Immuno 9 - Immune modulating therapies 1 Flashcards
How do steroids help modulate the immune response?
Activity on phagocytes
Activity on lymphocytes
Inhibiting NF-KB (pro-inf cytokines)
Inhibiting phospholipase A2
What effect do steroids have on phagocytes?
- ↓ trafficking to areas of inflammation
- Adhesion molecule expression
- Blocks chemotactic signals - ↓ phagocytosis
- ↓ release of proteolytic enzymes
What effect do steroids have on lymphocytes?
- Lymphocytes sequestered in lymphoid tissue
CD4+ve > T cells >CD8+ve > B cells - ↓ cytokine gene expression
- ↓ Ab production
- ↑ apoptosis
What effect do steroids have on Prostaglandin synthesis?
Inhibits phospholipase A2 –> ↓ breakdown of phospholipids to arachidonic acid –> ↓ conversion to prostaglandins and leukotrienes by COX2 –> ↓ inflammation
What effect do steroids have on NF-KB?
↓ NF-κB = ↓ production of inflammatory cytokines and chemokines
What are the adverse effects associated w/ steroid use?
STEROIDS Stomach ulcers Thin skin Edema Right heart failure Osteoporosis Infections Diabetes Cushing’s Syndrome (Central obesity, Moon face, Hirsutism, Proximal myopathy)
What are anti proliferative agents + some examples?
Antiproliferative drugs target cells with high turnover rates, leading to their use as immunosuppressants and anti-cancer drugs (inhibit DNA synthesis)
Azathioprine
Mycopheolate
Cyclophospamide
Methotrexate
What is the MoA of Azathioprine
Prodrug converted to 6-mercaptopurine in the liver –> inhibits de novo purine synthesis
azaThioprine inhibits T> B cells
What is azathiprine used for?
Transplantation – preventing graft rejection, autoimmune disease, autoinflammatory disease
What are the adverse effects associated w/?
Accumulation if have thiopurine methyltransferase (TPMT) polymorphisms -> Unable to metabolise azathioprine
+ Hepatotoxicity
Check TPMT activity or gene variants before treatment!!!
What is mycopheolate used for?
Blocks de novo guanosine synthesis
Affects T>B cells
What are the indications for mycopheolate use?
Transplantation – preventing graft rejection, autoimmune disease, vasculitis
What are the adverse effects associated w/ mycophenolate
Infection, particular risk of HSV reactivation and
progressive multifocal leukoencephalopathy (PML) (reactivated JC virus)
mycoPhenolate => Pml
What is the MoA of cyclophosphamide?
Alkylate guanine base -> stop DNA replication
Affects B>T cells
What is the indication for cyclophosphamide?
CTD, vasculitis, anticancer
What is the adverse side effect associated w/ cyclophosphamide?
Haemorrhagic cystitis + bladder cancer (Toxic metabolite acrolein excreted via urine so accumulate in bladder)
Haematological malignancies
Non-melanoma skin cancer
What is the MoA of Methotrexate?
Anti-folate, inhibit dihydrofolate reductase -> stop DNA synthesis
What is the indication for Methotrexate?
Autoimmune
RA, Psoriasis, Crohn’s
Anti-tumour
What is the adverse side effects associated w/ Methotrexate?
Pneumonitis
Pulmonary fibrosis
Cirrhosis
NB: Remember to replace folate + increased risk of NTD in pregnancy hence CI
What are the main features of PML?
PML:
- Reactivated John Cunningham (JC) virus
- Destroys oligodendrocytes
- Progressive, fatal condition
NB - associated w/ mycophenolate use
What is plasmapheresis?
Removal of pathogenic Ab from plasma
What are the indications for plasmapheresis?
Severe Type II Hypersensitivity:
- Goodpasture
- Myasthenia gravis
- Ab-mediated rejection
What are the different cell signalling inhibitors?
Calcineurin inhibitor (Tacrolimus)
mTOR inhibitor (Sirolimus)
JAK inhibitor (ofacitinib)
PDE4 inhibitor (Apremilast)
How do calineurin inhibitors work?
Blocks calcineurin-stimulated IL-2 expression -> inhibits T cell proliferation
What are the adverse effects associated w/ calineurin inhibitors?
Nephrotoxicity, neurotoxicity, HTN, gingival hyperplasia (cyclosporine causes this mainly)
What is the MoA of mTOR inhibitors?
Blocks IL-2 expression -> clonal expansion of T cells
What are the indications for mTOR inhibitors?
Transplantation
What are the adverse effects associated w/ mTOR inhibitors?
Similar to calcineurin inhibitors however causes less nephrotoxicitiy as it affects later stage in same chain
What is the indications for JAK inhibitors?
Inhibits JAK-STAT signalling -> decreases proinflammatory gene transcription
What are the adverse effects associated w/ JAK inhibitors?
RA
Polycythaemia vera
Psoriatic arthritis
Ank Spond
What is the MoA of PDE4 inhibitors?
PDE4 inhibition –> increased cAMP –> protein kinase A pathway –> decreased cytokine production
What are the indications for PDE4 inhibitors?
Psoriasis
Psoriatic arthritis
How do Tacrolimus and Sirolimus work?
Tacrolimus: “lime tacos in aisle two”
Used “for killing bad people” -> FK binding protein,
Aisle 2 -> blocks IL-2 expression
Sirolimus: “Sirius”
Sirius Black is known “for killing bad people” -> FK binding protein
Aisle 2 ->blocks IL-2 expression
What are the main agents directed at cel surface antigens?
Basiliximab
Natalizumab
Rabbit anti-thymocyte globulin (ATG)
Rituximad
Abatacept
What is the MoA of Basiliximab?
Anti-CD25 -> blocks IL-2 -> inhibits T cell proliferation
Basiliximab: “basilisk in HP 2” = IL-2
What are the indications and adverse effects of basliximab?
Indication:
Allograft rejection prophylaxis
Adverse:
Infusion reactions
Infection + malignancy
What is the MoA of Natalizumab?
Anti-α4 integrin inhibition -> prevents T cell migration
What is the indications and adverse effects associated with natalizumab?
Multiple sclerosis
Adverse: PML (JC virus), HBV reactivation, ↑ CVD
Natalizumab: “Natalie Portman” –> MS typically affects young white women
What is the MoA of Rabbit anti-thymocyte globulin (ATG)?
Specificities to CD proteins allow
- Lymphocyte depletion
- Modulation of T cell activation
- Modulation of T cell migration
Indications for rabbit ATG?
Acute allograft rejection
What is the MoA of Rituximab?
CD20 expressed on mature - B cells but not plasma cells
Left plasma cell population intact so Ab level remains
2 infusions can deplete B cell population for 6 months
Indications for Rituximab + adverse effects?
B cell lymphomas (MAIN)
RA, SLE
Adverse:
Infections - esp PML (JCV) + Hep B reactivation
What is the MoA of Abatacept?
CTLA4 is an inhibitory checkpoint for T cell activation. Abatacept enhances it
Opposite of Ipilimumab!
What is the indication for and side effect associated with abatacept?
RA
Adverse:
Infection - esp TB, HBV and HCV
What are anti-TNFa (Infliximab, adalimumab, certolizumab, golimumab, ETANERCEPT) used for + their mechanism?
RA, PsA, psoriasis, ankylosing spondylitis, IBD
Anti-TNFα mAB (etanercept = Anti-TNFα/TNFβ fusion protein)
What is the MoA of Anti-IL12/23(Ustekinumab) and what are they used for?
Inhibits differentiation of DCs to Th1 (IL-12) and Th17 (IL-23)
Psoriasis, psoriatic arthritis
Ank spond
IBD (IL23)
What is the MoA of Anti-IL23 (only) and what are they used for?
Inhibits differentiation of DCs to Th17
Psoriasis, psoriatic arthritis
Ank spond
What is anti-RANKL used for and its MoA?
RANK-L blocking inhibits osteoblast stimulation of osteoclast differentiation
Osteoporosis
What is anti-IL-6R used for + MoA?
Decreases neutrophil, macrophage, T/B cell activation
RA
Castleman’s disease
What therapies have broad use against autoinflammatory conditions?
Anti-TNFα and IL12/23
What is used to treat osteoporosis?
Anti RANKL therapy
What are antiproliferative drugs used for?
Immunosuppressants and anticancer drugs
What is generally used to prevent graft rejection following transplantation?
Cell signalling inhibitors tacrolimus, cyclosporine and sirolimus
A 30 year old woman with rheumatoid arthritis is seen in metabolic bone clinic with a t score of -3.5. Which medication is likely to have contributed to her condition? A – Infliximab B – Carbamazepine C – Prednisolone D – Methotrexate E – Tocilizumab
C – Prednisolone - steroids increase risk of osteoporosis
A 23 year old woman presents to her GP with loss of sensation and paraesthesia over the left foot. She reports an episode of blurry vision 6 months ago. She is treated and her symptoms improve.
Unfortunately, her condition worsens with time and she suffers two disabling relapses in the sixth year since her diagnosis. Which therapy may slow the progression of her disease?
A – Basiliximab
B – Ipilimumab
C – Rituximab
D – Natalizumab
E – Tocilizumab
D – Natalizumab - Used in mx of multiple sclerosis (natalie portman = MS)
Which type of rejection can be treated with plasmapheresis?
Acute antibody mediated Acute cell mediated Chronic Graft versus Host Disease Hyperacute
Acute antibody mediated
Which type of rejection leads to fibrosis? what do the others cause?
Acute antibody mediated Acute cell mediated Chronic Graft versus Host Disease Hyperacute
Chronic = 6+m = fibrosis, glomerulonephropathy
Hyperacute = mins to hrs - preformed abs activate complements -> thrombosis + necrosis
Acute cell mediated = <6m - Type IV hypersensitivity, cell infiltration
Acute antibody mediated = <6m -> vasculitis (ab attacking endothelium)
Which HLA antigens are the most important in matching organs?
DR > B > A
Theres 2 alleles for each of these hence there’s 6 possible oppurtunities for organ mismatch
