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Tuesday, October 22 • 2:30pm - 2:50pm
Complex Translational Models- Building a Multicellular 3D Model of the Human Salivary Gland to Study Immune Mechanism Underlying Sjogren’s Syndrome

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Sjogren's Syndrome (SS) is a chronic autoimmune condition causing exocrine tissue dysfunction, mainly in women, with a prevalence of around 1-3% in the general population. Most notably the lacrimal and salivary glands (SGs) are affected resulting in common symptoms of dry eyes and dry mouth, the latter associated with increased dental caries and fungal infections. Other symptoms may include dry skin, joint pain, fatigue, and swollen SGs. Currently there are no effective therapies for this condition and treatment is limited to palliative management of the symptoms.

At the cellular level, SS is characterised by lymphocytic infiltration in the lacrimal and SGs, as well as other exocrine glands in the body, resulting in tissue destruction. This adaptive immune response can manifest as lymphocytic foci in the tissue that develops and functions as ectopic germinal centre like structures. Activation of innate immune pathways may play an early role in SS and precede lymphocytic infiltration. In the SGs, dendritic cells (DCs), macrophages, salivary gland epithelial cells (SGECs) and natural killer cells (NK) are thought to be involved.

Animal models such as mouse and non-human primate are often used to study SS and to assess molecular targets for novel therapeutics. However, these have their limitations in that the chronic disease state is difficult to reproduce, while no single animal model exhibits all of the clinical characteristics associated with the condition. Progress has been made in developing SG in vitro models to study SS. These have employed animal and human cell lines, as well as primary SGECs derived from SG tissue of healthy subjects and SS patients. These have been cultured on plastic or permeable supports, while some have attempted co-culturing with immune cells and others have shown 3-Dimensional tissue structures in collagen/matrigel.

In order to build an organotypic model of the human salivary gland it is important to bring together appropriate cell types in a microenvironment where there is adequate interplay between these cells to form a 3-D architecture that closely resembles the tissue in vivo, as well as anatomical and functional features of the individual cell types. A collagen-fibroblast matrix component (stromal matrix) has been shown to promote SG acinar cell function, therefore including this element into an in vitro model is a sensible option. It has also been shown that DCs exist in substantial numbers in the acini, ducts and interstitial areas of the SG epithelium, as well as other immune cells.
Our work focussed on establishing a normal multicellular 3-D human SG model, by co-culturing various immune cell types with a collagen-fibroblast matrix and a SG epithelial layer in an air lifted microenvironment. We encountered optimisation challenges for keeping all cell types viable in this model up to 12 days on a robust platform, suitable for various applications of drug discovery and translational research. We have characterised the morphological and functional features of the different cell types to ascertain the potential for generating a SS like disease model.

Co-Authors:
1 Martin Vidgeon-Hart; GSK
2 Paul McGill; GSK
3 Jan Klapwijk; GSK
4 Emma Koppe; GSK
5 Timothy Radstake; Utrecht

Speakers
avatar for Anita Naidoo, MPhil, BSC

Anita Naidoo, MPhil, BSC

Scientific Leader, GlaxoSmithKline Research and Development
Anita joined GlaxoSmithKline as a Genetic Toxicologist in 1988 and then moved into Cellular Pathology & Toxicology and re-trained as an in vitro toxicologist, applying her knowledge and expertise to develop cellular models to address safety concerns through bespoke mechanistic studies... Read More →

Chair
TS

Timothy Spicer, BS, MS, Ph.D.

Senior Scientific Director, Scripps Research Florida


Tuesday October 22, 2019 2:30pm - 2:50pm
Wellcome Auditorium