immunosenescence:*the* sleeper*of*immunology*€¦ · adaptive*immunity* 1....
TRANSCRIPT
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IMMUNOSENESCENCE: The Sleeper of Immunology
E/Prof Robert Clancy AM FRS(N)
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TAKE THIS HOME • IMMUNE SENESCENCE IS MAINSTREAM IMMUNOLOGY
• OVERARCHING INFLUENCE ON BIOLOGY AND PATHOBIOLOGY
• PROGRAMMED IMMUNE SENESCENCE, WITH ENVIRONMENTAL INFLUENCE
• IMMUNISATION – LIFELONG INTERVENTION STRATEGY
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ADAPTIVE IMMUNITY
1. Maintenance of “self” integrity 2. EvoluUonary event – geneUc control 3. Clonal proliferaUon & SomaUc
HypermutaUon : Fundamental 4. Cell proliferaUon: Central & Peripheral 5. Tight connecUon with innate immunity
(protecUve inflammaUon)
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IMMUNOSENESCENCE
• Nothing special – common to all species. “Life span related”
• GeneUc influenced reversal of evoluUonary process
• Mechanisms :replicaUve senescence (geneUc – telomere shortening)
:accumulated damage (environmental)
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HOW DOES THE IMMUNE SYSTEM IN MAN AGE?
(AGING IS FAILED TISSUE HOMEOSTASIS)
Bone Marrow – Stem cell compart-‐ment
Myeloid series
Lymphoid series
Peripheral pre-‐
immune pool
AnUgen Experienced
pool
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NET OUTCOME
• Reduced response to anUgen sUmulaUon • Restricted memory development • InflammaUon switches from protecUon to damage
• Impaired immunity (infecUon; T cell containment)
• Failed “self discriminaUon”
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PATHOBIOLOGY IN MAN
• Profound bilateral relaUonship with chronic disease
• Poor immunisaUon outcomes in over 65’s • “Immune Risk Phenotype Disease” with short telomeres
• Accelerated aging: reduced T cell pool (eg cytotoxic drugs, CVID, HIV, CMV etc)
:chronic inflammaUon
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MORE ON MECHANISMS • Telomerase: 100 thousand base pair loss per division. With age/sex tel length 1/3 death risk
• DNA: (1)MutaUons : balance damage/repair OxidaUve Stress (alcohol, smoking, inflammaUon) (2)EpigeneUc regulaUon (+/-‐ by chemical tags . Gene silencing. ESP methylaUon of high CpG regions eg Promoter genes). Also glycaUon. 2/3 of death risk in aged
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CMV(1)
• 40-‐100% :co-‐evoluUon
• Latent infecUon (in HSC/myeloid cells)
• Restricts MHC expression
• Contained by CD8 “memory inflaUon”
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CMV(2)
• Latent CMV re-‐shapes immune system
• CMV memory CD8 T cells 50% of pool
• Acquires changes of senescence (restricted diversity, CD28-‐ve, impaired response, Th1>Th2 : flu vaccine response inversely proporUonal to CMV CD4 T cell response
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CMV(3)
• Immune risk profile (Wikdy 2005) : CMV +ve, CD4/CD8 <1, CD8+ CD28-‐ memory cells,
naïve CD4 • Especially in immune compromised
• Interplay with epigeneUcs
• Repeat anUgen > inflammaUon : viscious circle
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CHRONIC OBSTRUCTIVE PULMONARY DISEASE (a trap for the young and not
so young)
• Third commonest cause of death (50 billion $) • 90% smoking related • Acute exacerbaUons determine immediate and late outcomes
**a 2 phase disease (toxin/bacteria) • Trans-‐AtlanUc confusion (chronic bronchiUs/COPD)
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PATHOGENESIS OF SECOND PHASE DAMAGE
• Toxin > damage to airways > abnormal microbiome (dominant NTHi) > aspirate into gut – Peyer’s patches > Th17 cells “home” to bronchus mucosa > acUvate phagocyUc pool.
• THEN : (i)controlled inflammaUon, or (II)hypersensiUvity response
CLINICALLY : “increased volume/purulence of sputum”
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STRATEGY TO CONTROL COLONISATION
• Enhance “loop” of airways protecUon by oral inacUvated NTHi : ie specific acUvaUon of Th17 cells, but non-‐specific effector cells (phagocytes)
BUFFERS AGAINST INTERCURRENT VIRUS INFECTION
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ORAL IMMUNISATION IN CHRONIC BRONCHITIS
Number Age FEV1 % ColonisaUon
% ProtecUon
P value
Newcastle 1985
50 65 1.0 69 90 0.001
Perth 1991
64 72 0.9 29 33 0.024
PNG 1991 62 53 1.4 80 48 0.045
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MULTI-‐SITE (22) STUDY in COPD(2016)
NUMBER AGE FEV1 %COLONISATION
%PROTECTION
P VALUE
ALL SUBJECTS
320 71 0.98 5.5 0
<65 YEARS 91 59 1.00 6.0 54 0.001
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COPD STUDY (2010)
• Similar structure to 2016 study • ColonisaUon NTHi 30% • ProtecUon in all-‐age group (141) 44% (P 0.005) • ProtecUon in >65 group (67) 40% (P 0.02)
ie similar colonisaUon level and protecUon to those selected as “chronic bronchiUs”
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CONCLUSION RE MUCOSAL VACCINE IN COPD
1. Mucosal vaccine subject to immune senescence
2. Senescence becomes criUcal when protecUon otherwise marginal
3. Men subject more to immune senescence than women
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CONCLUSION (1)
• WHAT CAN BE DONE ? -‐biochemistry defining targets -‐telomere protecUon (boost telomerase) vaccines (dose, adjuvants, anUgen handling, schedules etc) -‐idenUfy and minimise accellerants
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CONCLUSION(2)
We need new ideas on (1) infecUon/anUbioUc resistance, immunisaUon strategies, chronic disease, within the context of aged biology, & (2)strategies to anUcipate outcomes of immunosenescence on a global basis (as 80% of the elderly live in developing countries)