Class C CpG Oligodeoxynucleotide Immunomodulatory Response in Aged Squirrel Monkey (Saimiri Boliviensis Boliviensis)

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.

Clearance of interstitial fluid (ISF) and CSF (CLIC) group—part of Vascular Professional Interest Area (PIA)

“…Rodent models for the study of vascular dysfunction include hyperhomocysteinemia and hypoperfusion due to occlusion of a carotid artery 29‐32 . In addition, non‐human primate models are known to develop extensive CAA thus offering potential preclinical avenues for investigation, especially in the context of white matter lesions 33,34 . Intramural accumulation of cystatin amyloid aggregates in Icelandic CAA are also observed in skin vessels, suggesting that in vitro models of this disorder could provide convenient platforms to study mechanistic properties of affected vessels 35 …”

Recent Advances in Oligonucleotide Therapeutics in Oncology

“…Class B CpG oligonucleotides (including CpG-7909, IMO-2055, and 1018-ISS) contain multiple CpG motifs and stimulate B-cell activation and pDC maturation [ 61 ]. Class C CpG oligonucleotides (including SD-101) combine the characteristics of both class A and B and can induce high levels of IL-12 secretion from pDCs [ 62 ]. CpG oligonucleotides are being tested both as monotherapy and immunotherapeutic adjuvants in combination with chemotherapy, radiotherapy, and targeted therapy [ 63 ].…”

Effects of relocation on immunological and physiological measures in female squirrel monkeys (Saimiri boliviensis boliviensis)

“…For flow cytometry analysis a series of commercially available human monoclonal antibodies that cross react with nonhuman primate mononuclear cells were used as described previously [10,[26][27][28]. Briefly, 100μl of whole blood from each sample was stained with a cocktail of monoclonal antibodies against CD3, CD4 and CD8 CD16 and CD20 (CD3−PE, clone SP-34; CD4-PerCP, clone L200; CD8-FITC, clone RPA-T8, CD16 APC (clone 3G8), and CD20-APC, clone L27 (all from BD Biosciences, San Diego, USA).…”

“…This research is also helping scientists to uncover information that makes human organ transplants easier and more accessible, literally giving new life to those whose kidneys, hearts, and lungs are failing. Squirrel monkeys, small New World NHP, have served an important role in studying pathogenesis of human disease conditions such as Alzheimer's disease [1][2][3], malaria [4][5][6], HIV [7], Creutzfeldt-Jakob disease [8,9] and Giardia infection [10].…”