T Lymphocyte Cells in Individuals Experiencing an Acute Exacerbation of Chronic Obstructive Pulmonary Disease

Pulmonary Disease, Chronic Obstructive Clinical Trial

Official title:

Innate and Adaptive Immunity in COPD Exacerbations: Surgical Volunteers

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00281229
• Other study ID #: 1328
• Secondary ID: R01HL082480
• Status: Completed
• Start date: September 2005
• Est. completion date: January 2015

Study information

• Verified date: January 2016
• Source: University of Michigan
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The purpose of this study is to determine whether the lungs of individuals with chronic obstructive pulmonary disease (COPD) contain resident memory T lymphocytes that can produce a combination of cytokines that induce the symptoms of an acute exacerbation of COPD (AE-COPD). Specifically, the study will determine cell-surface receptors of lung T cells in comparison with blood T cells from the same subject, and will examine anti-CD3-activated blood or lung T cells for interleukin (IL)-6 and interferon-gamma production in response to IL-18, and for IL-17A production in response to recombinant IL-23.

Description:

BACKGROUND:

COPD is one of the most pressing healthcare problems facing our nation. AE-COPD is responsible for the bulk of healthcare costs, and much of the morbidity and decline in health status among individuals with this common disease. The lack of accepted animal models of AE-COPD necessitates novel approaches using human samples. Advances in the understanding of the pathogenesis have been slowed, in part, due to controversy as to how exacerbations should be defined. The prevailing paradigm has defined AE-COPD as event-based. Such definitions clearly identify groups of patients with accelerated loss of pulmonary function and increased mortality. However, limited data show that symptom-based definitions of AE-COPD also capture episodes inducing significant morbidity and functional decline, and hence of concern to patients. Fundamental mechanisms are lacking to explain AE-COPD defined by either means.

Controversy also surrounds triggers of AE-COPD. Bacteria and viruses are involved in some episodes, but the relative importance of each is intertwined with disputes over the definition of AE-COPD. Progress at linking specific pathogens to molecular pathogenesis has been slow, both due to their diversity, and to the high rates of bacterial colonization of patients with COPD, even in the stable state. Moreover, in many AE-COPD cases, no pathogen can be identified. Without negating the value of analyzing infections with specific species of pathogens, it appears that progress in molecular pathogenesis could be accelerated by focusing on unifying features of the pulmonary immune response during AE-COPD.

DESIGN NARRATIVE:

The research protocol involves isolating lung lymphocytes from surgical specimens of patients already undergoing clinically indicated lung resections. Surgical lung resections may be performed either by open thoracotomy or by video-assisted thoracoscopic surgery (VATS), and could include pneumonectomies, lobectomies, or wedge-excisions, as dictated by clinical care of the patient. This protocol will exclusively use tissue that is of excess after a clinical diagnosis is established. The setting is the operating rooms at the Ann Arbor VA Hospital or the University of Michigan Hospital System. Subjects will be recruited from the outpatient clinics, but will be inpatients at the time of surgery.

Subjects will not undergo any additional procedures beyond routine clinical care as a result of participating in this protocol. However, it is anticipated that the study will have access to the medical record to extract results of demographic data, including occupational exposures and smoking history, pulmonary function testing, and results of imaging and other staging studies.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 481
• Est. completion date: January 2015
• Est. primary completion date: September 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 21 Years and older

Eligibility

Inclusion criteria:

• Diagnosis of COPD AND underwent lung resection for malignancy OR lung volume reduction surgery OR lung transplantation OR lung resection for nodules and masses

Exclusion criteria:

• Mental incompetence or active psychiatric illness

• Currently using more than 20 mg/day of Prednisone

• Asthma as primary clinical pulmonary diagnosis

• Cystic fibrosis

• Clinically significant bronchiectasis

• Other inflammatory or fibrotic lung disease

Related Conditions & MeSH terms

• Chronic Disease
• Lung Diseases
• Lung Diseases, Obstructive
• Pulmonary Disease, Chronic Obstructive

Locations

Country	Name	City	State
United States	University of Michigan at Ann Arbor	Ann Arbor	Michigan
United States	VA Ann Arbor Healthcare System	Ann Arbor	Michigan

Sponsors (2)

Lead Sponsor	Collaborator
University of Michigan	National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

References & Publications (9)

Curtis JL, Freeman CM, Hogg JC. The immunopathogenesis of chronic obstructive pulmonary disease: insights from recent research. Proc Am Thorac Soc. 2007 Oct 1;4(7):512-21. Review. — View Citation

Curtis JL. Cell-mediated adaptive immune defense of the lungs. Proc Am Thorac Soc. 2005;2(5):412-6. Review. — View Citation

Freeman CM, Curtis JL, Chensue SW. CC chemokine receptor 5 and CXC chemokine receptor 6 expression by lung CD8+ cells correlates with chronic obstructive pulmonary disease severity. Am J Pathol. 2007 Sep;171(3):767-76. Epub 2007 Jul 19. — View Citation

Freeman CM, Han MK, Martinez FJ, Murray S, Liu LX, Chensue SW, Polak TJ, Sonstein J, Todt JC, Ames TM, Arenberg DA, Meldrum CA, Getty C, McCloskey L, Curtis JL. Cytotoxic potential of lung CD8(+) T cells increases with chronic obstructive pulmonary diseas — View Citation

Freeman CM, Martinez CH, Todt JC, Martinez FJ, Han MK, Thompson DL, McCloskey L, Curtis JL. Acute exacerbations of chronic obstructive pulmonary disease are associated with decreased CD4+ & CD8+ T cells and increased growth & differentiation factor-15 (GD — View Citation

Freeman CM, Martinez FJ, Han MK, Ames TM, Chensue SW, Todt JC, Arenberg DA, Meldrum CA, Getty C, McCloskey L, Curtis JL. Lung dendritic cell expression of maturation molecules increases with worsening chronic obstructive pulmonary disease. Am J Respir Cri — View Citation

Freeman CM, Martinez FJ, Han MK, Washko GR Jr, McCubbrey AL, Chensue SW, Arenberg DA, Meldrum CA, McCloskey L, Curtis JL. Lung CD8+ T cells in COPD have increased expression of bacterial TLRs. Respir Res. 2013 Feb 1;14:13. doi: 10.1186/1465-9921-14-13. — View Citation

Freeman CM, McCubbrey AL, Crudgington S, Nelson J, Martinez FJ, Han MK, Washko GR Jr, Chensue SW, Arenberg DA, Meldrum CA, McCloskey L, Curtis JL. Basal gene expression by lung CD4+ T cells in chronic obstructive pulmonary disease identifies independent m — View Citation

Freeman CM, Stolberg VR, Crudgington S, Martinez FJ, Han MK, Chensue SW, Arenberg DA, Meldrum CA, McCloskey L, Curtis JL. Human CD56+ cytotoxic lung lymphocytes kill autologous lung cells in chronic obstructive pulmonary disease. PLoS One. 2014 Jul 31;9(7 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	phenotype and in vitro functions of lung lymphocytes		within 3 days of surgery

External Links

•   COPD Foundation