Lecture 16- Clocks and Immunity II Flashcards
Symptoms and underlying cause of rheumatoid arthritis
Autoimmune condition, inflammation and swelling within joints, tissue remodelling and disability, inflammation driven by resident synovial cells and infiltrating immune cells
Circadian variation in rheumatoid arthritis symptoms and disease markers
Patients report increased joint stiffness in the early morning
Higher levels of proinflammatory cytokines in the morning (IL2, IL6)
How can treatment of rheumatoid arthritis be made more effective?
Delayed release prednisone taken at night so onset of drug effect is morning (CAPRA-1)
Symptoms of asthma
Chronic inflammatory disorder of the airways, narrowing of the airways, reversible airflow limitation, shortness of breath, asthma attacks
Circadian rhythms in asthma
Nocturnal asthma (worse at night) increased symptoms and need for medication at night, worse at 4am (when sudden death from asthma also occurs)
Clinical evidence for nocturnal asthma
Lung function naturally fluctuates over 24hrs in healthy
FEV1 reading diurnal differences more pronounced in asthma patients
Main clinical marker for disease severity in asthma
Eosinophils (maintain and initiate inflammation in asthma)
migrate to lung irt eotaxin
Diurnal variation in eosinophil numbers
In asthmatics, circadian variation in sputum eotaxin 2x higher at 4am than 4pm
Implications of diurnal eosinophil variation for asthma treatment?
Sputum increase >3% ground for escalation, escalation more likely if attend morning appointment –> need to standardise sample collection time
MOA of vaccinations
Antigen detected by APC, APC present antigen to T and B cells, clonal expansion of T and B cells –> population of memory cells
When are vaccinations more effective?
In the morning (9-11) compared to afternoon (15-17)
Circadian variation in burn healing
Time it takes for burn to be 95% healed is 60% faster for daytime wounds
4 stages of wound healing
1) blood clotting
2) inflammation (damaged cells cleared out, GFs released)
3) Tissue growth (angiogenesis and wound contraction)
4) Tissue remodelling (collagen realigned)
Which stage is most important wrt circadian variation in wound healing?
Stage 3
Tissue growth (rhythmicity and cell motility)
Fibroblasts and keratinocytes migrate to wound area and then proliferate
Both cells have an intrinsic clock
This clock regulates cell motility via regulation of actin dynamics
Cell migration and circadian variation
Fibroblast and keratinocyte migration is more rapid during an animal’s active phase versus rest
phase
Chronotherapy
“timed application of therapeutics” and “utilising compounds which target the
clock”
Reasons for chronotherapy
Drug targets oscillate
De-toxification pathways and efflux mechanisms under clock control
Oscillations in off-target pathways
–> Maximise efficacy, reduce doses needed and reduce adverse effects
Chronotherapy in cancer
Cancer drugs – stop cancer cells growing and
dividing
Extremely toxic to healthy cells
Molecular clock in cancer cells, out of sync with
clocks in healthy cells
Time dosing to induce more damage to tumour
than healthy tissue.
Study on 5-FU (fluorouracil), FA (leucovorin) and L-OHP
oxaliplatin
Ch ronotherapeutic regime: Reduced incidence of some severe toxic symptoms (stomatitis); Increased rate of tumour response; Increased survival
REV-ERB alpha KO mice and chronotherapy
Increased inflammatory response to stimulation
Altered metabolic state …therefore potential therapeutic target for metabolic and inflammatory disease
REV-ERB alpha agonist
Anti-inflammatory effects in a model of myocardial infarction, improved survival
Reduced cartilage degradation in an osteoarthritis model
Protective effects in a mouse model of colitis
