Tuberculosis Immunology Group

43 Pages·2007·3.64 MB·English

Diagnosing TB in the 21st Century:
New Tools to Tackle an Old Enemy
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Tuberculosis Immunology Group
We are fighting a large & growing epidemic
with old tools
Diagnostics TST 1890
Sputum microscopy 1880s
Chest X-ray 1920
Vaccine BCG 1921
Treatment Streptomycin 1949
Isoniazid 1952
Pyrazinamide 1952
Ethambutol 1961
Rifampin 1966
Tuberculosis Immunology Group
Comstock: Flow Chart: The natural history of
M. tuberculosis infection

‘TB is an infectious
Exposure to M. tuberculosis

disease with an

?

incubation period

from a few weeks

No infection Infection Transient
to a lifetime’ infection with

clearance

TB control 5% 95%

strategies
Prim ary TB Latent TB
in th e first 1-2 infection
are based yea rs after
infe ction
on the biology Treat active TB

and natural

BCG vaccinate

history of
Long-term
immune
TB infection control
Treat LTBI
5% 90%
Reactivation Lifelong
TB containment Tuberculosis Immunology Group
Flow Chart: The natural history of
Factors
M. tuberculosis infection
promoting

Exposure to M. tuberculosis

progression

?

to active

No infection Infection Transient

infection with

disease clearance

5% 95%
Primary TB Latent TB
in the first 1-2 infection
years after
infection
Long-term
immune
control
5% 90%
Reactivation Lifelong
TB containment

Tuberculosis Immunology Group
Targeted tuberculin testing & treatment of LTBI
• Focus on high risk-groups who are at increased
risk of progression to active TB:
– Recent infection
• contacts of TB cases
– Impaired cellular immunity
• HIV
• Children, especially < 5yrs old
• Concomitant illnesses: renal failure, diabetes, etc
• Iatrogenic immunosuppression
– Steroids, organ transplants, methotrexate, ant-TNF
Tuberculosis Immunology Group
The TST is an inadequate tool to achieve the
aims of targeted tuberculin testing for LTBI
• Paradoxically, poor sensitivity in exactly those vulnerable groups
targeted by the strategy
• Poor specificity:
– Over half the burden of TB is in BCG-vaccinated immigrants
– as prevalence falls in low-prevalence countries, an increasing
proportion of positive TST results will be false-positives
• These problems apply equally to patients with suspected active TB
• Problems of in vivo test…….
– Need for return visit
– Operator variability (inoculation & reading)
– Standardisation of reagent
– Painful inflammation & scarring
Tuberculosis Immunology Group
M. tb infection activates many T cell subsets
Can we exploit
Th1-type CD4+ T cells
MTB-specific
T cells as a marker
of infection? Regulatory T cells
Guyot-revol et al AJRCCM 2006
CD8+ T cells
IFN-γγγγ
Lalvani et al PNAS 1998
CD1 restricted T cells
Stenger et al Science 1997
Moody et al Nature 2000
γδ T cells
Tuberculosis Immunology Group
Counting T cells quickly:
ELISPOT
(Enzyme-linked immunospot for interferon-gamma)
• Detects IFN-gamma
release at the single
cell level
• Each spot is the
footprint of a single
cell that has reacted
to the antigen
• Very sensitive
(detects 1:50,000
antigen-specific T
cells)
• Rapid (ex vivo)
– Overnight incubation
– detects effector-
memory T cells
– non-radioactive
– sterile tissue culture
facilities not required
Tuberculosis Immunology Group
Comparative genomics identified regions of
difference between BCG and M. bovis/M. tuberculosis
The RD1 genomic segment of M. tuberculosis
is absent from all strains of BCG and
most environmental mycobacteria
Tuberculosis Immunology Group
RD1 encodes the two strongest T cell antigens of
M. tuberculosis: ESAT6 and CFP10
= RD1 = ESAT6 & CFP10
M. bovis
M. tuberculosis
RD1 was lost from RD1 is present in
BCG early on all strains of
M. tuberculosis
BCG BCG
BCG
M. tuberculosis
Tuberculosis Immunology Group