Dennis Lindell, PhD

Overview

Medical/Professional School

University of Michigan, Ann Arbor, Immunology

Fellowship

Pulmonary Disease, University of Michigan, Ann Arbor
Pathology - Clinical, University of Michigan, Ann Arbor

Research Description

My laboratory is broadly interested in the mechanisms that control immunogenicity versus tolerance in the lungs. While exchanging the air we breathe, the lungs are continuously sampling the environment for the presence of disease causing pathogens. Health, (and in many cases, survival) depends upon simultaneously responding appropriately to dangerous pathogens, while tolerating the vast majority of harmless potential stimuli. Cells resident in the lungs are an important first line of communication for the immune system, and their behavior in response to pathogenic or other environmental stimuli influences the quality and magnitude of disease and disease resolution. These functions include, among others: microbicidal activity, the production of mediators to recruit and activate inflammatory cells (cytokines and chemokines), and redistribution to other tissues (lymph nodes) for interactions with T lymphocytes.

Within the greater field of pulmonary immunology, we have chosen to focus on a number of factors:

1) Biology of antigen-presenting cells in the lungs (especially dendritic cells and B lymphocytes), and how it influences pulmonary disease. One primary project involves the role of B cells as antigen-presenting cells during asthma and viral exacerbation of asthma. B cells are unique in that they are the only antigen presenting cell capable of antigen-specificity. Our studies have found that antigen-specific B cells accumulate in the lungs throughout chronic allergic disease, and have the ability to elicit Th2 cytokines from CD4+ T cells. These Th2 cytokines, including IL-4, IL-5, and IL-13 are central to the pathogenesis of asthma. We are ultimately interested in whether it may be possible to 1) pharmacologically target B cell antigen-presentation in asthma, or 2) manipulate a patient?s own (autologous) B cells to render them tolerogenic, rather than disease promoting, and infuse them back into the patient as a cellular therapy.

2) Regulatory T cell (Treg) trafficking and function in the lungs. Tregs are a subset of T lymphocytes that are critical for controlling inappropriate immune responses. Our studies examine the activation, trafficking, and function of these cells in a variety of pulmonary disease settings. Chemokines are small mediators produced during inflammation. The types of chemokines produced help dictate what types of inflammatory cells are attracted to the inflamed tissue. Our studies, as well as those by others, have thus far have identified two chemokine receptors, CXCR3 and CCR4, that appear to be important for the trafficking of regulatory T cells to the lungs following Th1 and Th2 mediated inflammation, respectively. However, there is considerable redundancy in chemokine receptor/ligand systems, with one cell type expressing many receptors, and multiple ligands for each receptor. Our studies seek to understand the temporal-spatial relationship during lung disease between inflammatory cells/mediators and inflammation-resolving Tregs, with the ultimate goal of modulating inflammation through Tregs.

We utilize a combination of in vivo and in vitro approaches to gain insight into these processes, including animal models of asthma, as well as viral infection.

Research Focus Area

Infectious Disease, Host: Pathogen Interaction, Pulmonary, Allergy, Immunology

Publications

Research Funding