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Studying the Players in Immune Regulation

By: Katherine Unger Baillie Published: Sep 26, 2018
Dr. Oliver Garden and Sabina Hlavaty view a plate of cultured canine bone marrow cells to compare conditions during an experiment.
Dr. Oliver Garden and Sabina Hlavaty, a Howard Hughes Medical Institute/Burroughs Wellcome Fund Medical Research Fellow,
view a plate of cultured canine bone marrow cells to compare conditions during an experiment.

The immune system is often framed as the part of our bodies responsible for fighting infection. But a key part of immunity involves restraining that battle-ready immune cell army so its artillery is only trained upon true threats.

This element of immune regulation — and how it can go awry in cancer and autoimmune conditions — is where Dr. Oliver Garden, Chair of Penn Vet’s Department of Clinical Sciences and Advanced Medicine and the Corinne R. and Henry Bower Professor of Medicine, rests his scientific attention.

Prior to joining Penn Vet last year, Garden pursued this work at the University of London’s Royal Veterinary College. For the first decade of his research career, Garden focused his attention on regulatory T cells (Tregs). These lymphoid cells play a critical role in immunosuppression and have the potential to reduce or prevent harmful autoimmune and inflammatory immune responses.

Using Tregs from mice, humans, and, most recently, dogs, Garden’s laboratory has identified the critical role of several signaling cascades in the induction, function, and development of Tregs. Among the group’s most significant achievements was being the first to document a key defect impairing the ability of Tregs to suppress the activity of nonregulatory T cells in a mouse model of lupus, a finding later upheld in T cells from human patients. The lab was also the first to demonstrate a role for Treg dysfunction in enhancing disease in a mouse model of type I diabetes.

In the last decade, Garden’s lab has shifted in focus to another key player in holding the immune response in check: myeloid-derived suppressor cells (MDSCs).

“The current projects in the lab are all about regulation, and how to overcome deranged regulation in autoimmune disease and cancer,” Garden said. “We have a keen interest in Tregs, but we also came to realize that immune regulation is multifactorial and doesn’t only involve lymphoid cells.”

In 2015 Garden received a grant to conduct an in-depth study of the ways in which Tregs interacted with MDSCs, an area his lab had begun to explore in the context of lymphoma in dogs.

“This sent us into the exciting realm of myeloid regulatory cells,” he noted.

MDSCs are a diverse set of cells that arise from abnormal differentiation pathways of myeloid cell precursors, including immature neutrophils and monocytes. Researchers are in the early days of understanding this population of cells, which form in disease conditions like cancer and autoimmune disease, and are believed to potently suppress T cells and NK cells in certain contexts. Garden and his colleagues’ work has supported the idea that tumor cells promote the differentiation and accumulation of MDSCs, which suppress the immune system’s ability to fight cancer.

For the most part, Garden’s lab has examined MDSCs’ role apart from lymphoid cells, and has embraced the concept of One Health, focusing studies in natural canine diseases alongside mouse models and, in some cases, samples from humans.

Recent studies have examined two sides of immune dysfunction: autoimmunity, when the immune system overreacts and causes disease, and cancer, in which a repressed immune system lacks the ability to recognize and kill malignancies.

On the cancer side, research conducted by former lab member Dr. Michelle Goulart and current research assistant Sabina Hlavaty, Howard Hughes Medical Institute/Burroughs Wellcome Fund Medical Research Fellow, is working to characterize different subtypes of MDSCs in dogs with a variety of cancer types. A collaboration with Wistar Institute’s Dr. Dmitry Gabrilovich, Professor and Program Leader, Immunology, Microenvironment, and Metastasis Program, is aimed at translating the work over to the human side as well.

“We’ve found that cancers with high-tumor burden tend to have higher frequencies of MDSCs in the peripheral blood compared to lower-burden cancers,” Garden explained. “It’s not only the case that MDSCs may be atherapeutic target, by reducing their influence, but they also may be a useful biomarker to predict outcome and response to conventional therapies. The dog offers several significant advantages over mouse models; this is something we’re uniquely poised to take advantage of, as veterinarians.”

Given the success of immunotherapies targeting T cells in addressing cancer, Garden believes that complementary therapeutics that enlist the myeloid arm of immunity may be a new frontier in cancer treatment.

“We’re clearly at the cusp of a revolution in cancer treatment,” Garden said, “and really, we’re already there in many respects. Adding in the myeloid side is likely to be an additional avenue of therapy.”

Garden’s group is already working with immune therapies to address autoimmunity. Dr. Jie Luo, a senior research investigator on Garden’s team, is an expert on myasthenia gravis, an autoimmune disease affecting both humans and dogs that causes extreme weakness and fatigue. Using a rodent model, he’s developed a targeted vaccine that suppresses the immune system and effectively cures animals of the disease. Luo, who trained under Dr. Jon Lindstrom, Trustee Professor in Neuroscience at Penn Medicine’s Perelman School of Medicine, is also working on a novel diagnostic test for dogs with myasthenia gravis.

At Penn Vet, Garden is growing his lab and forming a variety of collaborations with colleagues around campus.

Dr. Julia Ying Wu, who earned her PhD at RVC working under Garden, recently joined his lab in Philadelphia as a postdoctoral researcher, shifting her focus from Tregs to MDSCs.

Students Lauren Olenick and Andrew Pham, both undergraduates at Penn, as well as technician Brendan Lawson, are adding to the team. And Garden shares the lab with Dr. James Perry, a surgical oncologist with an interest in the role Tregs play in sarcomas. Garden has also welcomed his collaboration with Dr. Jennifer Punt, Associate Dean of One Health at Penn Vet and an immunologist, who has an interest in the influence of insulin-like growth factor-1 on immune cells in dogs in health and the cancer setting.

“We’re generating some nice data in a number of areas of clinical relevance,” Garden said. “I’m looking forward to continuing to get feedback from my colleagues on this work to advance the health of not only dogs, but also humans.”