Researchers at The Ohio State University have announced the development of the first chimeric mouse model of Sjögren's syndrome -- giving scientists an unprecedented look at the progression of the debilitating "dry eye" disease. Because the disease often doesn't respond to conventional immunosuppressive therapy, the model will also open the door for the development of new molecular-based, targeted drugs.
"While mouse models have existed for some time to study Sjögren's and other autoimmune diseases, an ideal model to use for early drug development was still lacking," said Nicholas Young, PhD, an immunologist with Ohio State's Wexner Medical Center who helped create and study the chimeric mice. "We're optimistic that the experimental platform resulting from this humanized mouse model will help jumpstart the creation of innovative therapies."
The chimeric mouse is engineered by transplanting human cells to replicate the activity of Sjögren's syndrome (SjS), an autoimmune disease where out-of-control inflammatory cells from the immune system inexplicably destroy tear ducts and salivary glands, and impact the function of other organs.
The research team hopes their new model will ultimately yield better insights and translate into more effective treatment options for the nearly 50 million Americans with some form of autoimmune disease.
Building a Better Mouse Model
Mouse models help scientists understand the origins of human disease and help identify safe and effective treatments. Despite genetic and physiological similarities between mice and humans, there are enough differences that medical results seen in mice do not always translate over to humans. This can lead to unexpected side effects or a lack of efficacy once an experimental treatment reaches human testing.
"Let's face it, mice are not humans. We should not expect the drugs that are successful in treating mice to work identically in the human version of the same disease. Not surprisingly, many of them do not," said Young.
Young is part of a team working under Wael Jarjour, MD, Director of Immunology and Rheumatology, that has been researching autoimmune diseases at Ohio State for the past 6 years. They saw an opportunity to fundamentally advance the conventional drug development process by creating a first-ever chimeric mouse model for Sjögren's.
Named after the chimera of Greek mythology, chimeric mice are engineered to contain both genetically distinct human and mouse cells. The mice are immunological "blank slates" -- meaning their bodies don't react to the presence of human cells, but instead act as a surrogate allowing them to thrive, creating a mini-laboratory to study human cells in a living system. In the last decade, techniques and technology to create chimeric mice have advanced significantly, and they are used frequently in cancer studies, but not many other disease areas.
In 2009, Jarjour and his research team were awarded a grant from The Medarva Foundation Fund (formerly known as the Richmond Eye and Ear Foundation Fund) to create this chimeric mouse model for Sjögren's.
Tiny Immune Systems, Big Implications
For the experiment, Young tapped into ResearchMatch, a research volunteer database supported by Ohio State's Center for Clinical and Translational Science, to collect peripheral blood mononuclear cells (PBMCs) from healthy volunteers or people with SjS. The research team then injected one set of mice with cells from people without SjS, and another group of mice with cells taken from people with the condition.
While no difference was observed in the distribution of engrafted human cells, chimeric mice that were given PBMCs from SjS patients produced higher levels of cytokines, proteins associated with inflammation. Under a microscope, scientists could see that the inflammatory responses in the tear ducts and salivary glands of the SjS chimeras were also exaggerated.
"We showed that the organs in the SjS chimeric mice were selectively targeted, creating an ideal in vivo environment to test experimental therapeutics and investigate T-cell disease pathology," said Young. "While this system will allow us to conduct a much more accurate study of Sjögren's pathology, the versatility of this model is very exciting because it is applicable to other autoimmune disorders, including lupus."
Lai-Chu Wu, DPhil, Associate Professor, Department of Molecular and Cellular Biochemistry and a collaborator on this project, added, "This chimeric mouse model also reveals intriguing therapeutic prospects that could lead to individualized patient care one day through the establishment of a fully functioning 'human' immune system."
Young agrees, noting that it's only a matter of time before science figures out how to replicate the full range of the human immune response within a chimeric model -- and predicting that it will be a game-changer.
"Once that happens, the possibilities for testing and drug development would extend well beyond autoimmune disease and into just about every field of medicine," said Young.
Nicholas Young is a Post-Doctoral Researcher at The Ohio State University Wexner Medical Center with the Department of Internal Medicine, Division of Immunology and Rheumatology. The study was published in the January issue of Clinical Immunology.
About Sjogren's Syndrome
Sjögrens syndrome is a common autoimmune disorder that typically attacks and progressively destroys moisture producing glands in the body, most commonly leading to dry eyes and mouth. Symptoms can develop slowly over several years, and the condition often goes undiagnosed, attributed instead to aging or other causes. Sjögren's syndrome affects about one percent of the United States population, and is one of the most prevalent autoimmune diseases in the country.
Materials provided by Ohio State University Center for Clinical and Translational Science. Note: Content may be edited for style and length.
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