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A chimeric human-mouse model of Sjögren’s syndrome

Significance Statement

Researchers at Ohio State create part human, part mouse hybrid model to study autoimmune disease. In the conventional process of drug design and development, successful candidates found from working with cells in flasks are then tried out in an animal model of a particular disease.  Promising results in these animals provide the foundation to justify further exploration of these experimental drugs in human clinical trials.  However, the successes observed in treating the animal model of the disease do not always translate into positive results with humans in the clinic.  To circumvent this problem and to allow studies that would not otherwise be ethically permissible in humans, researchers have developed humanized mice.  The technique involves engrafting human cells/tissue into immunodeficient mouse surrogates to study disease using human cells in a living system.  While the first such mice were characterized as early as the 1930’s, the mice have been significantly optimized over time and some great advancements have been made in the past 5 years.  Consequently, the creation of humanized mouse models may alter the traditional approach currently used in translational medicine and therapeutic development. A study published in the January issue of Clinical Immunology by researchers at Ohio State created a human-mouse hybrid model that can be used to study autoimmune-mediated inflammatory diseases in a whole new way.  Taking human cells from patients at The Ohio State University Wexner Medical Center, they were able to transfer them into mice and recapitulate immunological disease progression just as it is observed in humans.  The basis of the work was to confirm the validity of the surrogate model in autoimmunity and to demonstrate the specificity of target-organ inflammation.  Specifically, cells from either healthy controls or patients with Sjögren’s syndrome (SjS) were engrafted and they subsequently looked at inflammation in the target organs of the disease (the lacrimal and salivary glands).  These moisture producing glands are the targets of Sjögren’s Syndrome inflammation and glandular destruction leads to the clinical manifestation of dry eyes and dry mouth that is often seen in patients.  Their results showed that the lacrimal and salivary glands were selectively targeted in the mice receiving Sjögren’s Syndrome human cells and that this leads to loss of salivary gland function; thus establishing a novel humanized mouse model to study Sjögren’s Syndrome pathology and therapeutic development.  Another intriguing aspect of this work is the versatility of the model because it is applicable to any autoimmune disorder.  Since this publication, this research team has also successfully engrafted human lupus cells from patients into these mice.  Furthermore, inflammation was significantly suppressed with the immunotherapeutic transfer of purified Regulatory T-cells from human samples in an additional study. These results characterize a revolutionary model to use in developing more successful therapies to treat inflammatory diseases.  The publication of this human- mouse hybrid model has generated interest from several pharmaceutical companies and this research team is currently in the development phase of pilot studies to investigate pipeline drugs to treat autoimmune diseases, including lupus. The creation of these humanized models of disease establishes an experimental platform that will ultimately translate into a higher probability of success in the therapeutic development of new drugs.

Figure Legend.  Experimental summary used in this study to establish a human-mouse chimeric model for Sjögren’s syndrome (SjS).  Whole blood was drawn from SjS patients and age/sex-matched healthy controls. Peripheral blood mononuclear cells were isolated and adoptively transferred into immuno deficient mouse recipients via intraperitoneal injection.  After four weeks, salivary and lacrimal gland tissue was collected, processed, and paraffin-embedded for histopathological analysis and immuno histochemistry.  Target organ inflammation was predominated by CD4+ T-cells, but CD8+ T-cells and B-cells were also detected.  Pictured are CD4+ immunohistochemical stains from the lacrimal and salivary glands of SjS chimeras.

A chimeric human-mouse model of Sjögren's syndrome. global medical discovery

Journal Reference

Young NA1, Wu LC1, Bruss M1, Kaffenberger BH1, Hampton J1, Bolon B2, Jarjour WN3. Clin Immunol. 2015 ;156(1):1-8.

Show Affiliations

1Division of Rheumatology and Immunology, The Ohio State University, Columbus, OH 43210, USA; Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA; Wexner Medical Center at The Ohio State University, Columbus, OH 43210, USA.

2Department of Veterinary Biosciences and the Comparative Pathology and Mouse Phenotyping Shared Resource, The Ohio State University, Columbus, OH 43210, USA; Wexner Medical Center at The Ohio State University, Columbus, OH 43210, USA.

3Division of Rheumatology and Immunology, The Ohio State University, Columbus, OH 43210, USA; Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA; Wexner Medical Center at The Ohio State University, Columbus, OH 43210, USA.

Electronic address: [email protected]

 

Abstract

Despite recent advances in the understanding of Sjögren’s Syndrome (SjS), the pathogenic mechanisms remain elusive and an ideal model for early drug discovery is not yet available. To establish a humanized mouse model of SjS, peripheral blood mononuclear cells (PBMCs) from healthy volunteers or patients with SjS were transferred into immunodeficient NOD-scid IL-2rγ(null) mouse recipients to produce chimeric mice. While no difference was observed in the distribution of cells, chimeric mice transferred with PBMCs from Sjögren’s Syndrome patients produced enhanced cytokine levels, most significantly IFN-γ and IL-10. Histological examination revealed enhanced inflammatory responses in the lacrimal and salivary glands of SjS chimeras, as measured by digital image analysis and blinded histopathological scoring. Infiltrates were primarily CD4+, with minimal detection of CD8+ T-cells and B-cells. These results demonstrate a novel chimeric mouse model of human Sjögren’s Syndrome that provides a unique in vivo environment to test experimental therapeutics and investigate T-cell disease pathology.

Copyright © 2014. Published by Elsevier Inc.

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