A Chimeric Human-Mouse Model of Sjögren's Syndrome

Nicholas Young, PhD, 06/26/2014

No relevant financial or competing interests specific

to this project to declare

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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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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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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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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

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

SjS mice produce enhanced cytokine levels

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Analysis of inflammation

Analysis of inflammation

Enhanced target organ inflammation

Inflammatory responses consist chiefly of CD4+ T-cells

Inflammatory responses consist chiefly of CD4+ T-cells

Summary Robust CD4+ T-cell infiltration in the salivary and lacrimalglands at 28 days

Significantly higher levels of IFN-g, IL-6, IL-10, IL-17, andTNF-α.

Both IFN-g and IL-10 previously shown to be elevated inperipheral 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 pathology14

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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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