Chronic obstructive pulmonary disease (COPD) is a major cause of disability and death among older Americans. Over 16 million people in the U.S. suffer from COPD with costs to the health care system of $15 billion. In the absence of lung disease the tracheobronchial tree is sterile, however in COPD patients it is chronically colonized, predominantly with nontypeable Haemophilus influenzae (NTHI), Moraxella catarrhalis and Streptococcus pneumoniae. Like most infections, COPD is characterized by inflammation that is mediated by the production of local and systemic chemokines and cytokines. We hypothesize that key outer membrane antigens of two of the bacteria that are responsible for exacerbations of COPD stimulate both human innate and adaptive immune responses and their ?cross-talk? accounts for both the stimulation and damage that is manifest during the disease. The particular strength of our proposal and its distinguishing feature is that all experiments will be done with cells directly obtained from the patient population and thus have direct relevance to the disease. Our studies will also result in the very first comparative analysis of the lipooligosaccharide (LOS) molecules (both wild type and several isogenic mutants) from NTHI and M. cataharralis on the three key cell types (dendritic, lung macrophages and lung bronchial epithelial cells) involved in production of cytokines and chemokines that modulate both inflammatory responses and adaptive immunity. We propose the following 3 specific aims: (1) Evaluation of the ability of lipoprotein P6 of NTHI to bridge innate and adaptive immune responses, (2) Evaluation of T cell responses in COPD patients to outer membrane proteins of M. catarrhalis and (3) Evaluation of the effects of LOS of NTHI and M. catarrhalis and its isogenic mutants on innate and adaptive immune responses. The extraordinary wealth of clinical samples, availability of defined antigens and Co-Investigator and Collaborators who are leaders in their field, will all ensure the success of our strategy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56AI069379-01A2
Application #
7624482
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Khambaty, Farukh M
Project Start
2008-07-07
Project End
2009-12-30
Budget Start
2008-07-07
Budget End
2009-12-30
Support Year
1
Fiscal Year
2008
Total Cost
$398,735
Indirect Cost
Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
824771034
City
Buffalo
State
NY
Country
United States
Zip Code
14263
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