Latency in Pulmonary Tuberculosis

2014-08-27 03:12:30 | BioPortfolio


The immune responses in latent tuberculosis are poorly understood. While it is difficult to define the onset of latency during natural infection, patients undergoing treatment for tuberculosis are driven into a state of latency or cure. The present study on the effect of 3 and 4 month regimens containing moxifloxacin in sputum smear and culture positive pulmonary tuberculosis (TRC Study number 24) offers us the opportunity to study definitive immune responses pre and post treatment. We will evaluate a variety of innate and adaptive immune responses in patients before and after treatment and our study will compare the differences in immuno-phenotype (eg. Markers of T, B and NK cell activation, proliferation and regulatory phenotype) and function (eg. Production of cytokines, proliferative responses to TB antigens) at different time points following treatment. In addition, since a small percentage of patients will undergo relapse following treatment, the kinetics of immune responses in these patients will used to assess immunological predictors of relapse in tuberculosis.


Although Mycobacterium tuberculosis (Mtb) infects approximately 2 billion people worldwide, 90% of Mtb infected individuals are able to resist overt disease (active tuberculosis) development and manifest only latent infection. Latent tuberculosis (TB) is defined as the persistent presence of live Mtb within an infected host without causing disease. It is characterized by a delayed type hypersensitivity response to purified protein derivative (PPD) mediated by mycobacteria specific T cells. During latency, Mtb is contained in localized granulomas where the mycobacteria reside in macrophages and in which growth and replication appears to be constrained. Maintenance of the granulomatous lesion is mediated by CD4+ and CD8+ T cells. Based on murine models, immunity to Mtb requires Th1 responses and (to a lesser extent) Th17 responses. Thus, IL 12, IFN gamma, and TNF alpha (and IL 17 and IL 23) all play important roles in induction and maintenance of protective immune responses against tuberculous disease. Although CD4+ T lymphocytes of Th1 type are critical for protective immunity, evidence exists that CD8+ T cells as well as unconventional T cells (gamma-delta T cells and CD 1 restricted T cells) contribute to optimum protection in susceptible animal models. Aside from producing cytokines that activate macrophages and initiate granuloma formation, T cells also have direct mycobactericidal activities through the concerted actions of perforins and granulysins.

T cell differentiation into Th1 and Th2 lineages based on their cytokine profile and transcription factor expression has served as the basis of our understanding the pathogenesis of a variety of infectious and allergic diseases. With the advent of newer techniques, T cell differentiation has expanded into several subsets, including Tregs, Th17 cells, and polyfunctional T cells, among others. Th1 cells are absolutely essential for resistance to TB both in mice and humans. Deficiencies in the IL 12 IFN gamma Stat1 pathway leads to disseminated mycobacterial infection in humans and to abrogation of resistance in mice. In addition, TNF alpha, another Th1 cytokine, is of almost equal importance, as treatment with biologics (e.g., anti TNF alpha antibodies) for inflammatory disorders such as rheumatoid arthritis has caused reactivation of TB in some individuals.

Latent TB can be maintained for the lifetime of the individual unless the immunological balance between the host and the pathogen is perturbed, resulting in reactivation of Mtb and active disease. The host and environmental factors involved in compromising the ability to contain latent infection are human immunodeficiency virus co infection, malnutrition, aging, stress, Type 2 diabetes, use of immunosuppressive agents, and other genetic factors. On the pathogen side, latency is thought to reflect a transition from replicating to nonreplicating dormant bacilli, with this transition being influenced by a variety of factors including oxygen deprivation and nitric oxide. The use of in vitro and in vivo models of latency combined with genome wide transcriptome profiling has led to the identification of Mtb genes highly expressed during latency called dosR or devR (dormancy) genes; however, each of the host and pathogen related factors controlling resistance and/or susceptibility to TB awaits complete elucidation.

The subsets of CD4+ T cells constitute an ever expanding repertoire, classified by their discrete cytokine profiles and often by expression of prototypical transcription factors and/or cell surface molecules. Two relatively newly emerging CD4+ T cell subsets of importance are Th17 cells, characterized by production of IL 17 family of cytokines, and regulatory T cells (Tregs), characterized by surface expression of CD25 and the transcription factor FoxP3. Little is known about the role of these two subsets in latent TB. The mechanism by which Mtb subverts immune responses to establish chronic, latent infection is also not well understood. Recently, a number of regulatory factors, including Tregs, IL 10, TGF-beta, CTLA 4, and PD 1, have been implicated in the establishment of chronic viral, bacterial, and parasitic infections.

The role of T, B and NK cells in the evolution of the immune response following therapy in Mycobacterium tuberculosis infection has to be elucidated. The development of cellular immune responses in TB-infected patients post-chemotherapy to delineate the cellular arms of immunity in response to crude and defined TB antigens in treated patients needs to be studied.

Study Design

Allocation: Randomized, Control: Active Control, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment


Pulmonary Tuberculosis


Moxifloxacin, Isoniazid, Rifampicin Pyrazinamide, Ethambutol


Tuberculosis Research Centre




Tuberculosis Research Centre, India

Results (where available)

View Results


Published on BioPortfolio: 2014-08-27T03:12:30-0400

Clinical Trials [1625 Associated Clinical Trials listed on BioPortfolio]

TBTC Study 28: Moxifloxacin Versus Isoniazid for TB Treatment

This double-blind, randomized controlled trial evaluates moxifloxacin versus isoniazid in daily treatment during the first two months of treatment with rifampin, pyrazinamide and ethambuto...

TBTC Study 27: Moxifloxacin vs Ethambutol for TB Treatment

This study is a placebo-controlled factorial study, randomized to study drug (moxifloxacin vs. ethambutol) and treatment frequency (daily vs. thrice weekly after an initial two weeks of da...

Rapid Detection of Rifampin and Isoniazid Resistance by PCR Before Tuberculosis (TB) Treatment Initiation

French guidelines currently recommend to initiate a 4-drug containing regimen associating isoniazid (INH or H), rifampicin (RIFor RMP or R), pyrazinamide (PZA or Z) and ethambutol (EMB or ...

Rifapentine Plus Moxifloxacin for Treatment of Pulmonary Tuberculosis

Although effective therapy for tuberculosis is available, TB continues to cause significant problems worldwide, and rates of multi-drug resistant (MDR) TB cases are on the rise. A major ob...

Assessing PA-824 for Tuberculosis (the APT Trial)

Assess the mycobactericidal activity of PA-824 (given at 200 mg daily) when added to first-line TB treatment (isoniazid, pyrazinamide, and a rifamycin antibiotic) over 12 weeks of treatme...

PubMed Articles [3437 Associated PubMed Articles listed on BioPortfolio]

Treatment outcomes for isoniazid-monoresistant tuberculosis in Peru, 2012-2014.

Resistance to isoniazid is the most common form of drug-resistance in tuberculosis. However only a tiny proportion of TB patients in the world have access to isoniazid drug susceptibility testing-the ...

Pharmacokinetics of First-Line Drugs Among Children With Tuberculosis in Rural Tanzania.

Dosing recommendations for treating childhood tuberculosis (TB) were revised by the World Health Organization, yet so far, pharmacokinetic studies that have evaluated these changes are relatively limi...

Artificial intelligence-derived 3-Way Concentration-dependent Antagonism of Gatifloxacin, Pyrazinamide, and Rifampicin During Treatment of Pulmonary Tuberculosis.

In the experimental arm of the OFLOTUB trial, gatifloxacin replaced ethambutol in the standard 4-month regimen for drug-susceptible pulmonary tuberculosis. The study included a nested pharmacokinetic ...

Simultaneous quantification of four first line antitubercular drugs and metabolites in human plasma by hydrophilic interaction chromatography and tandem mass spectrometry.

Co-infection of tuberculosis in HIV-patients is a major health concern worldwide and especially so in Sub-Saharan Africa. To enhance the study of potential drug-drug interactions when simultaneously t...

Measurement of rifampicin concentrations in tuberculous pleural effusion before and after combination treatment with oral and local rifampicin.

To investigate the changes of rifampin concentrations in pleural effusion before and after combination treatment with oral and pleural administration of rifampicin by electro-phonophoresis(EP). A sel...

Medical and Biotech [MESH] Definitions

Tuberculosis resistant to chemotherapy with two or more ANTITUBERCULAR AGENTS, including at least ISONIAZID and RIFAMPICIN. The problem of resistance is particularly troublesome in tuberculous OPPORTUNISTIC INFECTIONS associated with HIV INFECTIONS. It requires the use of second line drugs which are more toxic than the first line regimens. TB with isolates that have developed further resistance to at least three of the six classes of second line drugs is defined as EXTENSIVELY DRUG-RESISTANT TUBERCULOSIS.

Tuberculosis resistant to ISONIAZID and RIFAMPIN and at least three of the six main classes of second-line drugs (AMINOGLYCOSIDES; polypeptide agents; FLUOROQUINOLONES; THIOAMIDES; CYCLOSERINE; and PARA-AMINOSALICYLIC ACID) as defined by the CDC.

Antibacterial agent used primarily as a tuberculostatic. It remains the treatment of choice for tuberculosis.

Tuberculosis of the brain, spinal cord, or meninges (TUBERCULOSIS, MENINGEAL), most often caused by MYCOBACTERIUM TUBERCULOSIS and rarely by MYCOBACTERIUM BOVIS. The infection may be limited to the nervous system or coexist in other organs (e.g., TUBERCULOSIS, PULMONARY). The organism tends to seed the meninges causing a diffuse meningitis and leads to the formation of TUBERCULOMA, which may occur within the brain, spinal cord, or perimeningeal spaces. Tuberculous involvement of the vertebral column (TUBERCULOSIS, SPINAL) may result in nerve root or spinal cord compression. (From Adams et al., Principles of Neurology, 6th ed, pp717-20)

The dormant form of TUBERCULOSIS where the person shows no obvious symptoms and no sign of the causative agent (Mycobacterium tuberculosis) in the SPUTUM despite being positive for tuberculosis infection skin test.

More From BioPortfolio on "Latency in Pulmonary Tuberculosis"

Quick Search


Relevant Topics

Tuberculosis TB
Tuberculosis (TB) is an infectious disease caused by bacteria belonging to the Mycobacterium tuberculosis complex. Over nine million new cases of TB, and nearly two million deaths from TB, are estimated to occur around the world every year, and new inf...

Antiretroviral Therapy Clostridium Difficile Ebola HIV & AIDS Infectious Diseases Influenza Malaria Measles Sepsis Swine Flu Tropical Medicine Tuberculosis Infectious diseases are caused by pathogenic...

Pulmonary relating to or associated with the lungs eg Asthma, chronic bronchitis, emphysema, COPD, Cystic Fibrosis, Influenza,  Lung Cancer, Pneumonia, Pulmonary Arterial Hypertension, Sleep Disorders etc Follow and track Lung Cancer News ...

Searches Linking to this Trial