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PHAL303 > Immuno > Flashcards

Immuno Flashcards

1
Q

Stroke

A

The 2nd leading cause of death and the leading cause of adult disability world wide
- affects 9,000 kiwis/year
- cost/person >200,000$$

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2
Q

Risk factors for ischaemic stroke

A
  • being male
  • high blood pressure
  • sedentary lifestyle
  • smoking
  • high alcohol consumption
  • diabetes
  • cardiac issues
  • SARs-CoV2 infection
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3
Q

Cardioembolism

A

The pumping of blood containing unwanted materials into the brain due to:
- atrial fibrillation (irregular and often rapid heartbeat)
- carotid/parent artery atherosclerosis (hardening of arteries)
- small vessel disease (increased risk of obstruction)

Results in ischaemic infarct and re-perfused penumbra

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4
Q

Diagnosis of ischaemic stroke

A
  • Non-contrast computerised tomography (CT) shows loss of grey/white matter differentiation
  • IV injection of iodinated contrast agent shows blockage and re-perfusion through CT angiography or time resolved series
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5
Q

Alteplase and Tenecteplase

A

structural analogues of tissue plasminogen activator (tPA)
- bind to fibrin in clots and convert entrapped plasminogen to plasmin facilitating clot degradation
- given via I.V. within 4.5 hours of stoke
- 28% decrease in disability and 6% risk of haemorrhage at day 90
- only applicable to ~10% of patients

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6
Q

Consequence of ischaemic

A

Blood vessel occlusion reduces cerebral blood flow
- reduced oxygen and glucose
- lack of available energy
- stress response occurs in neurons and glia
- excess glutamate
- excess calcium influx resulting in:

  • neurons: apoptotic cell death due to free radical production in neurons
  • glia: release of trophic factors (all), cytokines (microglia), formation of scar tissue (astrocytes)
    = inflammatory signalling and BBB dysfunction

= SPREAD OF NEURONAL DEATH

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7
Q

Acute immune response of ischaemic stroke (central & peripheral)

A

The ischaemic injury causes an increase in endothelial adhesion molecules, DAMPs, complement, and cytokines
- invasion of neutrophils via damaged BBB
- neutrophils produce ROS, cytokines, and NETs resulting in further neuronal damage

Peripherally, the adrenal glands are activated, causing release of glucocorticoids and catecholamines
- post-stroke immuno-depression (increased risk of infection)
- DAMPs leak from brain and mobilise lymphocytes in the lymph and gut

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8
Q

NET

A

neutrophil extracellular trap

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9
Q

Sub-acute inflammation in ischaemic stroke

A

In the days/weeks following ischaemic injury macrophages enter the CNS via the choroid plexus and BBB
- phagocytose clot debris, apoptotic neutrophils/neurons
- differentiate into reparative macrophages
- produce growth factors that dampen inflammation and induce glial scarring

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10
Q

Glial scar

A

Tissue formed from astrogliosis that acts to separate healthy tissue from damaged tissue
- creates an optimum environment for regeneration

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11
Q

Chronic stage of ischaemic inflammation

A

Antigen presenting cells encounter CNS antigens released due to ischaemic injury
- migrate to peripheral lymph nodes, and trigger differentiation and expansion of T/B cells

Days/weeks after stroke these auto-reactive T/B cells enter the brain through the choroid plexus and cause chronic inflammation and impair neural regeneration

Contributes to post-stroke depression, fatigue, and dementia

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12
Q

Neuronal regeneration

A

A naturally occurring process that is initiated by the secretion of growth factors (BDNF, NGF, neuregulin) from reparative microglia
- astrogliosis
- differentiation of NSPCs into neurons and glia
- migration and regeneration of synapses

Results in functional improvement in days/weeks/months following stroke

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13
Q

Current state of immunotherapy for ischaemic stroke

A

No drugs approved, but many in clinical trials
- generally target early stages of immune cell adhesion or recruitment (within 24hours)
- off-label use

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14
Q

Fingolimod Mechanism

A

(ischaemic stroke)
A structural analogue of S1P that activates the S1P1 GPCR on T cells
- transient activation, b-arrestin recruitment, and receptor internalisation
- prevents T cells from exiting lymph nodes

Action of S1P3/S1P5
- promotes neuronal and oligodendroglial survival

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15
Q

Fingolimod Clinical Trial

A

5 RCTs with 228 participants
- first (0.5mg) dose within 4.5 hours + two more doses each following day
- decreased infarct growth by 26% by day 1, and by 17% at day 7
- improvement of clinical function by 2.6 fold at day 90

Safe

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16
Q

Micocycline Mechanism

A

(ischaemic stroke)
Lipophilic antibiotic derivative of tetracycline
- antioxidant (inhibits ROS)

  • chelates Fe2+, Ca2+, Mg2+ thus interferes with NFAT, MAPK, MMPs, iNOS, COX, sPLA2
    = suppression of lymphocyte and microglia signalling and proliferation
  • Reduces caspase 1/3 expression and other pro-apoptotic features
  • Competitively inhibits PARP-1 to prevent DNA fragmentation
    = prevents apoptosis and enhances neuronal survival
  • promotes regulatory microglia phenotype

= REDUCTION OF CELL DEATH AND INFLAMMATION IN CNS AND PNS

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17
Q

Micocycline Clinical trial

A

seven RCTs with 426 participants
- improved clinical function 1.6 fold from standard care at day 30
- oral route more effective

Safe

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18
Q

Key point of immuno-therapeutic treatment of ischaemic stroke

A

There is a bias in stroke treatment that all treatments must be given within 24hours of stroke
- However, the inflammatory cascade of stoke occurs over months
- Thus drugs should be given at different time points based on their mechanism of action
- Combination treatment with different timings

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19
Q

Multiple sclerosis

A

A chronic neurodegenerative disease that is characterised by relapsing-remitting waves of inflammation that create worsening neurological deficits
- mainly affects young adults

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20
Q

Causes of multiple sclerosis

A

Genetic
- HLA-DRB1 (MHC that makes people more susceptible to autoimmune reaction)
- polymorphisms of IL2 and the IL7R

Environmental
- being female
- smoking
- herpes
- low vitamin D
- adolescent obesity

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21
Q

Pathology of multiple sclerosis

A
  • focal plaques
  • inflammation
  • BBB breakdown
  • leukocyte accumulation
  • reactive gliosis
  • demyelination
  • axonal degeneration

Within lesions there is neuroinflammation characterised by macrophages and T cells & degeneration of myelin, which leads to atrophy

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22
Q

Symptoms of MS

A
  • sensory disturbances
  • visual disturbances
  • motor impairments
  • fatigue
  • pain
  • cognitive deficits

50% of patients are in a wheelchair 25 years following diagnosis

23
Q

Autoimmune activation of MS

A
  1. T cells infiltrate the meningeal, perivascular, and ventricular spaces where
    macrophages present self-antigen to T cells
  2. Activation of patrolling T cells
  3. Microglia and astrocytes contribute to T cell activation through chronic, low grade inflammation
24
Q

Immune induction of MS

A

Macrophages and T/Cell cells infiltrate the perivascular spaces via BBB, subarachnoid, and choroid plexus
- produce cytokines and antibodies against myelin that promote demyelination and oligodendrocyte injury
- this leads to axonal injury

25
Q

Chronic inflammation of MS

A

Microglia and astrocytes contribute to chronic inflammation through production of cytokines, NO, ROS and RNS that exacerbate gliosis and prevent re-myelinaton by inhibiting the differentiation of progenitor cells into oligodendrocytes

26
Q

Neurodegeneration in MS

A
  • Chronic inflammation results in mitochondrial injury and metabolic stress in soma
    +
  • Glutamate excitotoxicity in axons

spreads in both anterograde and retrograde directions causing neuronal cell death

27
Q

What is the clinical outcome for MS, and how is this assessed?

A

The target in clinical practise is NEDA (no evidence of disease activity) which is shown through MRI
- T1 = active inflammation
- T2 = all scarring

28
Q

Escalation therapy for MS

A
  1. First-line treatment with moderate efficacy and good safety
    (IFNa analogues)
  2. Second-line treatment with high efficacy but more risky medication
    (Clabidrine, Natalizumab, Fingolimod)
29
Q

Induction therapy for MS

A
  1. First-line treatment with high efficacy but more risky medication to deplete lymphocytes and allow for disease remission
    (Clabidrine, Natalizumab, Fingolimod)
  2. Second-line treatment with moderate efficacy and good safety to provide long term maintenance
    (IFNa analogues)
30
Q

IFN-b analogues

A

Reduce T cell activation and adhesion thus preventing T cells from entering CNS
+
Increases anti-inflammatory cytokines and decreases pro-inflammatory cytokines

31
Q

IFNb clinical trial

A

9 placebo-controlled with 3216 patients
- reduction in annual relapse rate
- no effect of administration route or dose

32
Q

Cladribine

A

A small molecule prodrug and nucleoside analogue that is selectively activated in T/B cells and induces cell death

33
Q

Cladribine clinical trials

A

Two comparative trials with 3149 patients
- reduced annual relapse rate by 58% (not better than fingolimod/natalizumab)
- best efficacy in highly active disease

34
Q

Natalizumab

A

A humanised antibody against a4 integrin, which prevents the binding of lymphocytes to VCAM1 on the brain endothelium
= reduced CNS entry

35
Q

Natalizumab clinical trial

A
  • long term efficacy, reducing relapse rate by >90%
  • half of participants did not relapse after 12 years
  • serious adverse effects occurred in 4.6%, including PML
36
Q

PML

A

progressive multifocal leukoencephalopathy
- activation of dormant JC virus causes demyelination
- manifests as clumsiness, progressive weakness, and death after 3/4 months
- biomarkers can be used to detect at risk individuals

37
Q

Side effects of IFNb treatment

A
  • flu-like symptoms
  • reaction at injection site
  • increased liver enzymes (which can lead to rare cases of liver toxicity)
38
Q

Side effects of cladribine

A
  • infection
  • teratogenic (can cause birth defects in fetus)
39
Q

Natalizumab side effects

A
  • dizziness
  • shivering
  • nausea
  • itchy skin
  • rash
  • herpes
  • PML
40
Q

Immune reconstitution therapy for MS

A

Used for patients that do not respond to other immuno-therapies

  1. Isolation of bone-marrow derived haematopoetic stem cells
  2. Expansion of stem cells via GM-CSF treatment
  3. Depletion of autoreactive lymphocytes via anti-metabolite cancer drugs or cell depleting antibody therapy
  4. I.V. administration of cultured stem cells, which differentiate into leukocytes (immune cell)
41
Q

Stem cell clinical trial

A

24 (uncontrolled) studies with 1626 patients
- progression free survival at 74% after a year
- 50% remission after 5 years
- 30% remission after 10 years
- works best for earlier stage disease
- not impacted by prior treatment

42
Q

Alzheimer’s disease

A

A progressive neurodegenerative disease characterised by Ab plaques and NFTs, neural atrophy and ventricle enlargement, astrogliosis and microgliosis

43
Q

Forms of AD + risk factors

A

Familial: mutation in APP and PSEN1/2
Sporadic: mutations in TREM2 and APOE4 genotype, age, vascular health, being female

44
Q

The amyloid cascade hypothesis

A

Amyloidogenic cleave by b-secretase and y-secretase producing Ab42
- oligomerisation
- plaque formation

hyper-phosphorylation of tau causing destabilisation of microtubules and aggregation of tau, which eventually leads to neuronal degeneration

45
Q

Microglia pathology in AD

A

Impaired signalling though TREM2 leads to impaired phagocytic and migratory action against amyloid beta

46
Q

Astrocyte pathology in AD

A

Astrocytes produce APOE (apopoliproteins) that act to transport cholesterol and regulate microglial survival and phagocytosis
- implicated by APOE4 risk factor

47
Q

Diagnosis of AD

A
  • Ab PET, although this is controversial as amyloid burden poorly correlated to clinical AD and disease severity (30% of healthy individuals have amyloid pathology)
  • CSF biomarkers (Ab:ptau) being explored
48
Q

Approved drugs for AD

A
  • AChE inhibitors (donezapil, galantamine, rivastigmine) increase cholinergic transmission to give moderate benefit
  • NMDA antagonists (memantine) inhibit excitotoxicity by preventing excess calcium influx
49
Q

Broad drug classes being explored for AD treatment

A

Biologics: protein based molecules that stimulate that immune system to aid Ab clearance

Small molecules: target secretase enzymes to increase Ab breakdown

50
Q

Three targets of anti-Ab antibodies

A
  1. Individual Ab peptides (aim to prevent aggregation)
  2. Aggregated plaques (aim to break up plaques and facilitate clearance)
  3. Microglia (increase plaque recognition and phagocytosis)
51
Q

Aducanumab

A
  • Preclinical testing showed reduction of amyloid PET
  • two 18 month RCTs (EMERGE and ENGAGE) were conducted in patients with MCI/early AD
  • Both showed a reduction in amyloid with CSF/PET biomarkers
  • Only one trial showed a cognitive benefit of 0.45 (not meaningful), which arose from retrograde subgroup analysis of high dose group
  • ARIA-E occurred in 29-43% of APOE4 carriers

Approved by FDA
- 9/10 advisory committee voted no (last was unsure)
- statisticians voted no
- neurological drugs voted yes, due to lack of existing treatments
- waiting on clinical benefit in phase 4

52
Q

ARIA

A

amyloid-related imaging abnormalities

Antibody breakdown of amyloid causes
- increased perivascular drainage
- loss of vascular integrity
- BBB breakdown

Causes edema (ARIA-E) or micro-haemorrhage (ARIA-H)
- often asymptomatic but can cause headache, confusion, visuospatial impairment, stroke, or haemorrhage
- possible link to brain atophy

53
Q

Lecanemab

A

tested in an 18-month RCT in patients with MCI/early AD
- reduced amyloid PET burden
- reduced cognitive decline by 27% (not clinically meaningful)
- infusion-related reactions in 26.4% of participants
- ARIA-R occurred in 15.8% of APOE4 carriers

Full approval by FDA

54
Q

Reality of implementing Lecanemab

A
  • Extremely expensive at 26,500$ USD per treatment
    = prohibitive for low/middle income countries
  • need greater access to PET to ensure AD is detected early enough to provide clinical benefit ($$$)
  • need clinics to facilitate bi-weekly infusion
  • need access to MRIs to detect ARIA

PHAL303 (10 decks)

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