immunosenescence:*the* sleeper*of*immunology* · immunosenescence* •...
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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
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)
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)
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
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”
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
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
CMV(1)
• 40-‐100% :co-‐evoluUon
• Latent infecUon (in HSC/myeloid cells)
• Restricts MHC expression
• Contained by CD8 “memory inflaUon”
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
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
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)
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”
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
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
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
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”
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
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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