What is new regarding the immunotherapy of TB
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What is new regarding the
immunotherapy of TB
Keertan Dheda, MB.BCh, FCP(SA), FCCP, FRCP (UK), PhD (Lond)
Associate Professor and Head:
Lung Infection and Immunity Unit
Division of Pulmonology & UCT Lung Institute,
Department of Medicine, University of Cape Town, South Africa
email: keertan.dheda@uct.ac.za
Conflict of interest: none
Overview Why bother about immunotherapy? Brief overview of TB immunology Rationale for immunotherapy Immunothreapeutic agents under study Summary
Comprehensive reviews on this subject Churchyard CJ, Clinics in Chest Medicine, 2009 WHO. Report of the expert consultation on immunotherapeutic interventions for TB. 2007 Dheda K, Respirology, 2010
Why bother about immunotherapy? Shorten standard 6 month anti-TB treatment In those cured from TB to prevent relapse or re-infection Treatment for XDR and TDR-TB
M and XDR-TB: What is the size of the problem globally? Worldwide 440 000 cases of MDR-TB in 2008 (3·6% of the total incident TB episodes) (360 000 new cases) Only 7% reported and 1-2% actually treated to WHO standards XDR-TB: globally~ 25000 XDR-TB cases annually
Size of the problem in SA
2004: 3278 MDR cases
2005: 4305 MDR cases
2006: 6716 MDR cases
2007: 7369 MDR cases
(16000 to 18000 estimated cases for 2007/8)
About 5 to 10% thought to be XDR-TB
1. Anti-Tuberculosis Drug Resistance in the World Report 2008:Fourth
Global Report, WHO, 2008
2. South African National Department of Health Report, 2008
3. WHO. Global TB Control. A short update to the 2009 report.
Why is XDR-TB a threat? Mortality rates are substantially higher (annual mortality in patients with XDR TB approaches 40%) Dheda K, Lancet, 2010 O’Donnell M, IJTLD, 2010 Gandhi N, Lancet, 2006 Drastically increases the costs of running a TB program (despite annually treating 500 000 cases of drug- susceptible TB and < 10 000 MDR/XDR-TB, the latter eats up > 50% of the annual TB drug budget).
Cost of treating TB with different DST patterns: MDR-TB= 110 to 180 fold more expensive XDR-TB= ~400x more expensive Can destabilize well or modestly functioning National TB Programs (NTPs).
Initial optimism of encouraging outcomes in XDR-TB
Mitnick C, NEJM, 2008; Keshavjee S, Lancet, 2008; Sotgiu G, ERJ, 2009
replaced disappointing data
Review of 199 patients with XDR-TB
Dheda K, Shean K, Warren R, Willcox P; Lancet; 2010
Become apparent that outcomes in high burden settings like
South Africa are poorer than in intermediate to low burden
settings
Gandhi N, Lancet, 2006
O’Donnell M, IJTLD, 2009
Kaplan-Meier probabilities of XDR-TB culture-conversion (n= 174)
The overall culture-conversion rate was
19% (33/174)Sondalo (1938)- 3500 beds
St HelliereSurgical techniques promoting partial or complete lung collapse were also used. With the advent of effective anti-TB therapy, the need for sanatoria dwindled.
What is happening to these many culture
non-converters?
Given the poor conversion rates, there are large
numbers of treatment failures (defined as failure to culture-
convert after twelve months of intensive in-patient XDR treatment with
regimens including an injectable drug like capreomycin).
While some patients die within weeks or months, a
significant proportion of patients do survive for months
or years.
How should these living treatment failures be dealt with?
These are therapeutically destitute cases!!The life cycle and immunolgy of TB
Alveolar
Innate immunity pneumocytes
No detectable T cell priming (IGRA neg., TST neg.)
Clearance of 1.Close contacts
NK-cells
Neutrophils
Infection inhale M.tb
NK-T cells
Macrophages 2. ~50% or more of exposed
β- Cathelicidin persons have no immuno
γδ T-cells
defensin diagnostic evidence of M.tb
sensitisation and may
Adaptive immunity remain uninfected through
Evidence of T cell priming (IGRA pos., TST pos.)$ sterilizing immunity#
Cytokines
T cell Th1,Th2 & 3. The remainder of exposed persons have
Th17 conversion of TST or IGRA and a
CD4+ T cells CD4+ T cells
proportion have presumed infection**
CD1 CD4Naive
Macrophage lipid
T cell
TLR2
TLR4 MHC-II
TLR9
M.tb
MHC-I
Treg
CD8+ T cells In ~ 95 %
CD8 ~5%
Naive
6. Reversion of TST or containment
T cell
IGRA (Acute or chronic
resolving infection)
~ 2 to 5 %
5. Clinically detectable
7. Reinfection 4. LTBI** active or subclinical
disease
Schwander and Dheda, AJRCCM, 2011NK IFN -γ
M. tuberculosis cell
MMR TLR-2/4/9 T cell
DC-SIGN TLR NOD2
MyD88 MHC/
CR3
CD1
γδ T
cell
25D3
1, 25D3 NF-κB
IL-1β; IL-18/12/23;
Autophagy 1,25D3/VDR TNF-α; Il-8, Chemokines;
NOS-2/NO
Lysosome
Cathelicidin PMN Pathology ?
Macrophage/DC Other antimicrobial
peptide
Dheda K, Respirology, 2010Schwander and Dheda, AJRCCM,
2011
Killing CD8
+
CTL Alveolar Space
Perforin
Granzymes
Granulysin
Activation of
Apoptosis macrophages IL-17
IL-21
Th17
IL-22
IFN-γγ
TNF-αα
Th1 IL-2
GM-
CSF
IFN- IL-
γ 4
Cytokines
γδ T cell T IL-4
IL-4
cell IL-5
IL-5 Th2
CD4 IL-13
+ IL-13 IL-25
Phospho- CD1
antigen lipid T
TLR2
TLR4 MHC-II
cell
TLR9
Inflammation
M.t
b CD8 Tre
MHC-I
+ T g
Macrophage cell
TGF-β
β TGF-β
β
IL-10
IL-10
Surfactant Proteins
Antimicrobial peptides Alveolar Type I and II
Epithelial CellsWhy does TB progress to active disease in some?
Failure of CD4 cells e.g. HIV
Failure of multiple innate mechanisms (macrophages, TLR,
cathelicidin etc)
Failure of other protective mechanisms (apoptosis, lymphocyte-
killing mechanisms, CD8 T cells)
Suboptimal Th1 response (not enough IFN-g, IL-2 etc)
too much Th2 may subvert Th1 and CD8 T cells
Failure to regulate or inappropriate regulation by Treg
Skewing of the immnune response towards an
inappropriate phenotypeWhy does TB progress to active disease in some? Bacteriostatic immune response and immunopathology in the lung, cavitation and bacterial multiplication Poor drug penetration and poor response
Rationale for immunotherapy More effective treatment may require modulation of the immune system and a switch away from an immunopathologic phenotype to a protective one. Restoring this immunoregulatory balance may take several months Immuno-regulatory (turn off Th2, TGF-b but turn on Th1 and favorable Tregs) Immuno-suppressive Immuno-supplementary
An approach to immunotherapy for TB
Immuno-regulatory (turn off and/or on certain
components of the immune system)
(i) For which GMP manufacturing capacity exists
• High-dose intravenous immunoglobulin (IVIg)
• HE2000 (16a-bromoepiandrosterone)
• Multi-dose heat-killed Mycobacterium vaccae
• Anti-IL-4
(ii) For which GMP manufacturing capacity can be
established
• DNA vaccine (HSP65)
• Dzherelo
• SCV-07 SciCLone
• RUTIWhy does TB progress to active disease in some? Immuno-suppressive (increases access to and susceptibility to drugs) • Thalidomide analogs (lower TNF-a levels) • Etanercept (blocks TNF-a) • Prednisolone (reduces TNF-a levels) Immuno-supplementary (augment deficient cytokines/ biomarkers) • rh- IFN-g and rh-IFN-a • rh-IL-2 • rh-GM-CSF • IL-12
Immunology of XDR-TB- TH1 and Th17
Immunology of XDR-TB- Treg (n= 48)
High-dose intravenous immunoglobulin (IVIg) High-dose IVIg (treatment of human inflammatory disorders). Because anti-TNF-a shown to cause reactivation of TB, high- dose IVIg was tested in a mouse model of TB to check its safety. Rather than activating TB, it was found to exert a marked therapeutic effect Roy E, Infect Immun, 2005 Mechanism of action is unknown but may involve pathways implicating sialic acid residues on IgG Could be worthwhile to test this material in patients with XDR- TB, who fail to respond to conventional drug treatment
Multi-dose M.vaccae Drives Th1 and CD8+ CTL but down regulates Th2 through CD4+CD45+Rblow regulatory cells Zuany-Amorim C, Nat Med 2002 Single dose M. vaccae not effective in clinical trials Johnson JL, J Infect Dis, 2000 Mwinga A, Lancet 2002 One non-GCP multiple dose study showed improved culture outcomes Dlugovitzky D, Respir Med, 2006
Multi-dose M.vaccae RCT (n= 2000) in Tanzania using 5 injections showed that M.vaccae protected against acquiring definite TB in those with a CD4 count> 200. Von Reyn CF, AIDS, 2010 Multiple dose M.vaccae already used in China to treat MDR-TB. Luo Y. Zhonghua Jie He He Hu Xi Za Zhi, 2001 Fan M, Chinese Journal of Evidence-Based Medicine, 2007 (meta- analysis)
Dzherelo (Immunoxel; Ekomed) Dzherelo uses plant extracts & marketed by Ekomed LLC (a Ukrainian company) as a nonregulated health supplement. Widely used in the Ukraine, and seem to be safe. Recent studies describe their use as adjunct immunotherapy against MDR-TB (small case-controlled studies) Nikolaeva LG, Cytokine 2008 Nikolaeva LG, Int Immunopharmacol, 2008 Prihoda ND, Int J Biomed Pharmaceut Sci, 2008 ‘The claims are striking and cannot be ignored. There is a need for definitive GCP studies’.
RUTI RUTI is a liposomal preparation of M.tb cell wall skeleton. Designed as adjunctive treatment of latent TB infection, and is intended to accelerate treatment after drugs have killed the bulk of the M tuberculosis (not intended for MDR-TB) In a mouse model, RUTI accelerates bacterial clearance when given late in treatment as an adjunct to conventional chemotherapy. Cardona PJ, Vaccine 2005 Cardona PJ. Tuberculosis (Edinb), 2006 Further study results are awaited.
Other immunoregulatory agents Dheda K, Resprology, 2010
Immunosupressive agents Dheda K, Resprology, 2010
Supplementing effecter cytokines
Summary Now come a full circle with untreatable forms of TB increasing in numbers The TB drug pipeline will take decades to deliver Thus immunothreapy needs to be given serious thought Urgently need funding committed to carry out large GCP-standard studies that will resolve many outstanding questions
Acknowledgements
Division of Pulmonology and The Lung Infection and Immunity
Unit – Greg Symons, Caroline Whale, Elize Pietersen, Lititia
Pool, Karen Shean, Samuel Murray, Lwazi Mhlanti, Vonnita
Louw, Malika Davids, Motasim Badri, Paul Willcox
Division of Cardiothoracic Surgery - Luven Moodley, Mark de
Groot
Brooklyn Chest Hospital (Cape Town) - Erma Mostert, Richard
Burzelmann, Pieter Roussouw, Avril Burns
Gordonia Hospital (Northern Cape) - Barbara Mastrapa
UKZN Staff/Collaborators - Nesri Padayachee
University of Stellenbosch - Robin Warren, Thomas Victor, Paul
D. Van Helden
WHO Collaborating Centre for Tuberculosis and Lung Diseases
- Giovanni B. Migliori, Giovanni Sotgiu
Albert Einstein College of Medicine - Max R. O’Donnell
University of Florida- Kevin Fennelley
University of Calgary- Julie JarandFunding Agencies:
EUFP7 Discovery NIH Fogerty
South African
National Research South African
Foundation EDCTP MRCYou can also read
