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Dennis Lindell, PhD

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Dennis Lindell, PhD

Children's Title: Principal Investigator

Academic Title: Assistant Professor

Research Center: Center for Immunity and Immunotherapies

"The lost innocence that comes with childhood disease can either be simply sorrowful or it can feed us with the energy and creativity to advance medicine. I come to work each day for those children unlucky enough to be born premature in the peak of RSV season — for the children with asthma who cannot breathe but do not even understand why. I work so that we may help kids who struggle to breathe: so that they, too, can run the way only children run — not for exercise or competition, but just because it feels good and makes them feel alive."

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

Delta-like 4 differentially regulates murine CD4 T cell expansion via BMI1.
PloS one , 2010 Aug 17: e12172
Respiratory virus-induced TLR7 activation controls IL-17-associated increased mucus via IL-23 regulation.
Journal of immunology (Baltimore, Md. : 1950) , 2010 Aug 15: 2231-9
The post sepsis-induced expansion and enhanced function of regulatory T cells create an environment to potentiate tumor growth.
Blood , 2010 Jun 3: 4403-11
CCL20/CCR6 blockade enhances immunity to RSV by impairing recruitment of DC.
European journal of immunology , 2010 Apr: 1042-52
B cell antigen presentation promotes Th2 responses and immunopathology during chronic allergic lung disease.
PloS one , 2008 Sep 3: e3129
CXCL10/CXCR3-mediated responses promote immunity to respiratory syncytial virus infection by augmenting dendritic cell and CD8(+) T cell efficacy.
European journal of immunology , 2008 Aug: 2168-79
Regulation of immunity to respiratory syncytial virus by dendritic cells, toll-like receptors, and notch.
Viral immunology , 2008 Jun: 115-22
The balance between plasmacytoid DC versus conventional DC determines pulmonary immunity to virus infections.
PloS one , 2008 Mar 5: e1720
Pneumococcal conjugate vaccine is immunogenic in lung fluid of HIV-infected and immunocompetent adults.
The Journal of allergy and clinical immunology , 2007 Jul: 208-10
Respiratory syncytial virus-induced pulmonary disease and exacerbation of allergic asthma.
Contributions to microbiology , 2007: 68-82
Diversity of the T-cell response to pulmonary Cryptococcus neoformans infection.
Infection and immunity , 2006 Aug: 4538-48
Distinct compartmentalization of CD4+ T-cell effector function versus proliferative capacity during pulmonary cryptococcosis.
The American journal of pathology , 2006 Mar: 847-55
Generation of antifungal effector CD8+ T cells in the absence of CD4+ T cells during Cryptococcus neoformans infection.
Journal of immunology (Baltimore, Md. : 1950) , 2005 Jun 15: 7920-8

Research Funding

Grant TitleGrantorAmountAward Date
B cell antigen presentation in chronic allergic lung diseaseNIH $250,000.00Dec. 9, 2008
RSV vaccine development using a nanoemulsionNanobio Corp. $101,059.00Aug. 1, 2008

Primary Office

Seattle Children's Research Institute
JMB - 7 - Immunology
1900 - 9th Ave
Seattle, WA 98101
206-987-7450

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