Lecture 16- Clocks and Immunity II

Question 1

Symptoms and underlying cause of rheumatoid arthritis

Answer 1

Autoimmune condition, inflammation and swelling within joints, tissue remodelling and disability, inflammation driven by resident synovial cells and infiltrating immune cells

Question 2

Circadian variation in rheumatoid arthritis symptoms and disease markers

Answer 2

Patients report increased joint stiffness in the early morning
Higher levels of proinflammatory cytokines in the morning (IL2, IL6)

Question 3

How can treatment of rheumatoid arthritis be made more effective?

Answer 3

Delayed release prednisone taken at night so onset of drug effect is morning (CAPRA-1)

Question 4

Symptoms of asthma

Answer 4

Chronic inflammatory disorder of the airways, narrowing of the airways, reversible airflow limitation, shortness of breath, asthma attacks

Question 5

Circadian rhythms in asthma

Answer 5

Nocturnal asthma (worse at night) increased symptoms and need for medication at night, worse at 4am (when sudden death from asthma also occurs)

Question 6

Clinical evidence for nocturnal asthma

Answer 6

Lung function naturally fluctuates over 24hrs in healthy

FEV1 reading diurnal differences more pronounced in asthma patients

Question 7

Main clinical marker for disease severity in asthma

Answer 7

Eosinophils (maintain and initiate inflammation in asthma)

migrate to lung irt eotaxin

Question 8

Diurnal variation in eosinophil numbers

Answer 8

In asthmatics, circadian variation in sputum eotaxin 2x higher at 4am than 4pm

Question 9

Implications of diurnal eosinophil variation for asthma treatment?

Answer 9

Sputum increase >3% ground for escalation, escalation more likely if attend morning appointment –> need to standardise sample collection time

Question 10

MOA of vaccinations

Answer 10

Antigen detected by APC, APC present antigen to T and B cells, clonal expansion of T and B cells –> population of memory cells

Question 11

When are vaccinations more effective?

Answer 11

In the morning (9-11) compared to afternoon (15-17)

Question 12

Circadian variation in burn healing

Answer 12

Time it takes for burn to be 95% healed is 60% faster for daytime wounds

Question 13

4 stages of wound healing

Answer 13

1) blood clotting
2) inflammation (damaged cells cleared out, GFs released)
3) Tissue growth (angiogenesis and wound contraction)
4) Tissue remodelling (collagen realigned)

Question 14

Which stage is most important wrt circadian variation in wound healing?

Answer 14

Stage 3

Question 15

Tissue growth (rhythmicity and cell motility)

Answer 15

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

Question 16

Cell migration and circadian variation

Answer 16

Fibroblast and keratinocyte migration is more rapid during an animal’s active phase versus rest
phase

Question 17

Chronotherapy

Answer 17

“timed application of therapeutics” and “utilising compounds which target the
clock”

Question 18

Reasons for chronotherapy

Answer 18

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

Question 19

Chronotherapy in cancer

Answer 19

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.

Question 20

Study on 5-FU (fluorouracil), FA (leucovorin) and L-OHP

oxaliplatin

Answer 20

Ch ronotherapeutic regime: Reduced incidence of some severe toxic symptoms (stomatitis); Increased rate of tumour response; Increased survival

Question 21

REV-ERB alpha KO mice and chronotherapy

Answer 21

Increased inflammatory response to stimulation

Altered metabolic state …therefore potential therapeutic target for metabolic and inflammatory disease

Question 22

REV-ERB alpha agonist

Answer 22

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