Oliver A. Garden, BVetMed, PhD, joined Penn Vet in 2016 as chair of the Department of Clinical Studies and Advanced Medicine. He was named as the Corinne R. and Henry Bower Professor of Medicine. Garden graduated from the Royal Veterinary College (1993) after earning his Bachelor of Science degree from King’s College London (1990). Following a rotating internship in small animal medicine and surgery, he completed a Wellcome Trust Clinical PhD program in small animal gastroenterology and immunology at the Royal Veterinary College (1998), followed by a Wellcome Trust Research training fellowship at the School of Medicine at the University of South Carolina. He held a residency in small animal internal medicine at Cornell University. Current research in the Garden laboratory focuses on the role of regulatory cells of lymphoid and myeloid origin in the pathogenesis of cancer and autoimmune disease. While early studies were carried out in murine models, more recent studies embrace the over-arching ethos of One Health, One Medicine at Penn Vet and focus on natural canine diseases. Importantly, these canine diseases can provide critical insight for a plethora of human diseases—and studying canine disease clearly benefits both canine and human patients.
Immunosuppression by regulatory T cells – The key to reducing some autoimmune diseases
Regulatory T cells (Tregs) play a critical role in immunosuppression and therefore have the potential to reduce or prevent harmful autoimmune and inflammatory immune responses. Using Tregs from mice, humans and, most recently dogs, the Garden laboratory has identified the critical role of several signaling cascades, including phosphoinositide 3-kinase p110δ, cytokines utilizing the common gamma chain, and microRNA-155 -15b/16 in the induction, function, and development of Tregs. The Garden laboratory was also the first to document a key defect in the ability of conventional (non-regulatory) T cells to be regulated by Tregs in a murine model of systemic lupus erythematosus (SLE)1, a pathomechanism subsequently demonstrated in other murine models and T cells from human patients. Moreover, they showed that reduced T cell receptor α chain diversity of Tregs in NOD mice, a murine model of type 1 diabetes mellitus, compromised peripheral tolerance and enhanced disease. By discovering these mechanisms, their work has highlighted pathways that may underlie defects of Treg function in disease, potentially identifying novel targets by which these cells may be manipulated for therapeutic gain.
Suppressive immune cells promote “tolerance” of cancer in dogs
Dr. Garden’s laboratory is also interested in the role that Tregs and myeloid-derived suppressor cells (MDSCs) play in the development and progression of cancer in dogs. Dogs make excellent large animal models of various human cancers, recapitulating the human disease in a spontaneous manner that cannot be captured in genetically modified murine models. The Garden laboratory is first focusing on the role of Tregs and MDSCs in dogs with multicentric B cell lymphoma, a model of human non-Hodgkin lymphoma. They found that the frequency of Tregs in the affected lymph nodes of dogs with multicentric B cell lymphoma predicts survival in dogs undergoing chemotherapy2 and that
hypoxic changes in tumors appears to promote infiltration by FoxP3+ Tregs. In studies carried out by former post-doc Dr. Michelle Goulart, and currently carried out by Sabina Hlavaty, the Garden laboratory is phenotypically and functionally defining canine monocytic (M) and polymorphonuclear (PMN) MDSCs, and determining how the increased frequency of PMN-MDSCs in the peripheral blood of dogs with larger tumor burdens contributes to disease progression. Notably, their studies to date also demonstrate that the phenotypic and functional properties of both canine Tregs and MDSCs closely resemble their human counter-parts, further demonstrating that natural canine models will be invaluable for determining if immunotherapies targeting these cells can revolutionize cancer treatment.
Studying immune-mediated disease in dogs may permit refinement of therapeutic treatments
Current therapies for autoimmune and other immune-mediated diseases often rely on inelegant blanket immunsuppressive treatments that can elicit a number of intolerable side effects in treated patients. To identify means to avoid the use of immunosuppressive “sledgehammers”, the Garden laboratory is currently elucidating the pathogenic mechanisms that drive the onset and progression of immune-mediated hemolytic anemia (IMHA), the most common autoimmune disease in dogs. Interestingly, while dogs with IMHA have increased serum concentrations of pro-inflammatory cytokines, their frequency of Tregs did not differ from healthy dogs, suggesting that a deficiency of Tregs is not responsible for development of disease3. Further expansion of studies such as these that incorporate detailed phenotypic and functional data will allow for development of novel approaches that permit earlier diagnosis and more effective, targeted treatment for IMHA, and presumably other autoimmune and immunemediated diseases.
Attacking Myasthenia Gravis from the Inside Out
The Garden laboratory is also focused on understanding pathological mechanism driving myasthenia gravis (MG), an autoimmune disease in which the acetylcholine receptor (AChR) is targeted, disrupting neuromuscular transmission and causing characteristic weakness and fatigue. Previous studies in experimental autoimmune myasthenia gravis (EAMG) models utilized disease-inducing epitopes derived from the extracellular portion of the AChR in an attempt to induce antigen-specific immunosuppression. However, the use of such therapeutic antigens proved to be tricky and dangerous. Notably, autoantibodies generated during EAMG induce complement-dependent focal lysis and the subsequent shedding of AChR-rich fragments of the postsynaptic membrane stimulates an antibody response to the normally concealed cytoplasmic domain of the AChR. Dr. Jie Luo, a Senior Research Investigator in the Garden laboratory, exploited this finding and has successfully tested a novel vaccine consisting of the cytoplasmic domains of human muscle AChR subunits in rats4. This approach provided safe and effective immunosuppression, highlighting a new path towards antigen-specific immunotherapies for autoimmune diseases targeting transmembrane proteins. Ongoing work addresses the mechanistic basis for this therapy. Moreover, translating these rodent studies into a spontaneous large animal model that recapitulates the human disease will provide proof-of-principle studies that will inform and accelerate human clinical trials.
What is bugging the immune system?
There is increasing recognition that the “exposome”, environmental factors that include the patient’s mucosal microbiome, impacts the manifestation of autoimmune disease in human patients. The Garden laboratory is currently testing the hypothesis that alterations in intestinal microbiome are an etiological factor for IMHA and that idiopathic IMHA patients showing a poor response to immunosuppressive therapy will exhibit persistent disease-associated changes in their microbiome. Positive results would imply that strategies to address proximal pathological changes in microbiota, including prebiotics, probiotics, or focused antimicrobial agents, could complement immunosuppressive therapeutic regimens in non-responsive or relapsing patients to improve outcome. Moreover, signatures of microbiota associated with refractory disease may also be used in a predictive manner to stratify patients to particular treatment regimens and to provide important prognostic information.
Dr. Garden’s laboratory is located in 201E OVQ Building and his office is at 2011 Ryan.
Selected References
- Monk, C, Spachidou, M, Rovis, F, Botto, M, Lechler, RI and Garden, OA (2005) MRL/Mp CD4+CD25- T cells resist suppression by CD4+CD25+ Tregs in vitro: a novel defect of T cell regulation in systemic lupus erythematosus. Arthritis and Rheumatism 52(4): 1180-1184
- Pinheiro, D, Chang, YM, Bryant, H, Szladovits, B, Dalessandri, T, Davison, LJ, Yallop, E, Mills, E, Leo, C, Lara, A, Stell, A, Polton, G and Garden, OA (2014) Dissecting the regulatory microenvironment of a large animal model of non-Hodgkin lymphoma: evidence of a negative prognostic impact of FOXP3+ T cells in canine B cell lymphoma. PLOS ONE 9(8): e105027
- Swann, JW, Woods, K, Wu, Y, Glanemann, B and Garden, OA (2016) Characterisation of the immunophenotype of dogs with primary immune-mediated haemolytic anaemia, PLOS ONE 11(12): e0168296 4. Luo, J and Lindstrom J (2015) AChR-specific immunosuppressive therapy of myasthenia gravis. Biochem Pharmacol. 97(4):609-619