Cooperation of Oligodeoxynucleotides and Synthetic Molecules as Enhanced Immune Modulators

Unmethylated cytosine–guanine dinucleotide (CpG) motifs are potent stimulators of the host immune response. Cellular recognition of CpG motifs occurs via Toll-like receptor 9 (TLR9), which normally activates immune responses to pathogen-associated molecular patterns (PAMPs) indicative of infection. Oligodeoxynucleotides (ODNs) containing unmethylated CpGs mimic the immunostimulatory activity of viral/microbial DNA. Synthetic ODNs harboring CpG motifs resembling those identified in viral/microbial DNA trigger an identical response, such that these immunomodulatory ODNs have therapeutic potential. CpG DNA has been investigated as an agent for the management of malignancy, asthma, allergy, and contagious diseases, and as an adjuvant in immunotherapy. In this review, we discuss the potential synergy between synthetic ODNs and other synthetic molecules and their immunomodulatory effects. We also summarize the different synthetic molecules that function as immune modulators and outline the phenomenon of TLR-mediated immune responses. We previously reported a novel synthetic ODN that acts synergistically with other synthetic molecules (including CpG ODNs, the synthetic triacylated lipopeptide Pam3CSK4, lipopolysaccharide, and zymosan) that could serve as an immune therapy. Additionally, several clinical trials have evaluated the use of CpG ODNs with other immune factors such as granulocyte-macrophage colony-stimulating factor, cytokines, and both endosomal and cell-surface TLR ligands as adjuvants for the augmentation of vaccine activity. Furthermore, we discuss the structural recognition of ODNs by TLRs and the mechanism of functional modulation of TLRs in the context of the potential application of ODNs as wide-spectrum therapeutic agents.

• Publication year

  2019

• Venue

  Frontiers in Nutrition

• Publication date

  2019-08-27

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.3389/fnut.2019.00140PMID 31508424PMCID 6718720
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Immune synergistic oligodeoxynucleotide from Lactobacillus rhamnosus GG enhances the immune response upon co-stimulation by bacterial and fungal cell wall components.

  2018cited by this paper
• Encapsulation of two different TLR ligands into liposomes confer protective immunity and prevent tumor development

  2017cited by this paper
• Synergistic oligodeoxynucleotide strongly promotes CpG-induced interleukin-6 production

  2017cited by this paper
• A Role for Syntaxin 3 in the Secretion of IL-6 from Dendritic Cells Following Activation of Toll-Like Receptors

  2015cited by this paper
• TLR-9 and IL-15 Synergy Promotes the In Vitro Clonal Expansion of Chronic Lymphocytic Leukemia B Cells

  2015influential reference
• TLR9 and STING agonists synergistically induce innate and adaptive type-II IFN

  2015cited by this paper
• Inhibitory/suppressive oligodeoxynucleotide nanocapsules as simple oral delivery devices for preventing atopic dermatitis in mice.

  2015cited by this paper
• The Early Induction of Suppressor of Cytokine Signaling 1 and the Downregulation of Toll-like Receptors 7 and 9 Induce Tolerance in Costimulated Macrophages

  2014cited by this paper
• The effect of combined IL10 siRNA and CpG ODN as pathogen-mimicking microparticles on Th1/Th2 cytokine balance in dendritic cells and protective immunity against B cell lymphoma.

  2014cited by this paper
• Clinical evaluation of CpG oligonucleotides as adjuvants for vaccines targeting infectious diseases and cancer.

  2014cited by this paper
• Synergistic induction of interferon α through TLR-3 and TLR-9 agonists stimulates immune responses against measles virus in neonatal cotton rats.

  2014cited by this paper
• Leukocyte Behavior in Atherosclerosis, Myocardial Infarction, and Heart Failure

  2013cited by this paper
• Synergistic Induction of Interferon α through TLR-3 and TLR-9 Agonists Identifies CD21 as Interferon α Receptor for the B Cell Response

  2013cited by this paper
• Synergistic stimulation of antigen presenting cells via TLR by combining CpG ODN and poly(γ-glutamic acid)-based nanoparticles as vaccine adjuvants.

  2013cited by this paper
• A p53 Axis Regulates B Cell Receptor-Triggered, Innate Immune System-Driven B Cell Clonal Expansion

  2012cited by this paper
• Class I/II hybrid inhibitory oligodeoxynucleotide exerts Th1 and Th2 double immunosuppression

  2012cited by this paper
• Simultaneous TLR2 inhibition and TLR9 activation synergistically suppress tumor metastasis in mice

  2012cited by this paper
• Nano-particle vaccination combined with TLR-7 and -9 ligands triggers memory and effector CD8+ T-cell responses in melanoma patients

  2012cited by this paper
• CpG DNA in the Prevention and Treatment of Infections

  2012cited by this paper
• Hydroxychloroquine is associated with impaired interferon-alpha and tumor necrosis factor-alpha production by plasmacytoid dendritic cells in systemic lupus erythematosus

  2012cited by this paper
• Phase I trial of Wilms' Tumor 1 (WT1) peptide vaccine with GM-CSF or CpG in patients with solid malignancy.

  2012cited by this paper
• Natural innate and adaptive immunity to cancer.

  2011cited by this paper
• Insights into the regulatory mechanism controlling the inhibition of vaccine-induced seroconversion by maternal antibodies.

  2011cited by this paper
• Metabolism, migration and memory in cytotoxic T cells

  2011cited by this paper
• Autoimmunity and treatment outcome in melanoma

  2011cited by this paper
• A single vaccination with an inactivated bovine respiratory syncytial virus vaccine primes the cellular immune response in calves with maternal antibody

  2010cited by this paper
• TLR9 expression in glioma tissues correlated to glioma progression and the prognosis of GBM patients

  2010cited by this paper
• IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease-associated inflammation and lymphomagenesis.

  2010cited by this paper
• Response to experimentally induced infection with bovine respiratory syncytial virus following intranasal vaccination of seropositive and seronegative calves.

  2010cited by this paper
• Programming the magnitude and persistence of antibody responses with innate immunity

  2010cited by this paper
• A clear correlation between WT1-specific Th response and clinical response in WT1 CTL epitope vaccination.

  2010cited by this paper
• The role of mTOR in memory CD8+ T‐cell differentiation

  2010cited by this paper
• Macrophages, innate immunity and cancer: balance, tolerance, and diversity.

  2010cited by this paper
• Accelerated wound healing mediated by activation of Toll‐like receptor 9

  2010cited by this paper
• The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors

  2010cited by this paper
• A Novel Class of Immune-Stimulatory CpG Oligodeoxynucleotides Unifies High Potency in Type I Interferon Induction with Preferred Structural Properties

  2010cited by this paper
• Toll-like receptor 2 mediates invasion via activating NF-kappaB in MDA-MB-231 breast cancer cells.

  2009cited by this paper
• Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis

  2009cited by this paper
• Human immunology of measles virus infection.

  2009cited by this paper
• Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells

  2009cited by this paper
• New insights into the regulation of human B-cell differentiation.

  2009cited by this paper
• Blocking TLR2 Activity Attenuates Pulmonary Metastases of Tumor

  2009cited by this paper
• In vivo dynamics of stable chronic lymphocytic leukemia inversely correlate with somatic hypermutation levels and suggest no major leukemic turnover in bone marrow.

  2008cited by this paper
• Pathogen recognition by innate receptors

  2008cited by this paper
• Advances in tumour immunotherapy.

  2008cited by this paper
• The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions

  2007cited by this paper
• Measles Virus-Specific CD4 T-Cell Activity Does Not Correlate with Protection against Lung Infection or Viral Clearance

  2007cited by this paper
• CD4+ Th1 cells promote CD8+ Tc1 cell survival, memory response, tumor localization and therapy by targeted delivery of interleukin 2 via acquired pMHC I complexes

  2007cited by this paper
• Comparative sequence analysis of leucine-rich repeats (LRRs) within vertebrate toll-like receptors

  2007cited by this paper
• The Akt signaling pathway determines the different proliferative capacity of chronic lymphocytic leukemia B-cells from patients with progressive and stable disease

  2007cited by this paper
• Therapeutic potential of Toll-like receptor 9 activation

  2006cited by this paper
• CD8+ T‐cell memory in tumor immunology and immunotherapy

  2006cited by this paper
• APRIL and BAFF Promote Increased Viability of Replicating Human B2 Cells via Mechanism Involving Cyclooxygenase 21

  2006cited by this paper
• Immunostimulatory oligodeoxynucleotides induce apoptosis of B cell chronic lymphocytic leukemia cells

  2005cited by this paper
• Suppressive Oligodeoxynucleotides Protect Mice from Lethal Endotoxic Shock1

  2005cited by this paper
• TLR2 Agonist Ameliorates Established Allergic Airway Inflammation by Promoting Th1 Response and Not via Regulatory T Cells1

  2005cited by this paper
• Innate Immunity and Human B Cell Clonal Expansion: Effects on the Recirculating B2 Subpopulation1

  2005cited by this paper
• Innate Immunity and Human B Cell Clonal Expansion: Effects on the Recirculating B2 Subpopulation

  2005cited by this paper
• Virally stimulated plasmacytoid dendritic cells produce chemokines and induce migration of T and NK cells

  2004cited by this paper
• Effect of maternal antibody on immunogenicity of hepatitis A vaccine in infants.

  2004cited by this paper
• Lymphoid follicle destruction and immunosuppression after repeated CpG oligodeoxynucleotide administration

  2004cited by this paper
• Toll-like receptors as an escape mechanism from the host defense.

  2004cited by this paper
• Species-Specific Recognition of Single-Stranded RNA via Toll-like Receptor 7 and 8

  2004cited by this paper
• Immunotherapeutic uses of CpG oligodeoxynucleotides

  2004cited by this paper
• Maternally derived humoral immunity to bovine viral diarrhea virus (BVDV) 1a, BVDV1b, BVDV2, bovine herpesvirus-1, parainfluenza-3 virus bovine respiratory syncytial virus, Mannheimia haemolytica and Pasteurella multocida in beef calves, antibody decline by half-life studies and effect on response t

  2004cited by this paper
• Follicular Dendritic Cells Produce IL-15 That Enhances Germinal Center B Cell Proliferation in Membrane-Bound Form1

  2004cited by this paper
• LPS-TLR4 Signaling to IRF-3/7 and NF-κB Involves the Toll Adapters TRAM and TRIF

  2003cited by this paper
• Influence of stimulatory and suppressive DNA motifs on host susceptibility to inflammatory arthritis.

  2003cited by this paper
• Toll-like receptors.

  2003cited by this paper
• Recognition of pathogen-associated molecular patterns by TLR family.

  2003cited by this paper
• Measles and mumps vaccination as a model to investigate the developing immune system: passive and active immunity during the first year of life.

  2003cited by this paper
• Towards optimal design of second-generation immunomodulatory oligonucleotides.

  2002cited by this paper
• CpG motifs in bacterial DNA and their immune effects.

  2002cited by this paper
• Influence of maternal antibodies on efficacy of a subunit vaccine: transmission of classical swine fever virus between pigs vaccinated at 2 weeks of age.

  2002cited by this paper
• Toll‐like receptor 9 mediates CpG‐DNA signaling

  2002cited by this paper
• Toll-like receptors and their signaling mechanism in innate immunity

  2001cited by this paper
• Bacterial CpG-DNA Triggers Activation and Maturation of Human CD11c−, CD123+ Dendritic Cells1

  2001cited by this paper
• Roles of Toll‐like receptors in innate immune responses

  2001cited by this paper
• Toll-like receptors: critical proteins linking innate and acquired immunity

  2001cited by this paper
• Maternal antibody to infectious bronchitis virus: its role in protection against infection and development of active immunity to vaccine

  2001cited by this paper
• Human Peripheral Blood Cells Differentially Recognize and Respond to Two Distinct CpG Motifs1 2

  2001cited by this paper
• Cutting Edge: Role of Toll-Like Receptor 9 in CpG DNA-Induced Activation of Human Cells1

  2001cited by this paper
• Age‐ and dose‐interval‐dependent antibody responses to inactivated poliovirus vaccine

  2001cited by this paper
• Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3

  2001cited by this paper
• Type 1/Type 2 immunity in infectious diseases.

  2001cited by this paper
• Interleukin 15: biology and relevance to human disease.

  2001cited by this paper
• Immune responses to measles and mumps vaccination of infants at 6, 9, and 12 months.

  2001cited by this paper
• The Journal of Experimental Medicine

  2000cited by this paper
• Immune responses to DNA in normal and aberrant immunity

  2000cited by this paper
• Immunostimulatory CpG-oligonucleotides cause proliferation, cytokine production, and an immunogenic phenotype in chronic lymphocytic leukemia B cells.

  2000cited by this paper
• Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: Evidence in Crohn disease and experimental colitis in vivo

  2000cited by this paper
• Immunization against hepatitis A in the first year of life: priming despite the presence of maternal antibody.

  2000cited by this paper
• Cutting Edge: Cell Surface Expression and Lipopolysaccharide Signaling Via the Toll-Like Receptor 4-MD-2 Complex on Mouse Peritoneal Macrophages1

  2000cited by this paper
• IL-6 Is Required for the Development of Th1 Cell-Mediated Murine Colitis1

  2000cited by this paper
• Intra-articularly localized bacterial DNA containing CpG motifs induces arthritis

  1999cited by this paper
• IL-12, IFN-gamma, and T cell proliferation to measles in immunized infants.

  1999cited by this paper
• The effects of DNA containing CpG motif on dendritic cells

  1998cited by this paper
• Immunostimulatory CpG oligodeoxynucleotides enhance the immune response to vaccine strategies involving granulocyte-macrophage colony-stimulating factor.

  1998cited by this paper
• Bacterial DNA and immunostimulatory CpG oligonucleotides trigger maturation and activation of murine dendritic cells

  1998cited by this paper
• Interleukin 15 is produced by endothelial cells and increases the transendothelial migration of T cells In vitro and in the SCID mouse-human rheumatoid arthritis model In vivo.

  1998cited by this paper

• Engineered exosome based immunomodulation therapies: Advancements and clinical applications

  2026cites this paper
• Cancer Vaccines: Molecular Mechanisms, Clinical Progress, and Combination Immunotherapies with a Focus on Hepatocellular Carcinoma

  2025cites this paper
• Nucleic Acid-Based Therapeutics for Periodontal Tissue Regeneration: A Comprehensive Review

  2025cites this paper
• Navigating the Hurdles of Intra-Articular AAV Gene Therapy

  2025cites this paper
• Bladder cancer immunotherapy parallel advances in BCG optimization and next-generation vaccine platforms

  2025cites this paper
• Harnessing cellular immunity for next-generation vaccines against respiratory viruses: mechanisms, platforms, and optimization strategies

  2025cites this paper
• In vitro characterization of the E. ruminantium pLAMP multi-epitope DNA poly (lactic-co-glycolic acid) nanoparticle vaccine in sheep peripheral blood mononuclear cells.

  2025cites this paper
• Chitosan Microparticles Coupled with MAGE-AX and CpGs as a Treatment for Murine Melanoma

  2025cites this paper
• Lung cancer vaccine strategies: exploring the spectrum from traditional to RNA-based platforms

  2025cites this paper
• Extremely Low Doses of CpG Oligodeoxynucleotides From Streptococcus thermophilus LacZ Strongly Induce CXCL5 in Macrophages.

  2025cites this paper
• In-vitro evaluation of cationic Lipopeptides as adjuvant candidate for DNA plasmid vaccine.

  2025cites this paper
• DNA vaccines as promising immuno-therapeutics against cancer: a new insight

  2025cites this paper
• A novel trivalent inactivated Salmonella vaccine formulated with CpG ODNs to enhance the cellular immunity in chickens

  2025cites this paper
• Vaccine approaches to treat urothelial cancer

  2024cites this paper
• Revolutionizing Cancer Treatment: Unleashing the Power of Viral Vaccines, Monoclonal Antibodies, and Proteolysis-Targeting Chimeras in the New Era of Immunotherapy

  2024cites this paper
• Effects of Synthetic Toll-Like Receptor 9 Ligand Molecules on Pulpal Immunomodulatory Response and Repair after Injuries

  2024cites this paper
• A novel immunomodulating peptide with potential to complement oligodeoxynucleotide-mediated adjuvanticity in vaccination strategies

  2024cites this paper
• New insights for the development of efficient DNA vaccines

  2024cites this paper
• Toll-like Receptor Ligands Enhance Vaccine Efficacy against a Virulent Newcastle Disease Virus Challenge in Chickens

  2023cites this paper
• Advancement in Polymer-Based Carrier for DNA Vaccine.

  2023cites this paper
• Cancer Vaccine Therapeutics: Limitations and Effectiveness—A Literature Review

  2023cites this paper
• Airway Epithelial-Derived Immune Mediators in COVID-19

  2023cites this paper
• RETRACTED ARTICLE: Novel adjuvant nano-vaccine induced immune response against Acinetobacter baumannii

  2023cites this paper
• The Debate between the Human Microbiota and Immune System in Treating Aerodigestive and Digestive Tract Cancers: A Review

  2023cites this paper
• Uncovering the complex role of interferon-gamma in suppressing type 2 immunity to cancer.

  2023cites this paper
• Cancer vaccines as promising immuno-therapeutics: platforms and current progress

  2022cites this paper
• Psidium guajava leaves extract decreased leukocytes and lymphocytes count in Complete Freund's Adjuvant-induced arthritis rats

  2022cites this paper
• Immunotherapy and Microbiota for Targeting of Liver Tumor-Initiating Stem-like Cells

  2022cites this paper
• Emerging Roles of Green-Synthesized Chalcogen and Chalcogenide Nanoparticles in Cancer Theranostics

  2022cites this paper
• Identification of a Novel Osteogenetic Oligodeoxynucleotide (osteoDN) That Promotes Osteoblast Differentiation in a TLR9-Independent Manner

  2022cites this paper
• Extracellular DNA: Insight of a Signal Molecule in Crop Protection

  2021cites this paper
• Methods to improve the immunogenicity of plasmid DNA vaccines.

  2021cites this paper
• Overcoming the challenges of tissue delivery for oligonucleotide therapeutics.

  2021cites this paper
• Extracellular DNA in blood products and its potential effects on transfusion

  2020cites this paper