December 15, 2007; 179(12): 8200 - 8207.
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U. Bhan, N. W. Lukacs, J. J. Osterholzer, M. W. Newstead, X. Zeng, T. A. Moore, T. R. McMillan, A. M. Krieg, S. Akira, and T. J. Standiford
TLR9 Is Required for Protective Innate Immunity in Gram-Negative Bacterial Pneumonia: Role of Dendritic Cells
J. Immunol., September 15, 2007; 179(6): 3937 - 3946.
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A. M. Krieg
Antiinfective Applications of Toll-like Receptor 9 Agonists
Proceedings of the ATS, July 1, 2007; 4(3): 289 - 294.
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D. S. Spinner, R. B. Kascsak, G. LaFauci, H. C. Meeker, X. Ye, M. J. Flory, J. I. Kim, G. B. Schuller-Levis, W. R. Levis, T. Wisniewski, et al.
CpG oligodeoxynucleotide-enhanced humoral immune response and production of antibodies to prion protein PrPSc in mice immunized with 139A scrapie-associated fibrils
J. Leukoc. Biol., June 1, 2007; 81(6): 1374 - 1385.
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L. M. Johnson and P. Scott
STAT1 Expression in Dendritic Cells, but Not T Cells, Is Required for Immunity to Leishmania major
J. Immunol., June 1, 2007; 178(11): 7259 - 7266.
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T. H. Harris, J. M. Mansfield, and D. M. Paulnock
CpG Oligodeoxynucleotide Treatment Enhances Innate Resistance and Acquired Immunity to African Trypanosomes
Infect. Immun., May 1, 2007; 75(5): 2366 - 2373.
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R. R. Flores, K. A. Diggs, L. M. Tait, and P. A. Morel
IFN-{gamma} Negatively Regulates CpG-Induced IL-10 in Bone Marrow-Derived Dendritic Cells
J. Immunol., January 1, 2007; 178(1): 211 - 218.
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J. A. Pedras-Vasconcelos, D. Goucher, M. Puig, L. H. Tonelli, V. Wang, S. Ito, and D. Verthelyi
CpG oligodeoxynucleotides protect newborn mice from a lethal challenge with the neurotropic tacaribe arenavirus.
J. Immunol., April 15, 2006; 176(8): 4940 - 4949.
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Y. Wang, K. Abel, K. Lantz, A. M. Krieg, M. B. McChesney, and C. J. Miller
The Toll-Like Receptor 7 (TLR7) Agonist, Imiquimod, and the TLR9 Agonist, CpG ODN, Induce Antiviral Cytokines and Chemokines but Do Not Prevent Vaginal Transmission of Simian Immunodeficiency Virus When Applied Intravaginally to Rhesus Macaques
J. Virol., November 15, 2005; 79(22): 14355 - 14370.
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S. Iborra, J. Carrion, C. Anderson, C. Alonso, D. Sacks, and M. Soto
Vaccination with the Leishmania infantum Acidic Ribosomal P0 Protein plus CpG Oligodeoxynucleotides Induces Protection against Cutaneous Leishmaniasis in C57BL/6 Mice but Does Not Prevent Progressive Disease in BALB/c Mice
Infect. Immun., September 1, 2005; 73(9): 5842 - 5852.
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 Infect. Immun.Home page
S. Ito, J. Pedras-Vasconcelos, and D. M. Klinman
CpG Oligodeoxynucleotides Increase the Susceptibility of Normal Mice to Infection by Candida albicans
Infect. Immun., September 1, 2005; 73(9): 6154 - 6156.
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 Infect. Immun.Home page
B. Flynn, V. Wang, D. L. Sacks, R. A Seder, and D. Verthelyi
Prevention and Treatment of Cutaneous Leishmaniasis in Primates by Using Synthetic Type D/A Oligodeoxynucleotides Expressing CpG Motifs
Infect. Immun., August 1, 2005; 73(8): 4948 - 4954.
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S. Matsumoto, M. Matsumoto, K. Umemori, Y. Ozeki, M. Furugen, T. Tatsuo, Y. Hirayama, S. Yamamoto, T. Yamada, and K. Kobayashi
DNA Augments Antigenicity of Mycobacterial DNA-Binding Protein 1 and Confers Protection against Mycobacterium tuberculosis Infection in Mice
J. Immunol., July 1, 2005; 175(1): 441 - 449.
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 Nucleic Acids ResHome page
A. Grajkowski, J. Pedras-Vasconcelos, V. Wang, C. Ausin, S. Hess, D. Verthelyi, and S. L. Beaucage
Thermolytic CpG-containing DNA oligonucleotides as potential immunotherapeutic prodrugs
Nucleic Acids Res., June 21, 2005; 33(11): 3550 - 3560.
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 Infect. Immun.Home page
D. N. Wedlock, M. Denis, M. A. Skinner, J. Koach, G. W. de Lisle, H. M. Vordermeier, R. G. Hewinson, S. van Drunen Littel-van den Hurk, L. A. Babiuk, R. Hecker, et al.
Vaccination of Cattle with a CpG Oligodeoxynucleotide-Formulated Mycobacterial Protein Vaccine and Mycobacterium bovis BCG Induces Levels of Protection against Bovine Tuberculosis Superior to Those Induced by Vaccination with BCG Alone
Infect. Immun., June 1, 2005; 73(6): 3540 - 3546.
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 Infect. Immun.Home page
S. Ito, K. J. Ishii, A. Ihata, and D. M. Klinman
Contribution of Nitric Oxide to CpG-Mediated Protection against Listeria monocytogenes
Infect. Immun., June 1, 2005; 73(6): 3803 - 3805.
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 CVIHome page
K. Abel, Y. Wang, L. Fritts, E. Sanchez, E. Chung, P. Fitzgerald-Bocarsly, A. M. Krieg, and C. J. Miller
Deoxycytidyl-Deoxyguanosine Oligonucleotide Classes A, B, and C Induce Distinct Cytokine Gene Expression Patterns in Rhesus Monkey Peripheral Blood Mononuclear Cells and Distinct Alpha Interferon Responses in TLR9-Expressing Rhesus Monkey Plasmacytoid Dendritic Cells
Clin. Vaccine Immunol., May 1, 2005; 12(5): 606 - 621.
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S. Ito, K. J. Ishii, M. Gursel, H. Shirotra, A. Ihata, and D. M. Klinman
CpG Oligodeoxynucleotides Enhance Neonatal Resistance to Listeria Infection
J. Immunol., January 15, 2005; 174(2): 777 - 782.
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E. Schlaepfer, A. Audige, B. von Beust, V. Manolova, M. Weber, H. Joller, M. F. Bachmann, T. M. Kundig, and R. F. Speck
CpG Oligodeoxynucleotides Block Human Immunodeficiency Virus Type 1 Replication in Human Lymphoid Tissue Infected Ex Vivo
J. Virol., November 15, 2004; 78(22): 12344 - 12354.
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J. C. Deng, T. A. Moore, M. W. Newstead, X. Zeng, A. M. Krieg, and T. J. Standiford
CpG Oligodeoxynucleotides Stimulate Protective Innate Immunity against Pulmonary Klebsiella Infection
J. Immunol., October 15, 2004; 173(8): 5148 - 5155.
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 Infect. Immun.Home page
S.-i. Ito, K. J. Ishii, H. Shirota, and D. M. Klinman
CpG Oligodeoxynucleotides Improve the Survival of Pregnant and Fetal Mice following Listeria monocytogenes Infection
Infect. Immun., June 1, 2004; 72(6): 3543 - 3548.
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X. Jiao, R. Y.-H. Wang, Q. Qiu, H. J. Alter, and J. W.-K. Shih
Enhanced hepatitis C virus NS3 specific Th1 immune responses induced by co-delivery of protein antigen and CpG with cationic liposomes
J. Gen. Virol., June 1, 2004; 85(6): 1545 - 1553.
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J. R. Ramirez-Pineda, A. Frohlich, C. Berberich, and H. Moll
Dendritic Cells (DC) Activated by CpG DNA Ex Vivo Are Potent Inducers of Host Resistance to an Intracellular Pathogen That Is Independent of IL-12 Derived from the Immunizing DC
J. Immunol., May 15, 2004; 172(10): 6281 - 6289.
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Y.-F. Chen, C.-W. Lin, Y.-P. Tsao, and S.-L. Chen
Cytotoxic-T-Lymphocyte Human Papillomavirus Type 16 E5 Peptide with CpG-Oligodeoxynucleotide Can Eliminate Tumor Growth in C57BL/6 Mice
J. Virol., February 1, 2004; 78(3): 1333 - 1343.
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M. P. Gould, J. A. Greene, V. Bhoj, J. L. DeVecchio, and F. P. Heinzel
Distinct Modulatory Effects of LPS and CpG on IL-18-Dependent IFN-{gamma} Synthesis
J. Immunol., February 1, 2004; 172(3): 1754 - 1762.
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 Infect. Immun.Home page
S. Raghavan, J. Nystrom, M. Fredriksson, J. Holmgren, and A. M. Harandi
Orally Administered CpG Oligodeoxynucleotide Induces Production of CXC and CC Chemokines in the Gastric Mucosa and Suppresses Bacterial Colonization in a Mouse Model of Helicobacter pylori Infection
Infect. Immun., December 1, 2003; 71(12): 7014 - 7022.
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A. Debus, J. Glasner, M. Rollinghoff, and A. Gessner
High Levels of Susceptibility and T Helper 2 Response in MyD88-Deficient Mice Infected with Leishmania major Are Interleukin-4 Dependent
Infect. Immun., December 1, 2003; 71(12): 7215 - 7218.
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H. Shao, S. Lei, S. L. Sun, J. Xiang, H. J. Kaplan, and D. Sun
CpG-Containing Oligodeoxynucleotide 1826 Converts the Weak Uveitogenic Rat Interphotoreceptor Retinoid-Binding Protein Peptide 1181-1191 into a Strong Uveitogen
J. Immunol., November 1, 2003; 171(9): 4780 - 4785.
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A. R. M. Olbrich, S. Schimmer, and U. Dittmer
Preinfection Treatment of Resistant Mice with CpG Oligodeoxynucleotides Renders Them Susceptible to Friend Retrovirus-Induced Leukemia
J. Virol., October 1, 2003; 77(19): 10658 - 10662.
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S. Mendez, K. Tabbara, Y. Belkaid, S. Bertholet, D. Verthelyi, D. Klinman, R. A. Seder, and D. L. Sacks
Coinjection with CpG-Containing Immunostimulatory Oligodeoxynucleotides Reduces the Pathogenicity of a Live Vaccine against Cutaneous Leishmaniasis but Maintains Its Potency and Durability
Infect. Immun., September 1, 2003; 71(9): 5121 - 5129.
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A. A. Ashkar, S. Bauer, W. J. Mitchell, J. Vieira, and K. L. Rosenthal
Local Delivery of CpG Oligodeoxynucleotides Induces Rapid Changes in the Genital Mucosa and Inhibits Replication, but Not Entry, of Herpes Simplex Virus Type 2
J. Virol., August 15, 2003; 77(16): 8948 - 8956.
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J. Kochling, S. A. Konig-Merediz, R. Stripecke, D. Buchwald, A. Korte, H. G. von Einsiedel, F. Sack, G. Henze, K. Seeger, B. Wittig, et al.
Protection of Mice against Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia by Cell-based Vaccination Using Nonviral, Minimalistic Expression Vectors and Immunomodulatory Oligonucleotides
Clin. Cancer Res., August 1, 2003; 9(8): 3142 - 3149.
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I. Gursel, M. Gursel, H. Yamada, K. J. Ishii, F. Takeshita, and D. M. Klinman
Repetitive Elements in Mammalian Telomeres Suppress Bacterial DNA-Induced Immune Activation
J. Immunol., August 1, 2003; 171(3): 1393 - 1400.
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D. Verthelyi, M. Gursel, R. T. Kenney, J. D. Lifson, S. Liu, J. Mican, and D. M. Klinman
CpG Oligodeoxynucleotides Protect Normal and SIV-Infected Macaques from Leishmania Infection
J. Immunol., May 1, 2003; 170(9): 4717 - 4723.
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S. Gomis, L. Babiuk, D. L. Godson, B. Allan, T. Thrush, H. Townsend, P. Willson, E. Waters, R. Hecker, and A. Potter
Protection of Chickens against Escherichia coli Infections by DNA Containing CpG Motifs
Infect. Immun., February 1, 2003; 71(2): 857 - 863.
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 Int ImmunolHome page
Y. Wang and A. M. Krieg
Synergy between CpG- or non-CpG DNA and specific antigen for B cell activation
Int. Immunol., February 1, 2003; 15(2): 223 - 231.
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H.-J. Anders, B. Banas, Y. Linde, L. Weller, C. D. Cohen, M. Kretzler, S. Martin, V. Vielhauer, D. Schlondorff, and H.-J. Grone
Bacterial CpG-DNA Aggravates Immune Complex Glomerulonephritis: Role of TLR9-Mediated Expression of Chemokines and Chemokine Receptors
J. Am. Soc. Nephrol., February 1, 2003; 14(2): 317 - 326.
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A. M. Harandi, K. Eriksson, and J. Holmgren
A Protective Role of Locally Administered Immunostimulatory CpG Oligodeoxynucleotide in a Mouse Model of Genital Herpes Infection
J. Virol., December 20, 2002; 77(2): 953 - 962.
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F.-G. Zhu, C. F. Reich, and D. S. Pisetsky
Inhibition of murine dendritic cell activation by synthetic phosphorothioate oligodeoxynucleotides
J. Leukoc. Biol., December 1, 2002; 72(6): 1154 - 1163.
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H. Yamada, I. Gursel, F. Takeshita, J. Conover, K. J. Ishii, M. Gursel, S. Takeshita, and D. M. Klinman
Effect of Suppressive DNA on CpG-Induced Immune Activation
J. Immunol., November 15, 2002; 169(10): 5590 - 5594.
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L. SFONDRINI, D. BESUSSO, C. RUMIO, M. RODOLFO, S. MENARD, and A. BALSARI
Prevention of spontaneous mammary adenocarcinoma in HER-2/neu transgenic mice by foreign DNA
FASEB J, November 1, 2002; 16(13): 1749 - 1754.
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A. R. M. Olbrich, S. Schimmer, K. Heeg, K. Schepers, T. N. M. Schumacher, and U. Dittmer
Effective Postexposure Treatment of Retrovirus-Induced Disease with Immunostimulatory DNA Containing CpG Motifs
J. Virol., October 11, 2002; 76(22): 11397 - 11404.
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K. Heckelsmiller, K. Rall, S. Beck, A. Schlamp, J. Seiderer, B. Jahrsdorfer, A. Krug, S. Rothenfusser, S. Endres, and G. Hartmann
Peritumoral CpG DNA Elicits a Coordinated Response of CD8 T Cells and Innate Effectors to Cure Established Tumors in a Murine Colon Carcinoma Model
J. Immunol., October 1, 2002; 169(7): 3892 - 3899.
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L. Sfondrini, D. Besusso, M. T. Zoia, M. Rodolfo, A. M. Invernizzi, M. Taniguchi, T. Nakayama, M. P. Colombo, S. Menard, and A. Balsari
Absence of the CD1 Molecule Up-Regulates Antitumor Activity Induced by CpG Oligodeoxynucleotides in Mice
J. Immunol., July 1, 2002; 169(1): 151 - 158.
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E. G. Rhee, S. Mendez, J. A. Shah, C.-y. Wu, J. R. Kirman, T. N. Turon, D. F. Davey, H. Davis, D. M. Klinman, R. N. Coler, et al.
Vaccination with Heat-killed Leishmania Antigen or Recombinant Leishmanial Protein and CpG Oligodeoxynucleotides Induces Long-Term Memory CD4+and CD8+T Cell Responses and Protection Against Leishmania major Infection
J. Exp. Med., June 17, 2002; 195(12): 1565 - 1573.
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M. Gierynska, U. Kumaraguru, S.-K. Eo, S. Lee, A. Krieg, and B. T. Rouse
Induction of CD8 T-Cell-Specific Systemic and Mucosal Immunity against Herpes Simplex Virus with CpG-Peptide Complexes
J. Virol., June 5, 2002; 76(13): 6568 - 6576.
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A. Campos-Neto, J. R. Webb, K. Greeson, R. N. Coler, Y. A. W. Skeiky, and S. G. Reed
Vaccination with Plasmid DNA Encoding TSA/LmSTI1 Leishmanial Fusion Proteins Confers Protection against Leishmania major Infection in Susceptible BALB/c Mice
Infect. Immun., June 1, 2002; 70(6): 2828 - 2836.
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A. H. Dalpke, M. K.-H. Schafer, M. Frey, S. Zimmermann, J. Tebbe, E. Weihe, and K. Heeg
Immunostimulatory CpG-DNA Activates Murine Microglia
J. Immunol., May 15, 2002; 168(10): 4854 - 4863.
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Y. He, R. Vemulapalli, and G. G. Schurig
Recombinant Ochrobactrum anthropi Expressing Brucella abortus Cu,Zn Superoxide Dismutase Protects Mice against B. abortus Infection Only after Switching of Immune Responses to Th1 Type
Infect. Immun., May 1, 2002; 70(5): 2535 - 2543.
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 Nucleic Acids ResHome page
D. Yu, E. R. Kandimalla, Q. Zhao, Y. Cong, and S. Agrawal
Immunostimulatory properties of phosphorothioate CpG DNA containing both 3'-5'- and 2'-5'-internucleotide linkages
Nucleic Acids Res., April 1, 2002; 30(7): 1613 - 1619.
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N. P. Juffermans, J. C. Leemans, S. Florquin, A. Verbon, A. H. Kolk, P. Speelman, S. J. H. van Deventer, and T. van der Poll
CpG Oligodeoxynucleotides Enhance Host Defense during Murine Tuberculosis
Infect. Immun., January 1, 2002; 70(1): 147 - 152.
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Z. K. Ballas, A. M. Krieg, T. Warren, W. Rasmussen, H. L. Davis, M. Waldschmidt, and G. J. Weiner
Divergent Therapeutic and Immunologic Effects of Oligodeoxynucleotides with Distinct CpG Motifs
J. Immunol., November 1, 2001; 167(9): 4878 - 4886.
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T. Hayashi, S. P. Rao, K. Takabayashi, J. H. Van Uden, R. S. Kornbluth, S. M. Baird, M. W. Taylor, D. A. Carson, A. Catanzaro, and E. Raz
Enhancement of Innate Immunity against Mycobacterium avium Infection by Immunostimulatory DNA Is Mediated by Indoleamine 2,3-Dioxygenase
Infect. Immun., October 1, 2001; 69(10): 6156 - 6164.
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B. Mui, S. G. Raney, S. C. Semple, and M. J. Hope
Immune Stimulation by a CpG-Containing Oligodeoxynucleotide Is Enhanced When Encapsulated and Delivered in Lipid Particles
J. Pharmacol. Exp. Ther., September 1, 2001; 298(3): 1185 - 1192.
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K. H. Baek, S. J. Ha, and Y. C. Sung
A Novel Function of Phosphorothioate Oligodeoxynucleotides as Chemoattractants for Primary Macrophages
J. Immunol., September 1, 2001; 167(5): 2847 - 2854.
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B. E. Britigan, T. S. Lewis, M. Waldschmidt, M. L. McCormick, and A. M. Krieg
Lactoferrin Binds CpG-Containing Oligonucleotides and Inhibits Their Immunostimulatory Effects on Human B Cells
J. Immunol., September 1, 2001; 167(5): 2921 - 2928.
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 BloodHome page
B. R. Blazar, A. M. Krieg, and P. A. Taylor
Synthetic unmethylated cytosine-phosphate-guanosine oligodeoxynucleotides are potent stimulators of antileukemia responses in naive and bone marrow transplant recipients
Blood, August 15, 2001; 98(4): 1217 - 1225.
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H. W. Murray
Clinical and Experimental Advances in Treatment of Visceral Leishmaniasis
Antimicrob. Agents Chemother., August 1, 2001; 45(8): 2185 - 2197.
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A. Al-Mariri, A. Tibor, P. Mertens, X. De Bolle, P. Michel, J. Godefroid, K. Walravens, and J.-J. Letesson
Protection of BALB/c Mice against Brucella abortus 544 Challenge by Vaccination with Bacterioferritin or P39 Recombinant Proteins with CpG Oligodeoxynucleotides as Adjuvant
Infect. Immun., August 1, 2001; 69(8): 4816 - 4822.
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M. Hafner, R. Zawatzky, C. Hirtreiter, W. A. Buurman, B. Echtenacher, T. Hehlgans, and D. N. Mannel
Antimetastatic Effect of CpG DNA Mediated by Type I IFN
Cancer Res., July 1, 2001; 61(14): 5523 - 5528.
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H. Shirota, K. Sano, N. Hirasawa, T. Terui, K. Ohuchi, T. Hattori, K. Shirato, and G. Tamura
Novel Roles of CpG Oligodeoxynucleotides as a Leader for the Sampling and Presentation of CpG-Tagged Antigen by Dendritic Cells
J. Immunol., July 1, 2001; 167(1): 66 - 74.
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E. Handman
Leishmaniasis: Current Status of Vaccine Development
Clin. Microbiol. Rev., April 1, 2001; 14(2): 229 - 243.
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B. Bohle, L. Orel, D. Kraft, and C. Ebner
Oligodeoxynucleotides Containing CpG Motifs Induce Low Levels of TNF-{{alpha}} in Human B Lymphocytes: Possible Adjuvants for Th1 Responses
J. Immunol., March 15, 2001; 166(6): 3743 - 3748.
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R. A. Gramzinski, D. L. Doolan, M. Sedegah, H. L. Davis, A. M. Krieg, and S. L. Hoffman
Interleukin-12- and Gamma Interferon-Dependent Protection against Malaria Conferred by CpG Oligodeoxynucleotide in Mice
Infect. Immun., March 1, 2001; 69(3): 1643 - 1649.
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H. Ito, J. Kurtz, J. Shaffer, and M. Sykes
CD4 T Cell-Mediated Alloresistance to Fully MHC-Mismatched Allogeneic Bone Marrow Engraftment Is Dependent on CD40-CD40 Ligand Interactions, and Lasting T Cell Tolerance Is Induced by Bone Marrow Transplantation with Initial Blockade of this Pathway
J. Immunol., March 1, 2001; 166(5): 2970 - 2981.
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