[DDC 2021] AdapTive Immune Response Models for Discovery and Repurposing in the COVID-19 Era

[DDC 2021] AdapTive Immune Response Models for Discovery and Repurposing in the COVID-19 Era
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The pandemic caused by SARS-CoV-2 is expected to significantly alter the Global Health Burden, a measure of health-related impacts on world economies. Despite the availability of COVID-19 vaccines, newly emergent variants and long-term disease effects with immune system consequences pose challenges to the physical and mental health of patients. Resultant pathologies include not only Acute Respiratory Distress Syndrome (ARDS) and Cytokine Storm/Cytokine Release Syndrome, but a broad scope of immunological, cardiovascular, and neurological conditions. As the immune response is a central player in the recovery from, as well as exacerbation of, infectious disease, human-centric, in vitro assays and physiological models that capture relevant immune responses and inflamed tissue biology are critical to advance treatments for the sequelae of viral infection. In response to client needs in this space, Eurofins Discovery Phenotypic Center of Excellence has developed human primary cell-based AdapTive Immune Response Models with biomarker readouts specifically chosen for relevance to COVID-19, to inform on the immune response to approved and developmental therapies. Each system is a co-culture of pooled human primary PBMCs and one additional human primary tissue cell type stimulated with T Cell Receptor agonists to drive modeling of the adaptive immune response. With a comprehensive biomarker assessment that includes cell surface receptors, chemokines, cytokines and measures of cell health, these models serve a variety of program strategies from discovery to repurposing, and from individual to combination therapies.
In the current case study we present data on the effects of dexamethasone (DEX) and hydroxychloroquine (HCQ), two broad spectrum anti-inflammatories highlighted in the early response to COVID-19. Biomarker readouts in the three tissue-specific systems show that in the B cell germinal center model, HCQ induced stronger immune inhibitory and anti-inflammatory effects than DEX, consistent with HCQ’s clinical efficacy in treating lupus. In contrast, in the context of stromal and vascular tissues, the steroid DEX was more inhibitory on immune
and inflammation response biomarkers than HCQ, this was most notable for TNFα. These results may explain, in part, how DEX is more active on systemic inflammation, consistent with its efficacy in acute treatment for COVID-19. The ability of these models to differentiate drug activity based on human phenotypic outcomes in distinct tissue-specific contexts can help inform on therapeutic potential prior to clinical trials.