Immune Response to Mycobacterium Tuberculosis Infection

April 4, 2018 updated by: National Institute of Allergy and Infectious Diseases (NIAID)

Correlation of the Precursor Frequency of CD4 + Effector Memory T Cells With Induration Measured in the Tuberculin Skin Test (TST)

This study will examine how the immune system responds to infection with Mycobacterium tuberculosis bacteria (bacteria that cause tuberculosis) in order to better understand how the germ produces infection and how the immune response might work to control the infection.

Only about one in 10 people infected by M. tuberculosis become sick, sometimes years or even decades after exposure. It is not known why some people become sick and most do not, but the immune system of people who never develop disease may be better able to control the bacteria. This study will evaluate the latent form of M. tuberculosis infection to further the understanding of the immune mechanisms - particularly the role of certain white blood cells - involved in the disease process.

Healthy volunteers 18 years of age and older may be eligible for this study. Candidates are screened with a medical history, family history of medical conditions, sexual history, history of drug use, physical examination and blood tests, including a test for HIV. People in Mali, West Africa, and in local health clinics in the United States may participate.

At the start of the study, participants have blood tests and a tuberculin skin test (PPD test), which indicates whether a person has been exposed to tuberculosis bacteria. For the PPD, a tiny amount of liquid containing dead tuberculosis antigen is put under the skin of the forearm with a needle. The antigen cannot cause infection or disease.

After 3 days, participants have another blood test and the site of the tuberculin test is examined for swelling that would indicate a positive result. Participants with a positive PPD have a chest x-ray to check for tuberculosis disease. Those whose x-ray is also positive are withdrawn from the study and referred to their doctor for evaluation and treatment. Those whose x-ray is negative return to the clinic within 3 weeks of the tuberculin test to give another blood sample.

Participants whose PPD is negative have a second tuberculin test 10 to 21 days later and return 3 days after the test to determine if it is still negative or if it is positive. (Some people who are negative after the first test may test positive after the second procedure.) Those whose test is still negative end their participation in the study at that time. Participants whose second PPD is positive have a chest x-ray as described above, and those with a negative chest x-ray return in 3 weeks to donate one last blood sample.

The purpose of the present study is to evaluate the latent form of this infection, the prevalence of which worldwide exceeds that of active disease. Our hypothesis is that in latent tuberculosis antigen specific effector memory CD4+ T cells are responsible for the generation of clinically measurable delayed type hypersensitivity and that central memory CD4+T cells are not directly involved in this process. We base this idea on the assumption that latent tuberculosis is a state of antigen persistence and that effector memory T cells should be maintained as long as antigen/infection is present.

We propose to conduct this study in Mali, West Africa and local clinics in the U.S. Tuberculosis affects 593/100,000(2) individuals in Mali and most have been exposed to the disease. Additionally it would be important to evaluate the same parameters locally as latent infection is one of the major factors for reactivation tuberculosis in this country. Patients would be enrolled in 4 major groups: HIV-/TST- (Group A), HIV-/TST+ (Group B), HIV+/TST+(G roup C) and HIV+/TST- (Group D).

To evaluate this hypothesis we plan to enroll between 100 - 300 patients over the course of 2 years from both countries. Blood samples before and at predetermined time points after the application of Purified Protein Derivative (PPD) will be obtained to determine the fraction of CD4+ T cells which produce interferon gamma in response to stimulation with PPD with a 16hr antigen stimulation assay. Appropriate staining will be done to ascertain the phenotype as well as cytokine production (Interferon gamma,( IFN gamma), Interleukin 2 (IL2) and Tumour Necrosis Factor ( TNF)). Additionally lymphocyte proliferation will be studied using 5-(and-6)-carboxyflouorescein diacetate succinimidyl ester (CFSE.)

In conducting this study we hope to further the understanding of the immune mechanisms involved, particularly mechanisms of T cell memory, which would provide insights into TB and HIV pathogenesis. We also believe that understanding these mechanisms could lead towards establishment of surrogates for immunity in TB vaccine studies, which could enhance vaccine trial design. It might also help in understanding better the immunological dynamics of tuberculosis co-infection in individuals with HIV infection.

Study Overview

Status

Completed

Conditions

Detailed Description

Tuberculosis (TB) is a major global health concern. One third of the world's population is infected with Mycobacterium tuberculosis. Two to 3 million people die every year of the disease with 8-10 million new cases per year. It is projected that there will be 90 million new cases and 30 million deaths over the next decade. For a disease, which we know to have existed since 2400 BC, our understanding of its pathogenesis is incomplete, especially in relation to the human immune response and the role of lymphocytes in particular.

The purpose of the present study is to evaluate the latent form of this infection, the prevalence of which worldwide exceeds that of active disease. Our hypothesis is that in latent tuberculosis antigen specific effector memory CD4+ T cells are responsible for the generation of clinically measurable delayed type hypersensitivity and that central memory CD4+T cells are not directly involved in this process. We base this idea on the assumption that latent tuberculosis is a state of antigen persistence and that effector memory T cells should be maintained as long as antigen/infection is present.

We propose to conduct this study in Mali, West Africa and local clinics in the U.S. Tuberculosis affects 593/100,000(2) individuals in Mali and most have been exposed to the disease. Additionally it would be important to evaluate the same parameters locally as latent infection is one of the major factors for reactivation tuberculosis in this country. Patients would be enrolled in 4 major groups: HIV-/TST- (Group A), HIV-/TST+ (Group B), HIV+/TST+ (Group C) and HIV+/TST- (Group D).

To evaluate this hypothesis we plan to enroll between 100 - 300 patients over the course of 2 years from both countries. Blood samples before and at predetermined time points after the application of Purified Protein Derivative (PPD) will be obtained to determine the fraction of CD4+ T cells which produce interferon gamma in response to stimulation with PPD with a 16hr antigen stimulation assay. Appropriate staining will be done to ascertain the phenotype as well as cytokine production (Interferon gamma, ( IFN gamma), Interleukin 2 (IL2) and Tumour Necrosis Factor (TNF)). Additionally lymphocyte proliferation will be studied using 5-(and-6)-carboxyflouorescein diacetate succinimidyl ester (CFSE.)

In conducting this study we hope to further the understanding of the immune mechanisms involved, particularly mechanisms of T cell memory, which would provide insights into TB and HIV pathogenesis. We also believe that understanding these mechanisms could lead towards establishment of surrogates for immunity in TB vaccine studies, which could enhance vaccine trial design. It might also help in understanding better the immunological dynamics of tuberculosis co-infection in individuals with HIV infection.

Study Type

Observational

Enrollment (Actual)

157

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Mali
      • Bamako, Mali
        • Mali-NIAID HIV Research Initiative FMPOS
  • United States
    • Maryland
      • Bethesda, Maryland, United States, 20892
        • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

  • INCLUSION CRITERIA:
  • Age18 yrs. or older.
  • Adequate venous access.
  • Willingness to allow blood samples to be used for future studies of immune function and disease pathogenesis.
  • Ability to give informed consent and willingness to comply with study requirements and procedures.
  • Willingness to have PPD placed.
  • Willingness to undergo HIV testing.

EXCLUSION CRITERIA:

  • Hgb less than or equal to 7.9 g/dl
  • A known medical disorder or other circumstance which in the opinion of the PI might make the participation of the individual unsafe or difficult.
  • Active TB or a history of treated tuberculosis infection.
  • Presently suffering from an acute infection.
  • History of a severe reaction to PPD application or known allergy to a component of the PPD.
  • Severe burns or Eczema.
  • PPD less than or equal to 8 weeks previously.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

November 18, 2005

Study Completion

February 24, 2016

Study Registration Dates

First Submitted

November 22, 2005

First Submitted That Met QC Criteria

November 22, 2005

First Posted (Estimate)

November 23, 2005

Study Record Updates

Last Update Posted (Actual)

April 5, 2018

Last Update Submitted That Met QC Criteria

April 4, 2018

Last Verified

February 24, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 060030
  • 06-I-0030

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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