Physician Profile

Michael D. Gunn, MD

Education:

Medical School: MD, University of Texas Southwestern Medical School, 1983

Residency:
Internal Medicine, Parkland Memorial Hospital (Texas), 1986

Fellowship:
Cardiology, University of California, San Francisco, 1989

Clinical Interests:
Immunologic aspects of cardiovascular diseases

Research Interests:
The focus of our work is on understanding how dendritic cells and dendritic cell activation initiate and regulate immune responses. Our ultimate aim is to apply this knowledge to the development of vaccines and immunotherapeutics for human use.

Lab History
The lab started with our discovery of the lymphoid chemokines, which regulate the migration of lymphocytes and dendritic cells to and within secondary lymphoid organs. We identified CCL21 as the chemokine that mediates the entry of naïve T cells and dendritic cells into lymph nodes. We identified CXCL13 as the chemokine that mediates the entry of B cells into lymphoid follicles. We determined that the murine plt mutation is due to a loss of CCL21 expression in lymphoid organs and that this leads to major defects in dendritic cell migration.

Our focus then shifted to understanding how specific cell types, primarily dendritic cells, and cell migration events regulate immune responses. We were the first to describe murine plasmacytoid dendritic cells and the first to determine the full extent of monocyte-derived dendritic cell development during inflammation. Our current work continues these basic studies while applying our findings to models of human disease.

Current Research
Understanding how dendritic cells regulate the strength, duration, and character of immune response - Lymph nodes contain six distinct DC populations, including inflammatory monocyte-derived dendritic cells. Through the use of extensive flow cytometric analysis and chemokine-deficient mice, we are determining how these DC populations act to regulate innate and adaptive immune responses. Current projects include the identification of DC populations that induce Th1 and Th17 T cell polarization after immunization or acute infection, the identification of signals that regulate these DC phenotypes, and determining how DC regulate innate responses such as neutrophil accumulation. Once these pathways are defined in model systems, we examine how they contribute to the pathophysiology of specific infections and diseases.

Mechanisms of pulmonary immune pathology - Using the techniques we developed to characterize lymph node DC subsets, we have recently identified the lung inflammatory cell populations that arise during influenza infection. We have found that the CCR2-dependent accumulation of monocyte-derived DC and exudate macrophages is the cause of influenza-induced pulmonary immune pathology, morbidity, and mortality. We are currently examining the role that specific lung inflammatory cell populations play in other types of lung injury such as ARDS and chemical exposure and determining if such injury can be prevented by the pharmacologic inhibition of inflammatory cell migration.

The immunobiology of atherisclerosis - As a cardiologist, I have a strong interest in the contribution of immune response to atherosclerosis. We have determined that a population of resident "vascular" dendritic cells is present in the arteries of normal mice. Interestingly, the distribution of the vDC exactly mirrors the pattern in which atherosclerotic lesions develop in ApoE-deficient mice. Current studies seek to determine the activity of these vDC, their contribution to immune responses to atherosclerosis-associated antigens, and their contribution to atherosclerosis itself. We are also examining when and where T cell responses to atherosclerosis-associated antigens arise, how these responses are regulated by specific dendritic cell populations, and the antigen specificity of atherosclerotic T cell responses. I have found that few people have a strong interest in both immunology and atherosclerosis. If you are one of them, I have a job for you.

Development of novel reagents, adjuvants and immunotherapeutic agents - Our understanding of how immune responses are regulated at the DC level has direct applicability to the development of agents that can stimulate or inhibit specific immune responses. Using a novel method to generate recombinant single chain antibodies, we are currently developing antibodies specific for several toll-like receptors (TLRs). To date, we have generated novel antibodies against four TLRs, which can be used to assay TLR protein expression levels. Studies to determine the agonist and antagonist activities of these antibodies are in progress.