Latency in Pulmonary Tuberculosis
Information source: Tuberculosis Research Centre, India
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Pulmonary Tuberculosis
Intervention: Moxifloxacin, Isoniazid, Rifampicin Pyrazinamide, Ethambutol (Drug)
Phase: Phase 3
Status: Recruiting
Sponsored by: Tuberculosis Research Centre, India Official(s) and/or principal investigator(s): Subash Babu, MBBS, PhD, Principal Investigator, Affiliation: Tuberculosis Research Centre, India
Overall contact: Subash Babu, MBBS, PhD, Phone: 91-44-28369711, Email: sbabu@niaid.nih.gov
Summary
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.
Clinical Details
Official title: Characterization of Immune Responses in Treatment-induced Latency in Pulmonary Tuberculosis
Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: The immune response to crude antigens - PPD and CFA and defined antigens - ESAT-6 and CFP-10 as well as positive controls- SEB and anti-CD3.
Secondary outcome: Determining the correlation of increase in regulatory factors with the development of relapse in treated TB patients.
Detailed description:
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.
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
Inclusion Criteria:
- Age 18 years and above
- Residing in or around Chennai or Madurai
- No anti-TB treatment in the past or should have had less than one month of treatment
(but less than one week in the preceding one month before enrollment in the study)
- At least two sputum smears should be positive for tubercle bacilli by fluorescent
microscopy
- Express willingness to attend the treatment centre for supervised treatment
- Express willingness for home visits by the staff of the centre
- Express willingness to give written informed consent
Exclusion Criteria:
- Body weight less than 30 kg
- Hepatic or renal disease as evidenced by clinical or biochemical abnormalities
- Diabetes mellitus
- A history of seizure or loss of consciousness
- Psychiatric illness
- An abnormal electrocardiogram or anti-arrhythmic medication
- Those in a moribund state
- Sero-positive for HIV antibodies
- Pregnancy or lactation
- Visual disorders other than refractory error
Locations and Contacts
Subash Babu, MBBS, PhD, Phone: 91-44-28369711, Email: sbabu@niaid.nih.gov
Tuberculosis Research Centre, Chennai, Tamilnadu 600031, India; Recruiting Subash Babu, MBBS, PhD, Phone: 91-44-28369711, Email: sbabu@niaid.nih.gov Pavan Kumar, MSc, Phone: 91-44-28369766, Email: pavankumarn@trcchennai.in Subash Babu, MBBS, PhD, Principal Investigator
Additional Information
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Starting date: February 2010
Last updated: June 15, 2011
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