Immune modulating 2 Flashcards
- What is the action of phospholipase A2?
- What are actions of steroids on prostaglandins such as phospholipase A2?
- Phospholipase A2
- Breaks down phospholipids to form arachidonic acid which is converted to eicosanoids (eg prostaglandin)s, leukotrienes) by cyclo-oxygenases - Corticosteroids inhibit phospholipase A2
- Blocks arachidonic acid and prostaglandin formation and so reduces inflammation
What are the actions of steroids on phagocytes?
- Decreased traffic of phagocytes to inflamed tissue
- Decreased expression of adhesion molecules on endothelium
- Blocks the signals that tell immune cells to move from bloodstream and into tissues
- Results in transient increase in neutrophil counts
- Decreased phagocytosis
- Decreased release of proteolytic enzymes
What are the actions of steroids on lymphocyte function?
- Lymphopenia
- Sequestration of lymphocytes in lymphoid tissue
- Affects CD4+ T cells > CD8+ T cells > B cell
- Blocks cytokine gene expression
- Decreased antibody production
- Promotes apoptosis
What are the side effects of corticosteroids?
- Metabolic effects
- Diabetes, central obesity, moon face, lipid abnormalities, osteoporosis, hirsuitism, adrenal suppression
- Other effects
- Cataracts, glaucoma, peptic ulceration, pancreatitis, avascular necrosis
- Immunosuppression
- Name some cytotoxic agents - that act as anti-proliferative immunosuppressants
- Describe their actions
- Describe how they can be toxic
- Drugs (selected)
- Cyclophosphamide
- Mycophenolate
- Azathioprine
- Action
- Inhibit DNA synthesis
- Cells with rapid turnover most sensitive
Toxicity
- Bone marrow suppression
- Infection
- Malignancy
- Teratogenic
- Describe the MOA of cyclophosphamide (anti-proliferatie drug)
- What are it’s major indications?
1.
Mechanism of action – Alkylating agent
- Alkylates guanine base of DNA
- Damages DNA and prevents cell replication
- Affects B cells > T cells, but at high doses affects all cells with high turnover
- Major indications
- Multisystem connective tissue disease or vasculitis with severe end-organ involvement
- eg GPA (Wegener’s granulomatosis), SLE
- Anti-cancer agent
Describe the side effects of cyclophosphamide
Toxic to proliferating cells
- Bone marrow depression
- Hair loss
- Sterility (male>>female)
Haemorrhagic cystitis
- Toxic metabolite acrolein excreted via urine
Malignancy
- Bladder cancer
- Haematological malignancies
- Non-melanoma skin cancer
Infection
- Pneumocystis jiroveci (PCP)
- Describe the MOA of Azathoprine
- What are the indications for use of this drug?
- Mechanism of action – Anti-metabolite - purine
- Metabolised by liver to 6 mercaptopurine
- Purine analogue
- Interferes with DNA production – inhibits proliferating cells
- Affects T cells>B cells
- Indications:
- Transplantation
- Auto-immune disease
- Auto-inflammatory diseases, eg Crohn’s, ulcerative colitis
Describe the side effects of Azathioprine
Bone marrow suppression
- Cells with rapid turnover (leucocytes and platelets) are particularly sensitive
- 1:300 individuals are extremely susceptible to bone marrow suppression s
- Thiopurine methyltransferase (TPMT) polymorphisms
- Unable to metabolise azathioprine
- Check TPMT activity or gene variants before treatment if possible; always check full blood count after starting therapy
Hepatotoxicity
- Idiosyncratic and uncommon
Infection
- Serious infection less common than with cyclophosphamide
- Describe the MOA of Mycophenolate mofetil
- What are the major indications for use of this drug?
- Mechanism of action – Anti-metabolite - purine
- Blocks de novo guanosine nucleotide synthesis
- prevents replication of DNA
- Prevents T>B cell proliferation
- Indications:
- Widely used in transplantation as alternative to azathioprine
- Also used in auto-immune diseases and vasculitis as alternative to cyclophosphamide
What are the side effects of mycophenolate mofetil?
Bone marrow suppression Infection
- Cells with rapid turnover (leucocytes and platelets) are particularly sensitive
Infection
- Particular risk of herpes virus reactivation
- Progressive multifocal leukoencephalopathy (JC virus)
- Describe plasmaphersis and its aim
- What are the problems with it?
- Aim: removal of pathogenic antibody
- Patient’s blood passed through cell separator
- Own cellular constituents reinfused
- Plasma treated to remove immunoglobulins and then reinfused (or replaced with albumin in ‘plasma exchange’)
- Problems
Rebound antibody production limits efficacy, therefore usually given with anti-proliferative agent
What are the indications for the use of plasmapheresis?
- Severe antibody-mediated disease - type 2 hypersensitivity reactions - where the antibody is pathogenic
- Goodpastures syndrome
- Anti-glomerular basement membrane antibodies
- Severe acute myasthenia gravis
- Anti-acetyl choline receptor antibodies
- Severe vascular rejection
- Antibodies directed at donor HLA molecules
- Name two calcineurin inhibitors
- How do they act?
- Ciclosporin and Tacrolimus
- Stops the activation of calcineurin which is needed for T cell signalling. They act to block cytokine transcription, therefore prevent lymphocyte proliferation and effector functions

What are the side effect profiles of ciclosporin and tacrolimus?
Ciclosporin dysmorphic features - hirtuism and gum hypertrophy

- Name a JAK inhibitor
- Describe the action of JAK inhibitors
Inhibitor of cell signalling
- Tofacitinib (JAK1 and JAK3 inhibitor)
- MOA
- Interferes with JAK-STAT signalling
- Influences geme transcription
- Inhibits production of inflammatory molecules
- Effective in Rheumatoid arthritis

- What is Apremilast?
- What is its MOA?
- Uses?
- Apremilast is a PDE4 inhibitor
- MOA
- Inhibition of PDE4 leads
- to increase in cAMP
- Influences gene transcription
- via protein kinase A pathway
- Modulates cytokine production
- Effective in psoriasis and psoratic arthritis

Agents directed at cells surface antigens.
- Which cell surface antigen do each of these drugs target?
a) Basiliximab
b) Abatacept
c) Rituximab
d) Natalizumab
e) Tocilizumab - What do they all do?
1.
a) Basiliximab – anti-CD25
b) Abatacept – CTLA4-Ig
c) Rituximab – anti-CD20
d) Natalizumab – anti-a4 integrin
e) Tocilizumab – anti-IL-6 receptor
2. Action
- Block signalling
- Cell depletion
- What are the indications for using anti-thymocyte globulin?
- What is the MOA?
- What are the toxicity risks?
- Indications and dosing
- Allograft rejection (renal, heart)
- Daily intravenous infusion
- Specificities include CD2, CD3, CD4, CD8, CD28, CD11a, HLA class I and II
- Action
- Lymphocyte depletion
- Modulation of T cell activation
- Modulation of T cell migration
Toxicity
- Infusion reactions
- Leukopenia
- Infection
- Malignancy
- What is Basiliximab?
- What are the indications?
- What is the MOA?
- Toxicity?
- Basiliximab is an antibody diected at CD25 (IL-2Ralpha chain)
- Indications and dosing
- Prophylaxis of allograft rejection
- Intravenous given before and after transplant surgery
- Action
* Inhibits T cell proliferation - Toxicity
- Infusion reactions
- Infection
- Concern re long term risk malignancy

- What is Abatacept?
- What are the indications?
- What is the MOA?
- Toxicity?
- Abatacept is a CTLA4-Ig fusion protein
- Indications and dosing
- Rheumatoid arthritis
- Intravenous 4 weekly
- Subcutaneous weekly
- Action
* Reduces T cell activation - Toxicity
- Infusion reactions
- Infection (TB, HBV, HCV)
- Caution wrt malignancy

- What is Rituximab?
- What are the indications?
- What is the MOA?
- Toxicity?
- Rituximab is an antibody specific for CD20
- Indications and dose
- Lymphoma
- Rheumatoid arthritis
- SLE
- 2 doses intravenous every 6-12 months (RA)
- Action
* Depletes mature B cells - Toxicity
- Infusion reactions
- Infection (PML)
- Exacerbation CV disease

- What is Natalizumab?
- What are the indications?
- What is the MOA?
- Toxicity?
- Natalizumab is an antibody specific for alpha 4 integrin
- Indications and dosing
- Highly active relapsing-remitting multiple sclerosis
- (Crohn’s disease)
- Intravenous every 4 weeks
- Action
- Inhibits T cell migration
- alpha 4 is expressed with beta1 or beta7 integrin
- Bind to VCAM1 and MadCAM1 to mediate rolling/arrest of leukocytes
- Bind to non-endothelial VCAM1 in lymphoid tissue
- Toxicity
- Infusion reactions
- Infection (PML)
- Hepatotoxic
- Concern re malignancy

- What is Tocilizumab?
- What are the indications?
- What is the MOA?
- Toxicity?
- Tocilizumab is an antibody directed at IL-6 receptor
- Indications and dosing
- Castleman’s disease
- Rheumatoid arthritis
- Intravenous every 4 weeks
- Action
* Reduces macrophage, T cell, B cell, neutrophil activation - Toxicity
- Infusion reactions
- Infection
- Hepatotoxic
- Elevated lipids
- Caution wrt malignancy

Describe which cytokines each of these drugs targets
- Infliximab
- Adalimumab
- Certolizumab
- Golimumab
- Etanercept
- Ustekinumab
- Secukinumab
- Denosumab
- Infliximab – anti-TNFa
- Adalimumab – anti-TNFa
- Certolizumab – anti-TNFa
- Golimumab – anti-TNFa
- Etanercept – TNF receptor p75-IgG fusion protein
- Ustekinumab – anti-IL-12 and IL-23
- Secukinumab – anti-IL-17
- Denosumab – anti-RANK ligand
- What are Infliximab, Adalimumab, Certolizumab and Golimumab?
- What are the indications?
- What is the MOA?
- Toxicity?
- All are Anti-TNFalpha antibodies
- Indications and dosing
- Rheumatoid arthritis
- Ankylosing spondylitis
- Psoriasis and psoriatic arthritis
- Inflammatory bowel disease
- Subcutaneous or intravenous
- Action
* Inhibit TNFa - Toxicity
- Infusion or injection site reactions
- Infection (TB, HBV, HCV)
- Lupus-like conditions
- Demyelination
- Malignancy

- What is Etanercept?
- What are the indications?
- What is the MOA?
- Toxicity?
- Etanercept is a TNFalpha antagonist
- Indications and dosing
- Rheumatoid arthritis
- Ankylosing spondylitis
- Psoriasis and psoriatic arthritis
- Subcutaneous weekly
- Action
* Inhibits TNFa and TNFb - Toxicity
- Injection site reactions
- Infection (TB, HBV, HCV)
- Lupus-like conditions
- Demyelination
- Malignancy
- What is Ustekinumab?
- What are IL-12 and IL-23 comprised of?
- What are the indications?
- What is the MOA?
- Toxicity?
- Ustekinumab is an antibody to p40 subunit of IL-12 and IL-23
- IL-12 and IL-23
- IL-12 comprises p40+p35 subunits
- IL-23 comprises p40+p19 subunits
- Indications and dosing
- Psoriasis, psoriatic arthritis
- Crohns disease
- Subcutaneous every 12 weeks
- Action
* Inhibits IL-12 and IL-23 - Toxicity
- Injection site reactions
- Infection (TB)
- Concern re malignancy

- What is Secukinumab?
- What is IL-17a?
- What are the indications?
- What is the MOA?
- Toxicity?
- Secukinumab is an antibody to I-17a
- IL-17A
- IL17A protype of IL-17 family
- Dimer of IL-17A or IL-17A/F
- Binds to IL-17RA/RC receptor
- Indications and dosing
- Psoriasis and psoriatic arthritis
- Ankylosing spondylitis
- SC load and then monthly
- Action
* Inhibits IL-17A - Toxicity
* Infection (TB)

- What is Denosumab?
- What are the indications?
- What is the MOA?
- Toxicity?
- Denosumab is an antibody directed at RANK ligand
- Indications and dosing
- Osteoporosis
- Subcutaneous every 6 months
- Action
* Inhibits RANK mediated osteoclast differentiation and function - Toxicity
- Injection site reactions
- Infection – mildly immunosuppressive
- Avascular necrosis of jaw

Describe the following side effects of biological agents:
- Infusion reactions
- Injection site reactions
- Infusion reactions
- Urticaria, hypotension, tachycardia, wheeze – IgE mediated
- Headaches, fevers, myalgias – not classical type I hypersensitivity
- Cytokine storm
- Injection site reactions
- 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
Which of the following vaccines cannot be used in immunosuppressed patients and why?

- BCG
- Measles
- Polio
- Yellow fever
As all live attenuated vaccines
What is John Cunningham virus (JCV)?
- Common polyomavirus that can reactivate
- Infects and destroys oligodendrocytes
- Progressive multifocal leukoencephalopathy
What chronic infections can be prevelant in the immunosuppressed?
- TB
- HBV and HCV
- HIV
- John Cunningham virus
What autoimmune conditions can develop in the immunosuppressed?
Auto-immunity – dysregulation of immune response
- SLE and lupus-like syndromes
- Anti-phospholipid syndromes
- Vasculitis
- Interstitial lung disease
- Sarcoidosis
- Uveitis
- Autoimmune hepatitis
- Demyelination
What malignancies are associated with immunosuppression?
- Lymphoma (EBV)
- Non melanoma skin cancers (Human papilloma virus)
- Melanoma (increased in cohort treated with anti-TNF alpha)
- Risks appear lower with targeted forms of immunosuppression than with regimes used in transplantation