Evaluation of class C CpG ODN immunomodulatory potential in a non‐human primate model of sporadic CAA
Year: 2020
Type: article
Abstract: Background A number of studies have shown that the stimulation of innate immunity in transgenic mouse models can ameliorate AD‐related pathology. The failures of many immunotherapeutic clinical trials for AD has been related to poor translatability of promising transgenic mouse data to humans. Our recent data from a non‐human primate (NHP) model of sporadic cerebral amyloid angiopathy (CAA), squirrel monkey (SQM), indicate that treatment with TLR9 agonist, class B CpG ODN, results in reduction of CAA without toxicity. Here, we advanced our study using class C CpG ODN, which is currently being explored in a variety of human disease conditions and has shown favorable safety profiles. The present study is first to assess the effectiveness of class C CpG ODN to elicit an immune response in aged population whose immune system might be senescent. Method Elderly female SQMs received either CpG ODN or vehicle (saline) every 4 weeks as part of an ongoing chronic‐treatment study (14 injections so far). Phenotypes and frequency of lymphocyte/monocyte subsets were examined by flow cytometry (FC) in whole blood collected prior‐ and at multiple intervals post‐CpG ODN injection. SQM PBMCs were tested for functionality after incubation with CpG ODN (ELISPOT). Plasma taken at specific injection intervals was analyzed to identify cytokine/chemokine profiles and autoantibody responses toward Aβ40/42. Result FC enumeration of major lymphocyte/monocyte populations revealed significant decreases in the absolute numbers across study days with days 3 and 7 being significantly lower than baseline. These results likely reflect transient redistribution of cells out of peripheral blood. Further validation of CpG ODN immunostimulatory potential was demonstrated by increased levels of plasma cytokines/chemokines in vivo, and an increase in the numbers of PBMCs producing IL12, IFNγ, and IFNα in vitro. CpG ODN did not lead to increased production of IgG/IgM autoantibodies against Aβ when assessed periodically. Additionally, longitudinal MRI monitoring for ARIA will enhance the evaluation of CpG ODN efficacy and safety. Conclusion Overall, the present study provides essential information regarding immune response patterns of CpG ODN in this NHP model, enabling potential future clinical applicability of CpG ODN for AD therapeutics.
Source: Alzheimer s & Dementia
DOI: 10.1002/alz.045330
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W3110899989