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In Vitro Differentiation of Human CD4+FOXP3+ Induced Regulatory T Cells (iTregs) from Naïve CD4+ T Cells Using a TGF-β-containing Protocol
Published on: December 30, 2016
Immunoregulatory activity of CpG oligonucleotides in humans and nonhuman primates
Daniela Verthelyi1, Dennis M Klinman
1Division of Therapeutic Proteins, Food and Drug Administration, Building 29A Room 3B19, 8800 Rockville Pike, Bethesda, MD 20892, USA.
Abstract:
Oligodeoxynucleotides (ODN) containing CpG motifs mimic the ability of microbial DNA to activate the innate immune system. The resultant response limits the early spread of infectious organisms while promoting the development of adaptive immunity. CpG ODN show promise as vaccine adjuvants and in the treatment of asthma, allergy, infection, and cancer. Due to evolutionary divergence in CpG recognition between species, CpG ODN that are most active in rodents are poorly immunostimulatory in primates. Thus, evidence that CpG ODN have therapeutic activity in mice must be confirmed in primates. Two distinct types of CpG ODN were identified that stimulate primate PBMC. D-type ODN trigger plasmacytoid DC to secrete IFNalpha, monocytes to mature into functionally active DC, and NK cells to secrete IFNgamma. K-type ODN stimulate B cells and monocytes to proliferate and secrete IgM, IL-10, and/or IL-6. In vivo studies in nonhuman primates indicate that proinflammatory or humoral immune responses can be selectively facilitated by judicious use of these distinct types of ODN.
Insights
CpG oligodeoxynucleotides (ODN) activate the immune system, showing therapeutic potential. Different CpG ODN types selectively stimulate primate immune cells, offering targeted treatment strategies for various conditions.
Area of Science:
- Immunology
- Molecular Biology
- Pharmacology
Background:
- CpG oligodeoxynucleotides (ODN) mimic microbial DNA, activating innate immunity and promoting adaptive responses.
- CpG ODN are investigated as vaccine adjuvants and for treating asthma, allergy, infection, and cancer.
- Species-specific differences in CpG recognition necessitate primate studies for therapeutic translation.
Purpose of the Study:
- To identify and characterize CpG ODN that stimulate primate peripheral blood mononuclear cells (PBMC).
- To investigate the distinct immune responses elicited by different types of CpG ODN in primates.
- To explore the potential for selective immune response modulation using distinct CpG ODN types in vivo.
Main Methods:
- Isolation and stimulation of primate PBMC with distinct CpG ODN types.
- Analysis of cytokine secretion (IFN-alpha, IFN-gamma, IL-10, IL-6) and cellular responses (DC maturation, B cell proliferation).
- In vivo studies in nonhuman primates to assess immune responses.
Main Results:
- Two distinct CpG ODN types (D-type and K-type) were identified that stimulate primate PBMC.
- D-type ODN induced plasmacytoid DC to secrete IFN-alpha, monocytes to mature into active DC, and NK cells to secrete IFN-gamma.
- K-type ODN stimulated B cells and monocytes to proliferate and secrete IgM, IL-10, and/or IL-6.
- In vivo studies demonstrated selective facilitation of proinflammatory or humoral immune responses.
Conclusions:
- Distinct CpG ODN types differentially activate primate immune cells, including DC, NK cells, B cells, and monocytes.
- CpG ODN can selectively induce either proinflammatory or humoral immune responses in primates.
- These findings support the development of targeted CpG ODN-based immunotherapies in humans.
