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excellence in science
RS–IAP-ICSU international
workshop on science &
technology developments
relevant to the Biological & Toxin
Weapons Convention
4 – 6 September 2006
The Royal Society is the independent
scientific academy of the UK dedicated
to promoting excellence in science.
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Defences Under Attack:
The Potential Misuse of Innate Immunity
Kathryn Nixdorff
Department of Microbiology and Genetics
Darmstadt University of Technology, Germany
[email protected]
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The immune system plays a crucial role
in protecting against infectious diseases.
The ability of a microorganism to cause disease can
only rightly be defined within the scope of its
interaction with the immune system.
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Two types of immunity
Innate Immunity:
 Requires little or no induction
 Relatively non-specific (generic)
 All-important first line of immune defence
 Keeps an infection in check until adaptive immunity is induced
Acquired (Adaptive) Immunity:
 Requires induction
 Specific (reacts to specific antigens)
 Affords a long-lasting, high degree of specific protection
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The macrophage is a cell central to innate immunity
Cytokines
Regulate immune
responses
Proinflammatory
Cytokines
Makrophage
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Proinflammatory Cytokines
In moderate amounts, these contribute greatly to
immune defence and healing processes
When overproduced, these can lead to severe
inflammatory disorders, autoimmunity,
shock and even death
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Toll-like Receptors (TLRs) and NOD Receptors of Innate Immunity
Source: Strober, Murray, Kitani, Watanabe (2006)
Nature Reviews Immunology Vol. 6, pp. 9-20.
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Toll-like Receptors (TLRs) react to
Pathogen-associated molecular Patterns (PAMPs)
Receptor
PAMPs (Ligands/Agonists)
Synthetic Analogues
TLR2
Lipoproteins, Peptidoglycan
Lipoteichoic Acid,
Lipoarabinomannan
–
TLR4
Lipopolysaccharide
HSP60
Synthetic lipid A, E5564
TLR8
(G+U)-rich
single-stranded RNA
Imidazole quinolines
(Imiquimod, Resiquimod)
TLR9
Bacterial DNA, Viral DNA
CpG oligodeoxynucleotides
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NOD (Nucleotide-binding Oligomerization Domain) Receptors
Receptor
PAMPs (Ligand/Agonist)
Synthetic Analogues
NOD1
Peptidoglycan structures
Tripeptides with
terminal diaminopimelic acid
NOD2
Peptidoglycan structures
Muramyl-dipeptide
structures
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Targeting the Innate Immune System for Therapeutic Purposes:
 Imidazole quinolones to target TLR7 and TLR8 for treatment of
genital warts and other diseases caused by human papillomaviruses
 CpG oligodeoxynucleotides to target TLR9 for treatment of patients
for asthma
Targeting the Innate Immune System for Biodefence Purposes:
 CpG oligodeoxynucleotides afford generic immunoprotection in rodents
against::
- many different bacteria (e.g. agents of anthrax, tularemia, glanders)
- many viruses (e.g. pox viruses, Ebola, VEE, influenza)
- parasites (e.g. agents of malaria, toxoplasmosis)
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The possibilities for therapy and defence are great, but
at the same time the potential for misuse is huge.
Use of such bioactive substances for good or evil depends
to a great extent on the feasibility of targeted delivery.
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Growing potential for greatly improved methods
of aerosol delivery of bioactive substances:
Advances in nanotechnology combined with new methods
for making substances absorbable through the nasal and
respiratory tracts represent such growing potential for delivery.
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Workshop Report of the National Research Council of the
National Academies, USA 2005:
An International Perspective on Advancing Technologies and Strategies for
Managing Dual-Use Risks
www.nap.edu.
“A major theme that emerged from these discussions is that pathogens are not the
only potential bioterrorists agents. …bioregulators, which are non-pathogenic
organic compounds, may pose a more serious dual-use risk than had been
previously perceived,
particularly as improved targeted delivery technologies have made the
potential dissemination of these compounds much more feasible than in the past.”
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The immune system does not act alone!
The immune system interacts interdependently
with the nervous and endocrine systems through
biochemical bioregulators (cytokines, hormones,
neurotransmitters).
Manipulation of one system will also profoundly
affect the functions of the others.
This raises the dual-use dilemma to a
whole new order of complexity.
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With such rapid advances occurring in the life sciences,
dealing with this complexity becomes an enormous task.
The five-year review mechanism for S&T of
relevance to the BTWC at the review conferences
is increasingly inadequate.
States Parties will have to devise and implement
a better mechanism for review, with a more coherent
assessment of the ongoing S&T relevant to the Convention.
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