10. Immune modulating therapies II Flashcards
What are six approaches to suppressing the immune system?
- Steroids; 2. Anti-proliferative disease; 3. plasmapheresis; 4. inhibitors of cell signalling 5. agents directed against cell surface antigens 6. agents directed at cytokines
What are corticosteroids?
Synthetic glucocorticoids based upon naturally occurring steroids
What mineralocorticoid activity do steroids have?
They have NO mineralocorticoid activity
What corticosteroid is used in the UK and USA?
UK: prednisolone. USA: prednisone (metabolised into prednisolone in the liver)
What is the endogenous production of steroids?
Roughly equivalent to 5-7.5 mg
What are the effects of corticosteroids on prostaglandins?
Corticosteroids inhibit phospholipase A2. Phospholipase A2 is usually involved in the conversion of phospholipids into arachidonic acid which is then converted to eicosanoids (e.g. prostaglandins and leukotrienes) by COX. By inhibiting phospholipase A2, corticosteroids will block arachidonic acid and prostaglandin formation thereby reducing inflammation.
What is the effect of corticosteroids on phagocytes?
Decrease traffic of phagocytes to inflamed tissue by: reducing the expression of adhesion molecules on the endothelium; they also block the signals that tell immune cells to move from the bloodstream into tissues; this leads to a transient increase in neutrophil count. Decreased phagocytosis. Decreased release of proteolytic enzymes.
What is the effects of corticosteroids on lymphocyte function?
Lymphopaenia: sequestration of lymphocytes in lymphoid tissue; affects CD4 > CD8 > B cells. Blocks cytokine gene expression. Decreased antibody production. Promotes apoptosis.
What do corticosteroids affect, leading to decreased inflammation?
Effects on prostaglandins, lymphocyte function, and phagocytes
What are the side effects of corticosteroids?
Metabolic: central obesity; moon face; diabetes; lipid disorders; osteoporosis; hirstuitism; adrenal suppression. Others: cataracts, glaucoma, peptic ulceration, pancreatitis. Immunosuppression
What are anti-proliferative agents?
These are agents that inhibit lymphocyte proliferation
What are examples of anti-proliferative agents?
Cyclophosphamide, mycophenolate, azathioprine, methotrexate
What is the action of anti-proliferative agents?
Inhibit DNA synthesis, cells with rapid turnover are most sensitive
What is the mechanism of action of cyclophosphamide?
Alkylates guanine base of DNA. Damages DNA and prevents cell replication.
Affects B cells > T cells (tends to be used in antibody-mediated disorders). At high dose, affects all cells with high turnover
What are major indications for cyclophosphamide?
Multisystem connective tissue disease; vasculitis with severe end-organ involvement (e.g. GPA, SLE); anti-cancer agent
What are the side effects of cyclophosphamide?
Toxic to proliferating cells:
bone marrow suppression; sterility (mainly in males); hair loss. Haemorrhagic cystitis: toxic metabolite (acrolein) is excreted in the urine. Malignancy: bladder cancer; haematological malignancies; non-melanoma skin cancer. Teratogenic. Infection (e.g. Pneumocystic jirovecii).
What is the mechanism of azathioprine?
Metabolised by the liver to 6-mercaptopurine. Blocks de novo purine synthesis (e.g. adenine and guanine). Prevents replication of DNA. Preferentially inhibits T cell activation and proliferation.
What are the indications for azathioprine?
Transplantation, auto-immune disease, auto-inflammatory disease (e.g. Crohn’s, UC)
What are the side effects of azathioprine?
Bone marrow suppression: cells with rapid turnover (e.g. leucocytes and platelets) are particularly susceptible. Hepatotoxicity. Infection.
What should be checked before giving azathioprine?
Bone marrow suppression is a side effect of azathioprine. Cells with rapid turnover are particularly susceptible. 1 in 300 individuals are extremely susceptible to bone marrow suppression. CHECK TPMT ACTIVITY or gene variants before treatment is started?
Why are 1 in 300 individuals are extremely susceptible to bone marrow suppression when administered azathioprine?
Thiopurine methyl transferase (TPMT) polymorphisms - unable to metabolise azathioprine
What are the mechanisms of mycophenolate mofetil?
Blocks de novo nucleotide synthesis; prevents replication of DNA; prevent T cell > B cell proliferation.
What are indications for mycophenolate mofetil?
Widely used in transplantation (alternative to azathioprine). Also used in autoimmune disease and vasculitis as an alternative to cyclophosphamide.
What are side effects of mycophenolate mofetil?
Bone marrow suppression (cells with rapid turnover are particularly sensitive); teratogenic; infection (particularly herpes virus reactivation and progressive multifocal leukoencephalopathy (JC virus))
What is the aim of plasmapheresis?
Remove pathogenic antibody
What happens in plasmapheresis?
The patient’s blood is passed through a separator. Own cellular constituents are reinfused. Plasma is treated to remove immunoglobulins and is then reinfused (or replaced with albumin in plasma exchange)
What are the issues of plasmapheresis?
Rebound antibody production (because although you’ve got rid of the antibodies, the plasma cells are still there) limits efficacy. Therefore, it is usually given with an anti-proliferative agent.
What are indications for plasmapheresis?
Severe antibody-mediated disease: Goodpastures syndrome, severe acute myasthenia gravis, severe transplant rejection (antibodies against donor HHLA)
How do calcineurin inhibitors work and what do they do?
Inhibitors of calcineurin will prevent T cell signalling. Therefore, it blocks IL2 production. IL2 normally acts on T cells and drives proliferation. So, calcineurin inhibitors will prevent T cell activation and proliferation.
What are examples of calcineurin inhibitors?
Ciclosporin and tacrolimus
What are the side effects of ciclosporin?
Nephrotoxicity (++), hypertension (++), neurotoxic (++), diabetogenic (+), dysmorphic features (+++)
What are the side effects of tacrolimus?
Nephrotoxicity (++), hypertension (++), neurotoxic (++), diabetogenic (++), dysmorphic features (-)
What should be monitored when calcineurin inhibitors are given?
Monitor BP and renal function
What is an example of a JAK inhibitor?
Tofacitinib (JAK1 and JAK3 inhibitor)
What do JAK inhibitors do?
Interferes with JAK-STAT signalling (important in transducing the signals from cytokine binding); influences gene transcription; inhibits the production of inflammatory molecules
What are JAK inhibitors effective in?
Rheumatoid arthritis
What is an example to PDE4 inhibitors?
Apremilast
How to PDE4 inhibitors work?
Phosphdiesterase 4 (PDE4) is important in the metabolism of cAMP (degrades cAMP into 5’-AMP). Blocking PDE4 leads to increase in cAMP. cAMP activates PKA which prevent activation of transcription factors. This leads to a decrease in cytokine production.
What are PDE4 inhibitors effective in?
Effective in psoriasis and psoriatic arthritis
Which inhibitors do these side effects correspond to? A. osteoporosis B. infertility C. progressive multifocal leukoencephalopathy D. neutropenia particularly if TPMT low E. nephrotoxicity
A. prednisolone B. cyclophosphamide C. mycophenolate mofetil D. azathioprine E. tacrolimus
What does ‘-cept’ mean?
‘-cept’ means that it is a receptor that is usually put on the end of IgG Fc component
How are rabbit anti-thymocyte globulins used?
Thymocyte (lymphocytes from the thymus gland) from humans were injected into rabbits. The rabbits then produced antibodies against the thymocytes of varying specificities (e.g. antibodies to CD2, CD3, CD4, CD8 etc.). The serum was then taken and injected into patients. This is very effective at targeting T cells, however it is very non-specific.
What is the main aim of anti-thymocyte globulin?
The main aim is to cause T cell depletion (thereby reducing the activation and migration of T cells)
What is rabbit anti-thymocyte globulin useful in?
Useful in allograft rejection
What are the side effects of anti-thymocyte globulins?
Infusion reactions; leukopaenia; infection; malignancy
What is basiliximab?
Antibody directed at CD25 (IL-2Ralpha chain)
What is basiliximab used for?
Used for prophylaxis of allograft rejection. Used before and after transplant surgery.
How does basiliximab work?
Basiliximab targets part of the IL2 receptor. The gamma chain is shared amongst many interleukin receptors so this wont be a good target. The alpha chain of the IL2 receptor (aka CD25) is more specific for the IL2 receptor. This leads to inhibition of T cell proliferation.
What are the side effects of basiliximab?
Infusion reaction, infection, concern of long term malignancy risk
What is abatacept?
CTLA4-Ig fusion protein. It is a receptor that is made from a fusion of CTLA4 and IgG Fc component.
What do APCs which can bind to receptors on T cells (CD28 and CTLA4)?
CD80 and CD86
What does the T cell receptor CD28 do?
Activating signal
What does the T cell receptor CTLA4 do?
Inhibitory signal
How does abatacept do?
Abatacept will bind to CD80 and CD86, thereby meaning that these receptors can no longer engage with CD28 and CTLA4 to activate/ regulate the T cell response. This results in reduced T cell activation.
What is abatacept used in?
It is effective in rheumatoid arthritis
What are the side effects of abatacept?
Infusion reactions; infection (TB, HBV, HCV); caution with malignancy
What is rituximab?
Anti-CD20 antibodies
How does rituximab work?
CD20 is expressed on mature B cells but NOT plasma cells. This leads to depletion of mature B cells.
What are indications for rituximab?
Lymphoma, RA, SLE
How is rituximab given?
Given as 2 IV doses every 6-12 months (in rheumatoid arthritis)
What are the side effects of rituximab?
Infusion reactions; infection (PML); exacerbation of cardiovascular disease
What is natalizumab?
Antibody against alpha4 integrin
How does natalizumab work?
Alpha 4 is expressed with either beta-1 or beta-7 integrin. This complex binds to VCAM1 or MadCAM1 to mediate rolling and arrest of leukocytes. The complex can also bind to non-endothelial VCAM1 in lymphoid tissue. Therefore, blocking this integrin can inhibit leukocyte migration.
What is natalizumab used for?
Used in highly-active relapsing-remitting multiple sclerosis
What are side effects of natalizumab?
Infusion reactions, infection (PML), hepatotoxic, concerns regarding malignancy
What is tocilizumab?
Antibody against IL6 receptor
How does tocilizumab work?
Antibodies bind to IL6 receptor, leading to reduced activation of macrophages, T cells, B cells and neutrophils
What are indications for tocilizumab?
Castleman’s disease (IL6 producing tumour) and rheumatoid arthritis
What are side effects of tocilizumab?
Infusion reactions; infection; hepatotoxic; elevated lipids; caution with malignancy
Which drug inhibits leukocyte migration but may only be used in highly active remitting/relapsing MS?
Natalizumab (anti-alpha4 integrin)
Which drug inhibits T cell activation and is effective in rheumatoid arthritis?
Abatacept (CTLA4-Ig fusion protein)
Which drug depletes B cells and is effective in treatment of B cell lymphomas and rheumatoid arthritis?
Rituximab (anti-CD20)
Which drug inhibits function of lymphoid and myeloid cells and used in management of rheumatoid arthritis?
Tocilizumab (anti-IL6 receptor)
Which drug is antibody specific for CD25 which inhibits T cell activation and is used to prevent rejection?
Basiliximab (Anti-IL2 receptor)
Why is etanercept NOT effective in IBD?
It does not have the functionality of the Fc portion of an IgG
How is infliximab administered?
Needs to be administered IV
What is the name of the anti-RANK ligand which is used to treat osteoporosis?
Denosumab
What are examples of anti-TNFalpha antibodies?
Infliximab, adalimumab, certolizumab, golimumab
How do anti-TNF alpha antibodies work?
TNF-alpha is a critical molecule within the cytokine cascade that is responsible for the inflammatory response in inflammatory arthritis
What are indications for anti-TNF alpha antibodies?
Rheumatoid arthritis, ankylosing spondylitis, psoriasis and psoriatic arthritis, inflammatory bowel disease
What are side effects of anti-TNF alpha antibodies?
Infusion or injection site reactions; infection (TB, HBV, HCV); lupus-like conditions; demyelination; malignancy
What is etanercept?
TNF-alpha antagonist
How does etanercept work?
TNF-alpha antagonist - it is essentially a decoy receptor that mops up TNF-alpha. This inhibits the action of TNF-alpha and TNF-beta.
How is etanercept given?
It is given as a subcutaneous injection
What are indications for etanercept?
Rheumatoid arthritis, ankylosing spondylitis, psoriasis and psoriatic arthritis
What are the side effects of etanercept?
Injection site reactions; infection (TB, HBV, HCV); lupus-like conditions; demyelination; malignancy
What is ustekinumab?
Antibody to p40 subunit of IL12 and IL23
How does ustekinumab work?
p40 subunit antibody. The p40 subunit is present in both IL12 and IL23 (IL12 = p40 + p35; IL23 = p40 + p19). This leads to inhibition of IL12 and IL23. These cytokines mainly act on T cells and NK cells thereby modulating their activity.
What are indications of ustekinumab?
Psoriasis and psoriatic arthritis: the action of IL23 leading to the production of IL17 by T cells is important in psoriasis. Crohn’s disease
What are the side effects of ustekinumab?
Injection site reactions; infection (TB); concern about malignancy
What is secukinumab?
Antibody to IL17A.
How does secukinumab work?
Dimer of IL17A or IL17A/F from Th 17 cells (NK cells, Tc 17 cells) will bind to IL17RA/RC receptor (keratinocyte). Secukinumab leads to inhibition of IL17A.
What are indications for secukinumab?
Psoriasis and psoriatic arthritis, ankylosing spondylitis
What are side effects of secukinumab?
Infection (TB)
What is denosumab?
Antibody against RANKL
How does denosumab work?
- RANKL is produced by osteoblasts and it acts on RANK (receptor) on osteoclasts.
- The binding of RANKL to RANK will leads to osteoclast differentiation and function.
- This leads to increased bone resorption.
- There is a natural decoy receptor called osteoprotegrin (OPG) which can bind to RANKL and regulate the system.
- Denosumab is an antibody directed against RANKL which prevents RANKL from binding to RANK on osteoclasts, thereby reducing osteoclast differentiation and function (and, therefore, reducing bone resorption).
What are the indications of denosumab?
Osteoporosis, given subcutaneously every 6 months
What are the side effects of denosumab?
Injection site reactions; infection (mildly immunosuppressive because RANKL has some role in other parts of the immune system); avascular necrosis of the jaw
What are treatment options (against cytokines) for osteoporosis?
Treatment options include inhibition of RANK ligand
What are treatment options (against cytokines) for psoriasis?
Treatment options include inhibition of IL12/23, TNF alpha and IL17A
What are treatment options (against cytokines) for rheumatoid arthritis?
Treatment options include inhibition of IL6, TNF alpha and depletion of B cells
What are side effects of biologic agents?
Infusion reactions, injection site reactions, and acute infections
What are infusion reactions to biologic agents?
Urticaria, hypotension, tachycardia, wheeze - IgE mediated, headaches, fevers, myalgias - not classical type I hypersensitivity, cytokine storm
What injection site reactions occur due to biologic agents? **
Peak reaction at ~48 hours; may also occur at previous injection sites (recall reactions), mixed cellular infiltrates often with CD8 t cells, not generally IgE or immune complexes. **
What are features of acute reaction due to biologic agents?
Risk often >= 2 x background; avoidance; vaccination; temporarily stop immunosuppression; consider atypical organisms; appropriate antibiotics
Who should not have live vaccines?
Immunosuppressed patients
What are examples of live vaccines?
Polio (Sabin - oral); measles; BCG; yellow fever
Briefly how is TB managed?
History, residence, travel, contacts, CXR, TBElispot. Prophylaxis or treatment if required.
Briefly, how do you check for HBV and HCV? *
Check Hep B core antibody and Hep C antibody
What should be done promptly in CMV?
Treat reactivation promptly
What is John Cunningham Virus (JCV)?
Common polyomavirus that can reactivate. Infects and destroys oligodendrocytes. Progressive multifocal leukoencephalopathy.
What increases risk of lymphoma?
EBV
What increases risk of non melanoma skin cancers?
Human papilloma virus
What increases the risk of melanoma?
Increased in cohort treated with anti-TNF alpha
When does risk of malignancy appear lower?
Risks appear lower with targeted forms of immunosuppression than with regimes used in transplantation.
