Immunopharmacology of autoimmunity Flashcards
— is a pathologic response to auto- or self-antigens, generally via the — / — immune response
Generates injury via —, —, or altered— …with clinical consequences
* Reflects a loss of “— ”
auto immunity
specific/adaptive
inflammation cell injury altered function
self tolerance
the problem is:
selt reacitve — –> attack — –> —- or —
the solution :
1- reduce immune response by –
2- or block the consequence of the immune response by —
3- or replace/by pass function ( if feasible and less toxic ) as :
- the management principle for autoimmune patients is to control — and damage and at the same time limit — for immune targeting rugs
lymphocyte clones
attack single/multiple organs or tissues
tissue damage or altered function
immunosuppressants
anti inflammatories
as:
Thyroxine (autoimmune hypothyroidism)
Vitamin B12 (pernicious anaemia)
longterm disease n manage disease flare ups
toxicity
group of drugs used in autoimmune patients:
- Anti-proliferative agents
- Immune cell-depleting agents
- Cytokine inhibitors
- Inhibitors of cell signalling functions
- Precision medicine
cyclophosphamide is a —- agent
- inactive form of — which is metabolised in — to active form
mechanism of action is:
1- binds to —
2- DNA/RNA —
3- leading to inhibition of —
* Causes absolute leucopenia with — granulocytes, lymphocytes
and monocytes; NK cells inhibited
* <100 mg/m2 targets B cells; <600 mg/m2 spares CD4+ T cells
* Side effects: include alopecia, nausea, bone marrow suppression
-Practical use now limited to life-threatening/organ-threatening episodes ineg. SLE, myositis, ANCA-associated vasculitides
anti proliferative agents
nitrogen mustard
liver
dna
crosslinking
protein sythesis
decreased
methotrexate is a — agent by which the mechanism of action ( high dose oncology ) as it interferes w —– which leads to reduced —-
-inhibition replication of —
- – doses of methotrexate used for rheumatoid arthritis, psoriasis, in
combination with cyclosporine to prevent GvHD
- Multiple immune mechanisms likely to responsible at — doses
- Side effects: include — , —suppression
anti proliferaitve
dihydrogolate reductase
dna sythesis
b and T cells
lower doses
lower doses
alopecia n bone marrow
question : If you inhibit AICAR transformylase ( (AICAR = 5‐aminoimidazole‐4‐carboxamide ribonucleotide) do Adenosinelevels go upor down ? ( increases? )
* Dose used for autoimmune patients is much — than for cancer patients
* Anti-inflammatory effect is not inhibited by —
- mechanism of action ( low dose - autoimmunity ) :
1- thought to involve blockade of —
2- – adenosine levels and signals
3- mutable anti inflammatory effects via —
lower ( we r still talking ab methotrexate)
folic acid supplementation
AICAR transformylase
increased
adenosine receptors
immune cell depleting agents:
1- b cells: Depletion used to treat
B cell — or in certain — conditions
2- T cells: Depletion (via ATG or
anti-CD25) usually for– patients to
prevent —
3- innate immune cells: Specific depletion of — or – not used
in patients. Anti-proliferative reagents will reduce both.
b cell lymphoma
autoimmune
transplant
organ rejection
neutrophils or macrophages
rituxinab is for — depletion by which MAb that binds — on b cell surface
- mechanism of action:
1- causes b cell depletion via —
2- — activatation leading to —
3- fewer — leads to less —
- used in :
- potentially – or – side effects:
- Reactivation of — virus in infected hosts
- Progressive Multifocal Leukoencephalopathy (PML) – via Polyomavirus JC
- — Syndrome (SIRS)
b cell
CD20
ADCC
complement
apoptosis
fewer b cells
autoantibodies
used in :
- rheumatoid arthritis (alongside methotrexate if patient is resistant to anti-TNF therapy)
- granulomatosis with polyangiitis (GPA) alongside glucocorticoids
- Pemphigus vulgaris
serious or fatal
hepatitis b virus
system inflammatory response
ATG and antiCD25 are used for – depletion
mechanism of action: T cell— or — of the T cell — which leads to —-
* ATG (anti-thymocyte globulin) = pooled polyclonal antibody preparation;
binds to T cell surface antigens and causes T cell depletion (multiple mechanisms)
* Anti-CD25 antibody (eg. Basiliximab/SimulectTM) = Anti-IL-2 receptor Ab; prevents actions of IL-2 in clonal expansion of T cells
* Used mainly to prevent — in — transplantation
T cell depletion
destruction or blockage of T cell proliferation leading to fewer T cells to attack
graft rejection
solid organ
pharmacological inhibition of cytokines goal is to reduce — from —- eg. TNF-alpha, IL-1, IL-6
( check slide 18)
pro inflammatory
Cks
pharmacological inhibition of TNF alpha:
* TNF-alpha is produced by cells including — and —
* Induces expression of other — (eg. IL-1, IL-6), upregulates– molecule expression on the vasculature
* Multiple TNF-alpha inhibitors in clinical use:
- Infliximab / Remicade (Chimeric whole antibody)
- Adalimumab, golimumab (whole human antibodies)
- Etanercept (Human TNFR2-Fcg fusion)
- Certolizumab (humanized Fab conjugated with PEG)
* Approved for rheumatoid arthritis, psoriatic arthritis, psoriasis, ankylosing
spondylitis and some inflammatory conditions (eg. Crohn’s disease)
* Side effects
- — reactions
- Serious risk of reactivating —
monocytes n macrophages
pro inflammatory cks
adhesion
injection site
latent TB
( check slide 21)
pharmacological inhibition of other cks:
—:
Anakinra– modified IL-1 receptor antagonist protein (rheumatoid arthritis)
Canakinumab– anti-IL-1β MAb (systemic juvenile idiopathic arthritis)
— :
Siltuximab, Tocilizumab, Sarilumab, Vobarilizumab– anti-IL-6 receptor MAbs (rheumatoid arthritis)
—- :
Ustekinumab– Anti-IL-12 and IL-23 MAb (psoriasis & Crohn’s disease)
— :
Ixekizumab & secukinumab– Anti-IL-17A MAb (psoriasis)
Brodalumab– Anti-IL-17 receptor MAb (psoriasis)
IL-1
IL-6
IL-12 , 23
IL-17
(all of these are pro inflammatory in nsture )
inhibitors of cell function :
inhibitors to reduce — from —- , the mechanism of action depends on — being targeted
Example: — inhibitors
* Simultaneous inhibition of —
CKs via a common downstream signalling pathway
* Approved for rheumatoid arthritis, psoriatic arthritis,juvenile idiopathic arthritis, psoriasis
* Eg: tofacitinib, ruxolitinib, baricitinib, upadacitinib
* Side effects:
- Cytopenias, gastrointestinal problems
- Risk of serious infections, thrombosis, cancer
pro infiammatori sigillining
from immune cells
biological pathway
JAK kinase
multiple pro-inflammatory
CKs
precision medicine :
Goal– to target — pathways that drive disease in individual patients/patient groups
Challenge– autoimmune diseases are extremely –
How to address– better understanding the molecular dysfunctions underlying different autoimmune diseases will reveal new knowledge on potential treatment targets. Biomarkers
are important too!
Example: In —- leukocytes infiltrate the brain and attack the – protecting neurons. Blocking leukocyte – reduces – .
molecular
heterogeneous
multiple slecorsis MS
myelin sheath
movement
inflammation
( check slide 25 26)
plasma exchange and plasmapheresis in autoimmune patients:
- Mechanical method of removing unwanted components from the
blood (eg. autoantibodies) - Exchanges blood plasma for either donor plasma (plasma
exchange) or other fluids (plasmapheresis) - Some indications: for idiopathic thrombocytopenic purpura, anti-
GBM disease - Risks: Leakage or clotting; bleeding whilst on anti-coagulants
intravenous immunoglobulin IVIG
What is it?
Purified, pooled, sterilised – from the plasma of >1,000 donors
What does it do?
* Acts as an – therapy (in immunodeficiency)
* Used as an — (in autoimmune or inflammatory disease)
- IVIG for autoimmune patients indication :
- mechanism of action : Blockade of – receptors; interference with – activation; inhibition of —
function; alteration of immunoglobulin – ….and other undescribed activities?!
collectively anti-inflammatory
IgG
antibody replacement
immunomodualtor
indication :
* Immune-mediated thrombocytopenia
* Neurological conditions – Guillain-Barré Syndrome, some neuropathies
* Kawasaki disease
* Toxic epidermal necrolysis
MOA:
Fc receptor
complement
t n b cell
degradation
rheumtoid arthritis:
* Affects all ages, peak 40-65
* Involves synovial joints, usually symmetrically
* Joint pain and stiffness; esp. small joints, esp. mornings
* Both genetic and environmental links
(eg. smoking increases risk and severity)
* — increased risk of mortality from heart attack and
stroke reduced by treatment
- immune mechanism :
Multiple…but anti-rheumatoid factor, anti-CCP antibodies often detected.
Immune complexes –> inflammation, increased TNF-alpha production
management :
Ideally:
* Arrive at a diagnosis as early as possible
* Ensure specialist care by a rheumatologist
* Early initiation of treatment with DMARDs (Disease-Modifiying Anti-Rheumatic Drugs)
* Achieve tight control - regularly monitor progression, adjust drug doses to reduce
disease activity
* Use NSAIDs and glucocortocoids as adjunct rather than main therapies
2 folds
rheumatoid arthritis pharmacological management:
Start monotherapy ASAP with oral — *
(hydroxychloroquine* > sulfasalazine* > methotrexate* > leflunomide* for patients with low disease activity)
*conventional synthetic DMARDs
Use — (eg. NSAIDs, glucocorticoids) to speed up disease control until the DMARDs are maximally effective
Treat disease flares with —
(intra-articular if possible, systemic if not)
methotrexate
anti inflammatories
glucorotcoids
what if the drug doesnt work or stop woking:
Sustained disease activity = repeated — treatments are necessary
OR the patient has reached the maximum advisable dose of DMARDs —>
Add additional — and continue anti-inflammatory drugs.
Can use synthetic or biologic DMARDs (eg. anti-TNF MAbs)
Failure on combination of synthetic + biologic DMARDs – > —
steroids
DMARDS
rituxiab
( check last slides )