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Toll-like Receptor 2 Gene Polymorphism, Serum Cytokines and Susceptibility to Disease Severity or Treatment Response of Pulmonary Tuberculosis

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Chang Gung Memorial Hospital
ClinicalTrials.gov Identifier:
NCT00772408
First received: October 13, 2008
Last updated: February 27, 2013
Last verified: October 2008
  Purpose

Infection with Mycobacterium tuberculosis remains at epidemic levels globally. Innate and adaptive immune responses evolve as protective mechanisms against mycobacterial infection in humans. Toll-like receptors (TLRs) are transmembrane proteins characterized by an extracellular leucine-rich domain that participates in ligand recognition and an intracellular tail. TLRs are the first defense system to detect potential pathogens, initiate immune responses and form the crucial link between innate and adaptive immune systems. Stimulation of TLR initiates a signaling cascade that involves a number of proteins, such as MyD88 and IL-1 receptor-associated kinase. This signal cascade leads to NF-κB activation, which induce the secretion of pro-inflammatory cytokines.

TLR2 is a family of TLR family and has been reported to be the principle mediator of macrophage activation in response to mycobacterium. Growing amounts of data suggest that the ability of certain individuals to respond properly to TLR ligands may be impaired by single nucleotide polymorphisms (SNPs) within TLR genes, resulting in an altered susceptibility to, or course of, infectious disease. The genetic polymorphism of TLR2 (arginine to glutamine substitution at residue 753 (Arg753Gln)) has been associated with a negative influence on TLR2 function, which may, in turn, determine the innate host response to mycobacteria. In addition, another polymorphism (Arg677Trp) of the TLR2 was reported to be associated with susceptibility to tuberculosis in Tunisian patients. Moreover, in Mycobacterium leprosy patients with TLR2 mutation (Arg677Trp), production of IL-2, IL-12, IFN-gamma, and TNF-alpha by M. leprae-stimulated peripheral blood mononuclear cell were decreased compared with that in groups with wild-type TLR2.

To date, there have been no studies of the association of SNPs of TLR2 with cytokine profiles and clinical outcomes on M. tuberculosis. We hypothesize that polymorphisms in the TLR2 are associated with :

  1. increased prevalence of active pulmonary TB infection,
  2. altered levels of pro-inflammatory and anti-inflammatory cytokines in serum,
  3. clinical outcomes and presentations. We thus design a prospective case-control study to test this hypothesis. The frequency of TLR2 polymorphisms in both pulmonary TB patients and healthy controls will be determined by polymerase chain reaction-restriction fragment length polymorphism. Serial serum levels of IL-12, IFN-γ, and IL-10 in pulmonary TB patients with or without TLR2 polymorphisms will be measured by enzyme linked immunosorbent assay. Relationships between TLR2 polymorphisms and serum cytokines dynamics or clinical outcomes will be analyzed.

Condition
Pulmonary Tuberculosis
Genetic Variants of Host
Immune Response of Host

Study Type: Observational
Study Design: Observational Model: Case Control
Time Perspective: Prospective
Official Title: Relationship Between TLR2 Polymorphism and Pulmonary Tuberculosis

Resource links provided by NLM:


Further study details as provided by Chang Gung Memorial Hospital:

Primary Outcome Measures:
  • susceptibility of pulmonary tuberculosis [ Time Frame: At diagnosis ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • clinical presentation of pulmonary TB [ Time Frame: at diagnosis ] [ Designated as safety issue: No ]

Biospecimen Retention:   Samples With DNA

peripheral blood leukocyte DNA and plasma


Enrollment: 300
Study Start Date: August 2006
Study Completion Date: November 2009
Primary Completion Date: November 2009 (Final data collection date for primary outcome measure)
Groups/Cohorts
TB
patients with pulmonary TB
control
healthy controls

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   20 Years to 90 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Sampling Method:   Probability Sample
Study Population

Case: patients visiting the Pulmonary department of Chang Gung Memorial Hospital, Kaohsiung, Taiwan Control:healthy subjects visiting the Center of health examination at Chang Gung Memorial Hospital, Kaohsiung, Taiwan

Criteria

Inclusion Criteria:

  • a) findings on CXR that are compatible with presentations of Mycobacterium tuberculosis b) clinical symptoms, such as fever, body weight loss, night sweating, chest pain and chronic cough, that indicate active infection of pulmonary tuberculosis (TB) c) microbiological diagnosis by sputum smear and culture, bronchoalveolar lavage fluid culture, or DNA probe examination.

    d) Resolution on CXR with anti-TB regimens e) Written informed consent form prior to participation into this study

Exclusion Criteria:

  • a) concurrent active disease of other chronic illnesses, such as lung cancer, chronic bronchitis and bronchial asthma b) poor physical conditions that make any examination infeasible c) participation in another trial with use of an investigated drug within on month d) use of corticosteroid or immunosuppressant drugs
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00772408

Locations
Taiwan
Kaohsiung Chang Gung Memorial Hospital
Kaohsiung, Taiwan, 886
Kaohsiung Chang Gung Memorial Hospital
Kaohsiung Hsien, Taiwan, 886
Sponsors and Collaborators
Chang Gung Memorial Hospital
Investigators
Principal Investigator: Meng-Chih Lin, MD Kaohsiung Chang Gung Memorial Hospital
  More Information

No publications provided

Responsible Party: Chang Gung Memorial Hospital
ClinicalTrials.gov Identifier: NCT00772408     History of Changes
Other Study ID Numbers: NSC 95-2314-B-182A-030
Study First Received: October 13, 2008
Last Updated: February 27, 2013
Health Authority: Taiwan: Institutional Review Board

Keywords provided by Chang Gung Memorial Hospital:
pulmonary tuberculosis
Toll-like receptor 2 gene polymorphisms
blood lymphocyte subsets
systemic symptoms
pleural effusion

Additional relevant MeSH terms:
Tuberculosis
Tuberculosis, Pulmonary
Actinomycetales Infections
Bacterial Infections
Gram-Positive Bacterial Infections
Lung Diseases
Mycobacterium Infections
Respiratory Tract Diseases
Respiratory Tract Infections

ClinicalTrials.gov processed this record on November 27, 2014