This document describes the development of a novel chimeric mouse model of Sjögren's syndrome (SjS) using human peripheral blood mononuclear cells (PBMCs) engrafted into NOD scid gamma (NSG) mice. The model showed robust CD4+ T-cell infiltration in the salivary and lacrimal glands of mice engrafted with SjS PBMCs compared to healthy controls. SjS mice also exhibited significantly higher levels of pro-inflammatory cytokines associated with SjS and histopathological features that mimic human SjS. This chimeric mouse model provides a tool for studying the molecular mechanisms and evaluating potential therapies for SjS.

1. A Chimeric Human-Mouse Model of
Sjögren's Syndrome
Nicholas Young, PhD, 06/26/2014

2. No relevant financial or
competing interests specific
to this project to declare
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3. Introduction
 Sjögren’s syndrome (SjS) is one of the most common autoimmune diseases,
affecting 4 million Americans
 Although systemic inflammatory responses are observed, this autoimmune
disease mainly affects the salivary and lacrimal glands
 The pathogenic mechanisms remain elusive and an ideal model for early
drug discovery is not yet available
 The pathogenesis of SjS is currently thought to involve many factors
 research concerning SjS development, progression, and molecular-
based therapeutics requires in vivo animal models
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4. Background
 Mouse models do not translate efficaciously into human patients
 Ethical and technical constraints limit such studies in human systems
 humanized mice, or human-mouse chimeras
 The transgenic mouse strain NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ is more
commonly known as NOD scid gamma (NSG)
 Cannot produce T-cells, B-cells, or functional NK cells due to several
targeted mutations.
 Successful human engraftment using 10-fold fewer human cells than
the preceding humanized mouse strains
 NSG chimeras display no symptoms of graft versus host disease for at
least 30 days
 allowing a 4-5 week window for investigation
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5. Objective
 NSG mice have not been used extensively in the investigation
of autoimmune disorders
 New SjS models can be used in the discovery of therapeutic
alternatives to the current management of SjS
 Non-specific and largely supportive
 We take advantage of the NSG model to engraft and study SjS
pathology in vivo.
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6. Experimental set-up
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Blood-flow cytometry
Histology
Serum- cytokines
IHC
28 days
Healthy
or
SjS
IP
5 X 10^6 cells

7. Recovery is similar with transfers from healthy and SjS PBMCs at 28 days

8. SjS mice produce enhanced cytokine levels
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9. Analysis of inflammation

10. Analysis of inflammation

11. Enhanced target organ inflammation

12. Inflammatory responses consist chiefly of CD4+ T-cells

13. Inflammatory responses consist chiefly of CD4+ T-cells

14. Summary
 Robust CD4+ T-cell infiltration in the salivary and lacrimal
glands at 28 days
 Significantly higher levels of IFN-g, IL-6, IL-10, IL-17, and
TNF-α.
 Both IFN-g and IL-10 previously shown to be elevated in
peripheral blood T-cells of SjS patients
 Histopathology and immunohistochemistry recapitulate
what is seen in SjS patients
 Useful for the study of molecular-based therapies to treat
and prevent disease pathology
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15. Conclusions
 Immunohistochemical data on lacrimal glands in SjS is lacking
due to the inaccessibility of this tissue in humans for biopsy
 Novel chimeric mouse model of SjS that will allow the in vivo
study of autoimmune-mediated inflammation on human
immune cells
 Opens new avenues to study disease progression and
therapeutic intervention
 Future work: investigate molecular-based targets to prevent
target organ inflammation in SjS and other autoimmune
disorders
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16. Acknowledgements
Lai-Chu Wu, PhD
William Willis, PhD
Benjamin Kaffenberger, MD
Alexandra Friedman
Michael Bruss
Giancarlo Valiente
Mark Gardner
Amanda Kibler
The Ohio State University Wexner Medical Center, Columbus, OH
Department of Internal Medicine
Division of Rheumatology and Immunology
Department of Microbial Infection
and Immunity
Center for Microbial Interface Biology
The Ohio State University
College of Veterinary Medicine
Larry S. Schlesinger, MD
Murugesan V.S. Rajaram, PhD
Brad Bolon, DVM, MS, PhD
Wael Jarjour, MD
Department of Internal Medicine
Division of Rheumatology and Immunology