Pathogenic T Cell Recruitment into the Human Asthmatic Airway

Andrew D. Luster, M.D., Ph.D.

Massachusetts General Hospital

Funded in June, 2002: $300000 for 4 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY . SELECTED PUBLICATIONS .

LAY SUMMARY

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Understanding the Inflammatory Response in Asthma

Asthma is characterized by inflammation of the lungs, yet we still do not know why this inflammatory response is generated in response to harmless environmental antigens. Asthma is believed to result when a susceptible person has an allergic reaction in the lung to a substance inhaled from the environment. The inflammatory response occurs when certain immune T cells move into the airways in response to the inhaled substance. These pathogenic T cells are attracted into the lung by protein mediators called chemokines. Once in the airways, these T cells secrete substances that contribute to the inflammatory response.

Researchers propose to characterize the chemokine receptors that are on this subset of T cells and the cytokines and chemokines that these T cells secrete. The investigators anticipate that identification of the chemokines that recruit this subset of T cells into the lungs will be a major step toward developing novel effective therapies for asthma.

ABSTRACT

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Pathogenic T Cell Recruitment into the Human Asthmatic Airway

Asthma is a complex syndrome broadly defined by inflammation of the airways. Affecting more than 10 million Americans, and with prevalence estimated at 5% of the population, asthma is one of the most common chronic diseases worldwide. Despite our increased understanding of the pathogenesis of asthma from murine models, the incidence of this disease and the frequency of its significant complications are increasing. Furthermore, rationale therapies developed based on animal model data have not proved effective. For example, anti-IL-5 therapy, which looked so promising in murine and primate models, was not effective at reducing or ameliorating human asthma, despite reducing pulmonary eosinophilia. This failure underscores the need to understand the pathogenic factors involved in human asthma, which can only be accomplished by studying humans with asthma.

Human asthma is driven by a distinct subset of T cells that are recruited into the lung following antigen challenge. But where these cells have been identified as Th2 cells in animal models, their phenotypic characteristics in humans have yet to be clearly identified. We hypothesize that there is a pathogenic population of T cells uniquely present in the lung of asthmatic patients following inhaled antigen challenge that can be defined based on their expression of cytokines, chemokines, and chemokine receptors. We further hypothesize that the factors recruiting these T cells into the lung will be found in the airways following antigen challenge and their identification will lead to novel therapies for asthma.

Aim 1: To identify chemokine receptors preferentially expressed on T cells recruited into the bronchoalveolar lavage (BAL) following aerosol antigen challenge of atopic asthmatic patients vs. T cells in their peripheral blood, and to compare the expression of these receptors on BAL T cells from atopic asthmatics vs. atopic persons without asthma.

Aim 2: To define the phenotype of T cells recruited into the BAL following antigen challenge of atopic asthmatics vs. atopic nonasthmatics, using flow cytometry, quantitative PCR and microarray analysis on sorted cells.

Aim 3: To determine the proteome profile of the factors released into the BAL following antigen challenge to identify chemoattractants responsible for recruiting T cells into the human allergic lung.

INVESTIGATOR BIOGRAPHIES

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Andrew D. Luster, M.D., Ph.D.

Andrew D. Luster, M.D., Ph.D., is Chief of the Division of Rheumatology, Allergy and Immunology and Director of the Center for Immunology and Inflammatory Diseases at the Massachusetts General Hospital. He is an Associate Professor of Medicine at Harvard Medical School and Member of the Harvard Immunology Graduate Program.

Dr. Luster received a B.S. from Duke University, summa cum laude, a Ph.D. from the Rockefeller University, and an M.D. from Cornell Medical College. He trained in Internal Medicine and Infectious Diseases at the Massachusetts General Hospital and was a post-doctoral research fellow in the Department of Genetics at Harvard Medical School. Dr. Luster's laboratory studies the role of chemokines and chemoattractant receptors in leukocyte trafficking, particularly as it relates to the regulation of the immune and inflammatory response.

SELECTED PUBLICATIONS

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Thomas S.Y., Lilly C.M., and Luster A.D.  Invariant natural killer T cells in bronchial asthma.  N Engl J Med. 2006 Jun 15;354(24):2613-6.

Islam S.A., Thomas S.Y., Hess C., Medoff B.D., Means T.K., Brander C., Lilly C.M., Tager A.M., and Luster A.D.  The leukotriene B4 lipid chemoattractant receptor BLT1 defines antigen-primed T cells in humans.  Blood. 2006 Jan 15;107(2):444-53.

Luster A.D., Alon R., and von Andrian U.H.  Immune cell migration in inflammation: present and future therapeutic targets.  Nat Immunol. 2005 Dec;6(12):1182-90.

Luster A.D. and Tager A.M.  T-cell trafficking in asthma: lipid mediators grease the way.  Nat Rev Immunol. 2004 Sep;4(9):711-24.