Immuno 7 - Immune Modulating therapies 2 Flashcards
Steroids MOA
• Effects on Prostaglandins – inhibit phospholipase A2
o Phospholipids (enzyme: phospholipase A2) arachidonic acid (enzyme: COX) eicosanoids (e.g. prostaglandins and leukotrienes; these are proinflammatory)
o Steroids inhibit phospholipase A2 block arachidonic acid + PG formation reduce inflammation
• Effects on Phagocytes:
o Decrease chemotaxis to inflamed tissue (transient increase in neutrophils)
Reduce expression of adhesion molecules on the endothelium
Block chemokines
o Decreased phagocytosis
o Decreased release of proteolytic enzyme
• Effects on Lymphocyte Function o Lymphopenia (sequestration of lymphocytes in lymphoid tissue; affects: CD4 > CD8 > B cells) o Blocks cytokine gene expression o Decreased antibody production o Promotes apoptosis
Examples of antiproliferative agents + toxicity
Cyclophosphamide
Mycophenolate mofetil
Azathioprine
Methotrexate
• Toxicity o BM suppression o Infection o Malignancy o Teratogenic
Cyclophosphamide MOA
Use
SE
Alkylating agent
Alkylates guanine base of DNA - damages DNA + prevents replication
Use
Multisystem connective tissue disease
Vasculitis
cancer
- Haemorrhagic cystitis – toxic metabolite acrolein excrete via urine
- Malignancy – bladder cancer, haematological malignancies, non-melanoma skin cancer
- Infection – pneumocystis jiroveci, PCP pneumonia
- BM suppression, hair loss, infertility
Mycophenolate MOA
SE
Anti-metabolite
Blocks de novo guanosine nucleotide synthesis
Use transplantation auto-immune disease SLE Vasculitis
SE
Herpes reactivation
JC virus (John Cunningham) - progressive multifocal leukoencephalopathy
Azathioprine MOA
Use
SE
Purine analogue
Blocks de novo purine synthesis (adenine, guanine)
Use
transplantation
auto-immune disease
auto-inflammatory disease
SE
Severe BM suppression in individuals with TPMT (thiopurine methyltransferase polymorphism)
Homozygous for TPMT polymorphism - do not give
Heterozygous - half the dose
Methotrexate MOA
Use
SE
Inhibits dihydrofolate reductase - decreases DNA synthesis
Use
RA, psoriasis
CD
SE
Pneumonitis
Pulmonary fibrosis
Macrocytic Megaloblastic anaemia
Idea behind plasmapheresis/ plasma exchange
Indications
Problem
- Removal of pathogenic antibodies
- The patient’s blood is passed through a separator and their own cellular constituents are reinfused (or replaced with albumin in plasma exchange)
Indications
Type II hypersensitivity reactions where the antibody itself is directly pathogenic
o Goodpasture’s syndrome (anti-GBM)
o Severe acute myasthenia gravis (anti-ACh-R)
o Antibody mediated severe transplant rejection/ ABO incompatible (antibodies against donor HLA/AB molecules)
Problem
• Rebound antibody production (although ABs gone, the plasma cells are still there) co-administer an anti-proliferative (cyclophosphamide)
MOA of
Tacrolimus
Cyclosporin
Sirolimus
Tacrolimus + cyclosporin are calcineurin inhibitors
They inhibit calcineurin which normally activates transcription of IL-2 which is responsible for T cell proliferation/ function
Blocked IL-2 - reduced T cell clonal expansion and proliferation
Sirolimus (rapamycin) - mTOR (mechanistic target of rapamycin) inhibitor
Inhibits IL-2 pathway
All of them used in transplantation, psoriatic arthritis, SLE
SE of calcineurin inhibitors
Tacrolimus
Ciclosporin Cyclosporin
HTN Nephrotoxic Neurotoxic Diabetogenic Dysmorphic features - hirsutism, gingival hypertrophy
How do JAK inhibitors work?
+ example of drug
+ indications
Inhibitors of cell signalling
Inhibit JAK-STAT signalling
This pathway is important in transducing the signals from cytokines + in turn producing more cytokines
Inhibit production of inflammatory molecules
Influences gene transcription
Tofacitinib
Used in conditions mediated by high levels of cytokines
Rheumatoid arthritis
Psoriatic arthritis
Axial spondyloarthritis
What is Apremilast and who does it work
Inhibits cell signalling
Inhibits PDE4 –> increase in cAMP –> influences gene transcription via PKA pathway (protein kinase A) –> prevent activation of transcription factors which modulate cytokine production –> decreased cytokine production
Psoriasis
Psoriatic arthritis
How does anti-thymocyte globulin work?
- Lymphocyte depletion
- Modulation of T cell activation (e.g. CD28)
- Modulation of T cell migration
- Thymocyte (lymphocytes from thymus) from humans injected into rabbits rabbits produced ABs against the thymocytes of varying specificities
- Serum injected into patients very effective at targeting T cells, however it is very non-specific
use - prophylaxis of allograft rejection
How does Basiliximab work?
- Basiliximab prevents IL-2 from binding to its receptor + blocks IL-2 induced signalling + Inhibits T cell proliferation
- Anti-CD25 (alpha chain of IL-2 receptor)
- Normally - T cells produce IL-2 binds to IL-2 receptor T cell stimulation
use - prophylaxis of allograft rejection
How does Abatacept work?
Anti-CTLA4-Ig fusion protein
Binds on CD80 + CD86 on APCs + prevents interaction with CD28 + CTLA4 on T cells
- APC CD80 and CD86 interact with CD28 transmit a stimulatory signal
- APC CD80 and CD86 interact with CTLA4 transmit an inhibitory signal
Blocked interaction with CD28 –> No T cell co-stimulation –> No T cell response
Blocked interaction with CTL4A –> upregulated CTL4A-mediated reduced T cell activation
use - rheumatoid arthritis
IV 4 weekly
SC weekly
How does Rituximab work?
use
- Anti-CD20
- Depletes mature B cells (not plasma cells)
- (CD20 is expressed on mature B cells but not plasma cells)
Use • B cell Lymphoma • Rheumatoid arthritis • SLE • 2 doses IV every 6-12 months (RA)
How does Vedolizumab/ Natalizumab work?
antibody for α4β7 integrin
inhibits leukocyte migration
this integrin interacts with MadCAM1 + VCAM1 –> responsible for leukocyte rolling and arrest to enter tissues
Use
• IBD
• Remitting/relapsing MS
• IV every 8 weeks
Cytokines + applications
TNFa IL-1 IL-6 IL 17/23 pathway IL 4, 5, 13 pathway RANK pathway
TNFa
Psoriasis, psoriatic arthritis, rheumatoid arthritis
FMF, IBD
IL-1
Gout
FMF
IL-6
Rheumatoid arthritis
IL17/23
Psoriasis, psoriatic arthritis
IBD (not IL17)
Axial spondyloarthritis
IL 4, 5, 13
Asthma
Eczema
RANK pathway
Osteoporosis
Give examples of anti TNF a ab
Infliximab
Adalimumab
Cetrolizumab
Golimumab
• Directly binds to TNFa released by macrophages and mops it up
- Rheumatoid arthritis
- Ankylosing spondylitis
- Psoriasis
- Psoriatic arthritis
- Inflammatory bowel disease
- Familial Mediterranean fever (other monogenic inflammatory diseases)
- SC or IV
What is Etanercept and where is it used?
Inhibits TNFa TNFb
Rheumatoid arthritis
Psoriasis
Psoriatic arthritis
Ankylosing spondylitis
not useful in IBD
Look at the inflammasome
Produces IL-1 after activation of the cryopyrin pathway by urate. microbial pathogens, toxins
slide 98
What is the function of
Tocilizumab
Sarlimumab
Anti-IL-6 receptor ab
reduced activation of macrophages, neutrophils, B cells, T cells
Used in rheumatoid arthritis
Castleman disease (IL6 producing tumour)
SC every 1-2w
What is the function of IL 23?
Which antibody can be used against that and how does it work?
IL 23 consists of 2 subunits - p 19 +p40
IL-23 stimulates Th17 differentiation + IL-17+ IL-22 production
Guselkumab binds on p19 subunit of IL23
this inhibits action of IL23 + hence production of IL23
Used in psoriasis, psoriatic arthritis
SC ever 8w
Where can each of the antibodies be used?
IL4/13
Anti IL13
Anti IL5
IL4/13
eczema + asthma
Anti IL13
eczema
Anti IL5
asthma
What is denosumab, how does it work and where is it used?
Denosumab is a RANK Ligand antibody
RANK Ligand is produced by osteoblasts
It acts on RANK receptors found on osteoclasts
stimulates osteoclasts to break down bone
Used in
osteoporosis
MM
Bone mets
SC every 6m
SE avascular necrosis of the jaw
Treatment options for
Psoriasis
Psoriasis
Inhibition of L12/23
TNFa
IL17a
Rheumatoid arthritis
Inhibition of IL6, TNFa
B cell depletion
Increased risk of malignancy with immunosuppression
Lymphoma (EBV)
Non-melanoma skin cancers (HPV)
Melanoma (more in those treated with TNFa inhibitors)
No increased risk in solid tumour malignancies
Where are steroids used?
• Allergic disorders • Auto-immune disease • Auto-inflammatory disease • Transplant rejection Malignant disease – when there is associated inflammation leading to a space occupying effect
