Abstract
One means of stimulating the mammalian innate immune system is via Toll-like receptor 9 (TLR9) being exposed to unmethylated cytosine-phosphate-guanine (CpG) DNA, also known as pathogen-associated molecular patterns (PAMPs) of microbial origin. Synthetic CpG oligodeoxynucleotides (ODNs) with defined CpG motifs possess broad immunostimulatory properties that make CpG ODNs suitable as therapeutic interventions in a variety of human disease conditions, including Alzheimer’s disease (AD). Rodent models are often used to preclinically test the effectiveness of CpG ODN therapeutic agents for AD and other disorders. However, the translatability of findings in such models is limited due to the significant difference of the expression of TLR9 between primates and rodents. The squirrel monkey (SQM), a New World non-human primate (NHP), is known to be phylogenetically proximate to humans, and develops extensive age-dependent cerebral amyloid angiopathy (CAA), a key pathological feature of AD. Hence, this model is currently being used to test AD therapeutics. In the present study, we conducted the first examination of Class C CpG ODN’s immunomodulatory role in elderly SQMs. We documented the effectiveness of CpG ODN to trigger an immune response in an aged cohort whose immune system is senescent. The specific immune response patterns detected here closely resembled CpG ODN-induced immunostimulatory patterns observed in prior human studies. Overall, our findings provide critical data regarding the immunomodulatory potential of CpG ODN in this NHP model, allowing for future translational studies of innate immunity stimulation via TLR9 agonists for diverse indications, including AD therapeutics.
Highlights
The mammalian innate immune system naturally recognizes unmethylated cytosine-phosphate-guanine (CpG) DNA as pathogen-associated molecular patterns (PAMPs) indicative of viruses or bacteria
We further examined the viability as well as functional activity of peripheral blood mononuclear cells (PBMCs) exposed to different concentrations of Class C CpG ODN
When eliciting a desirable immune response against human disease, modeling therapeutic approaches in non-human primates (NHPs) is advantageous because of the highly conserved innate immune system among primates (Messaoudi et al, 2011). One of these highly conserved immunological mechanisms in humans and in NHPs is the recognition of unmethylated cytosine-phosphate-guanine (CpG) DNA that is commonly found in the genomes of prokaryotes, while being underrepresented in those of eukaryotes
Summary
The mammalian innate immune system naturally recognizes unmethylated cytosine-phosphate-guanine (CpG) DNA as pathogen-associated molecular patterns (PAMPs) indicative of viruses or bacteria. Three classes of TLR9 agonists, CpG ODN Class A, B, and C, each pose a distinct biologic activity, due to their unique structures and different cell activations, to produce varying innate immune signaling cascades. Class A CpG ODNs are single CpG motifs of partially phosphorothioated (PS-modified) and phosphodiester backbone bases in a palindromic sequence that induce the production of IFNα by peripheral dendritic cells (pDCs) and indirectly activate NK cells. Unlike Class A CpG ODNs, Class B contain B-cell activators and stimulate pDC maturation. The Class C CpG ODNs, which combine characteristics of the A and B classes, are generally fully PS-modified, double-stranded palindromic motifs that induce strong IFNα production, pDC maturation, and efficient B cell stimulation (Scheiermann and Klinman, 2014; Adamus and Kortylewski, 2018)
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