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Immune modulating 2 Flashcards

1
Q
  1. What is the action of phospholipase A2?
  2. What are actions of steroids on prostaglandins such as phospholipase A2?
A
  1. Phospholipase A2
    - Breaks down phospholipids to form arachidonic acid which is converted to eicosanoids (eg prostaglandin)s, leukotrienes) by cyclo-oxygenases
  2. Corticosteroids inhibit phospholipase A2
    - Blocks arachidonic acid and prostaglandin formation and so reduces inflammation
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2
Q

What are the actions of steroids on phagocytes?

A
  • 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
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3
Q

What are the actions of steroids on lymphocyte function?

A
  • 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
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4
Q

What are the side effects of corticosteroids?

A
  • Metabolic effects
    • Diabetes, central obesity, moon face, lipid abnormalities, osteoporosis, hirsuitism, adrenal suppression
  • Other effects
  • Cataracts, glaucoma, peptic ulceration, pancreatitis, avascular necrosis
  • Immunosuppression
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5
Q
  1. Name some cytotoxic agents - that act as anti-proliferative immunosuppressants
  2. Describe their actions
  3. Describe how they can be toxic
A
  1. Drugs (selected)
  • Cyclophosphamide
  • Mycophenolate
  • Azathioprine
  1. Action
  • Inhibit DNA synthesis
  • Cells with rapid turnover most sensitive

Toxicity

  • Bone marrow suppression
  • Infection
  • Malignancy
  • Teratogenic
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6
Q
  1. Describe the MOA of cyclophosphamide (anti-proliferatie drug)
  2. What are it’s major indications?
A

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
  1. Major indications
  • Multisystem connective tissue disease or vasculitis with severe end-organ involvement
    • eg GPA (Wegener’s granulomatosis), SLE
  • Anti-cancer agent
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7
Q

Describe the side effects of cyclophosphamide

A

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)
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8
Q
  1. Describe the MOA of Azathoprine
  2. What are the indications for use of this drug?
A
  1. 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
  1. Indications:
  • Transplantation
  • Auto-immune disease
  • Auto-inflammatory diseases, eg Crohn’s, ulcerative colitis
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9
Q

Describe the side effects of Azathioprine

A

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
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10
Q
  1. Describe the MOA of Mycophenolate mofetil
  2. What are the major indications for use of this drug?
A
  1. Mechanism of action – Anti-metabolite - purine
  • Blocks de novo guanosine nucleotide synthesis
  • prevents replication of DNA
  • Prevents T>B cell proliferation
  1. Indications:
  • Widely used in transplantation as alternative to azathioprine
  • Also used in auto-immune diseases and vasculitis as alternative to cyclophosphamide
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11
Q

What are the side effects of mycophenolate mofetil?

A

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)
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12
Q
  1. Describe plasmaphersis and its aim
  2. What are the problems with it?
A
  1. 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’)
  1. Problems

Rebound antibody production limits efficacy, therefore usually given with anti-proliferative agent

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13
Q

What are the indications for the use of plasmapheresis?

A
  • 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
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14
Q
  1. Name two calcineurin inhibitors
  2. How do they act?
A
  1. Ciclosporin and Tacrolimus
  2. 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
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15
Q

What are the side effect profiles of ciclosporin and tacrolimus?

A

Ciclosporin dysmorphic features - hirtuism and gum hypertrophy

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16
Q
  1. Name a JAK inhibitor
  2. Describe the action of JAK inhibitors
A

Inhibitor of cell signalling

  1. Tofacitinib (JAK1 and JAK3 inhibitor)
  2. MOA
  • Interferes with JAK-STAT signalling
  • Influences geme transcription
  • Inhibits production of inflammatory molecules
  • Effective in Rheumatoid arthritis
17
Q
  1. What is Apremilast?
  2. What is its MOA?
  3. Uses?
A
  1. Apremilast is a PDE4 inhibitor
  2. MOA
  • Inhibition of PDE4 leads
  • to increase in cAMP
  • Influences gene transcription
  • via protein kinase A pathway
  • Modulates cytokine production
  1. Effective in psoriasis and psoratic arthritis
18
Q

Agents directed at cells surface antigens.

  1. Which cell surface antigen do each of these drugs target?
    a) Basiliximab
    b) Abatacept
    c) Rituximab
    d) Natalizumab
    e) Tocilizumab
  2. What do they all do?
A

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
19
Q
  1. What are the indications for using anti-thymocyte globulin?
  2. What is the MOA?
  3. What are the toxicity risks?
A
  1. Indications and dosing
  • Allograft rejection (renal, heart)
  • Daily intravenous infusion
  • Specificities include CD2, CD3, CD4, CD8, CD28, CD11a, HLA class I and II
  1. Action
  • Lymphocyte depletion
  • Modulation of T cell activation
  • Modulation of T cell migration

Toxicity

  • Infusion reactions
  • Leukopenia
  • Infection
  • Malignancy
20
Q
  1. What is Basiliximab?
  2. What are the indications?
  3. What is the MOA?
  4. Toxicity?
A
  1. Basiliximab is an antibody diected at CD25 (IL-2Ralpha chain)
  2. Indications and dosing
  • Prophylaxis of allograft rejection
  • Intravenous given before and after transplant surgery
  1. Action
    * Inhibits T cell proliferation
  2. Toxicity
  • Infusion reactions
  • Infection
  • Concern re long term risk malignancy
21
Q
  1. What is Abatacept?
  2. What are the indications?
  3. What is the MOA?
  4. Toxicity?
A
  1. Abatacept is a CTLA4-Ig fusion protein
  2. Indications and dosing
  • Rheumatoid arthritis
  • Intravenous 4 weekly
  • Subcutaneous weekly
  1. Action
    * Reduces T cell activation
  2. Toxicity
  • Infusion reactions
  • Infection (TB, HBV, HCV)
  • Caution wrt malignancy
22
Q
  1. What is Rituximab?
  2. What are the indications?
  3. What is the MOA?
  4. Toxicity?
A
  1. Rituximab is an antibody specific for CD20
  2. Indications and dose
  • Lymphoma
  • Rheumatoid arthritis
  • SLE
  • 2 doses intravenous every 6-12 months (RA)
  1. Action
    * Depletes mature B cells
  2. Toxicity
  • Infusion reactions
  • Infection (PML)
  • Exacerbation CV disease
23
Q
  1. What is Natalizumab?
  2. What are the indications?
  3. What is the MOA?
  4. Toxicity?
A
  1. Natalizumab is an antibody specific for alpha 4 integrin
  2. Indications and dosing
  • Highly active relapsing-remitting multiple sclerosis
  • (Crohn’s disease)
  • Intravenous every 4 weeks
  1. 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
  1. Toxicity
  • Infusion reactions
  • Infection (PML)
  • Hepatotoxic
  • Concern re malignancy
24
Q
  1. What is Tocilizumab?
  2. What are the indications?
  3. What is the MOA?
  4. Toxicity?
A
  1. Tocilizumab is an antibody directed at IL-6 receptor
  2. Indications and dosing
  • Castleman’s disease
  • Rheumatoid arthritis
  • Intravenous every 4 weeks
  1. Action
    * Reduces macrophage, T cell, B cell, neutrophil activation
  2. Toxicity
  • Infusion reactions
  • Infection
  • Hepatotoxic
  • Elevated lipids
  • Caution wrt malignancy
25
Q

Describe which cytokines each of these drugs targets

  • Infliximab
  • Adalimumab
  • Certolizumab
  • Golimumab
  • Etanercept
  • Ustekinumab
  • Secukinumab
  • Denosumab
A
  • 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
26
Q
  1. What are Infliximab, Adalimumab, Certolizumab and Golimumab?
  2. What are the indications?
  3. What is the MOA?
  4. Toxicity?
A
  1. All are Anti-TNFalpha antibodies
  2. Indications and dosing
  • Rheumatoid arthritis
  • Ankylosing spondylitis
  • Psoriasis and psoriatic arthritis
  • Inflammatory bowel disease
  • Subcutaneous or intravenous
  1. Action
    * Inhibit TNFa
  2. Toxicity
  • Infusion or injection site reactions
  • Infection (TB, HBV, HCV)
  • Lupus-like conditions
  • Demyelination
  • Malignancy
27
Q
  1. What is Etanercept?
  2. What are the indications?
  3. What is the MOA?
  4. Toxicity?
A
  1. Etanercept is a TNFalpha antagonist
  2. Indications and dosing
  • Rheumatoid arthritis
  • Ankylosing spondylitis
  • Psoriasis and psoriatic arthritis
  • Subcutaneous weekly
  1. Action
    * Inhibits TNFa and TNFb
  2. Toxicity
  • Injection site reactions
  • Infection (TB, HBV, HCV)
  • Lupus-like conditions
  • Demyelination
  • Malignancy
28
Q
  1. What is Ustekinumab?
  2. What are IL-12 and IL-23 comprised of?
  3. What are the indications?
  4. What is the MOA?
  5. Toxicity?
A
  1. Ustekinumab is an antibody to p40 subunit of IL-12 and IL-23
  2. IL-12 and IL-23
  • IL-12 comprises p40+p35 subunits
  • IL-23 comprises p40+p19 subunits
  1. Indications and dosing
  • Psoriasis, psoriatic arthritis
  • Crohns disease
  • Subcutaneous every 12 weeks
  1. Action
    * Inhibits IL-12 and IL-23
  2. Toxicity
  • Injection site reactions
  • Infection (TB)
  • Concern re malignancy
29
Q
  1. What is Secukinumab?
  2. What is IL-17a?
  3. What are the indications?
  4. What is the MOA?
  5. Toxicity?
A
  1. Secukinumab is an antibody to I-17a
  2. IL-17A
  • IL17A protype of IL-17 family
  • Dimer of IL-17A or IL-17A/F
  • Binds to IL-17RA/RC receptor
  1. Indications and dosing
  • Psoriasis and psoriatic arthritis
  • Ankylosing spondylitis
  • SC load and then monthly
  1. Action
    * Inhibits IL-17A
  2. Toxicity
    * Infection (TB)
30
Q
  1. What is Denosumab?
  2. What are the indications?
  3. What is the MOA?
  4. Toxicity?
A
  1. Denosumab is an antibody directed at RANK ligand
  2. Indications and dosing
  • Osteoporosis
  • Subcutaneous every 6 months
  1. Action
    * Inhibits RANK mediated osteoclast differentiation and function
  2. Toxicity
  • Injection site reactions
  • Infection – mildly immunosuppressive
  • Avascular necrosis of jaw
31
Q

Describe the following side effects of biological agents:

  1. Infusion reactions
  2. Injection site reactions
A
  1. Infusion reactions
  • Urticaria, hypotension, tachycardia, wheeze – IgE mediated
  • Headaches, fevers, myalgias – not classical type I hypersensitivity
  • Cytokine storm
  1. 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
32
Q

Which of the following vaccines cannot be used in immunosuppressed patients and why?

A
  • BCG
  • Measles
  • Polio
  • Yellow fever

As all live attenuated vaccines

33
Q

What is John Cunningham virus (JCV)?

A
  • Common polyomavirus that can reactivate
  • Infects and destroys oligodendrocytes
  • Progressive multifocal leukoencephalopathy
34
Q

What chronic infections can be prevelant in the immunosuppressed?

A
  • TB
  • HBV and HCV
  • HIV
  • John Cunningham virus
35
Q

What autoimmune conditions can develop in the immunosuppressed?

A

Auto-immunity – dysregulation of immune response

  • SLE and lupus-like syndromes
  • Anti-phospholipid syndromes
  • Vasculitis
  • Interstitial lung disease
  • Sarcoidosis
  • Uveitis
  • Autoimmune hepatitis
  • Demyelination
36
Q

What malignancies are associated with immunosuppression?

A
  • 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

Immunology - Path (9 decks)

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