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Pathology by week > W22 - Imm modulating therapies 1&2 > Flashcards

W22 - Imm modulating therapies 1&2 Flashcards

1
Q

There are 4 main ways to “boost” the immune system - name them

A

Boosting the immune response

  1. Vaccination
  2. Replacement of missing components
  3. Cytokine therapy
  4. Blocking immune checkpoints
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2
Q

What sort of immunological memory do we want from a vaccine *ideally*?

A
  • Preformed abs
  • memory T cells
  • memory B cells
  • LONG-TERM protection!
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3
Q

In influenz infection, its the _______ response that controls the viral load but it is the _______ response that provides protection by blocking ________

A

In influenz infection, its the T cell response that controls the viral load but it is the antibody (nabs) response that provides protection by blocking hemagglutinin (HA) of the virus

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4
Q

Describe the haemagglutintion inhibition assay

A

RBC + virus => haemagluttination

RBC + virus + pt serum with previous HA-abs => haemagluttination inhibition (NO REACTION, RBCs will just drop to bottom of the well)

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6
Q

BCG vaccine - what immune response does it induce?

A

T cell response is important in protection here

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7
Q

Give 5 examples of live attenuated vaccines

A
  1. MMR
  2. BCG
  3. Yellow Fever
  4. Polio (oral)
  5. Typhoid (oral)
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8
Q

Benefits of live vaccines (4)

A
  1. Establishes a mild infection
  2. Rises broad immune response to multiple ags, hence likely to protect against different strins
  3. Activates all phases of immune system ( B cell, T cell)
  4. may confer lifelong immunity after 1 dose
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9
Q

Cons of live vaccines (3)

A
  1. Possible reversion to virulence
  2. Spread to contacts (immunosuppressed, immunodeficient)
  3. Storage problems
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10
Q

Inactivated vaccines - name 6

A
  1. Influenza
  2. Cholera
  3. Polio (salk)
  4. Hep A
  5. Pertussis
  6. Rabies
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11
Q

Benefits of inctivated/component vaccines (5)

A
  1. No mutation or reversion
  2. Can be used with immunodeficient patients
  3. Can lead to elimination of wild type virus from the community
  4. Storage easier
  5. Lower cost
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12
Q

Cons of inactivated/component vaccines (4)

A
  1. Often do not follow normal route of infection
  2. Some components have poor immunogenicity
  3. May need multiple injections
  4. May require conjugate protein carrier or adjuvants to enhance immunogenicity
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13
Q

Name 3 conjugate vaccines

A
  1. Haemophilus influenzae B
  2. Meningococcus
  3. Pneumococcus
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14
Q

Adjuvant increases the immune response without altering its specificity - give 2 examples of adjuvants

A

Aluminum salts

lipids/oils

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15
Q

What is the use of DC vaccines currently?

A

We take DCs, pulse them with tumour antigens, and we inject them and so you they get a stronger immune response

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16
Q

Immune booster - replacement of missing component.

Give a few examples of treatments that fall under this category

A
  1. HSCT
  2. IVIG replacement
  3. Specific Ig replacement
  4. TIL T cell therapy
  5. CAR T cell therapy
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17
Q

Indications for having a HSCT

A

• Life-threatening primary immunodeficiencies

–Severe combined immunodeficiency (SCID)

–Leukocyte adhesion defect

•Haematological malignancy etc

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18
Q

Indications for having an IVIG replacement

A

Primary antibody deficiency

  1. X linked agammaglobulinaemia
  2. X linked hyper IgM syndrome
  3. Common variable immune deficiency (CVID)

Secondary antibody deficiency

  1. Haematological malignancies
  • Chronic lymphocytic leukaemia (CLL)
  • Multiple myeloma (MM)
  1. After BM transplantation
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19
Q

Indications for specific Ig replacement

A

Human immunoglobulin used for post-exposure prophylaxis (passive immunisation), i.e.:

  • Needlestick/bite/sexual contact => hepatitis B IVIG
  • Potential rabies exposure => Rabies IVIG
  • Potential ZVZ exposure in pregnancy => VZV IVIG
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20
Q

Cytokine therapy:

IL2 - what does it stimulate? What is it used to treat?

IFN-a - What is it used to treat?

IFN-g - what does it stimulate? What is it used to treat?

A

Cytokine therapy:

IL2 - T cell response, renal cell carcinoma

IFN-a - antiviral effect, HBV/HCV

IFN-g - macrophage function, chronic granulomatous disease

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21
Q

T cells have _______ which receives stimulatory signals

T cells have _______ which receives inhibitory signals

A

T cells have CD28 which receives stimulatory signals

T cells have CTLA4 which receives inhibitory signals

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22
Q

how does anti-CTLA4 work in terms of blocking immune checkpoints?

What disease is it used to treat?

A

anti-CTLA4 ab (ipilimumab) binds to CTLA4 on T cell => blocks immune checkpoint => allows T cell activation => T cell specific for our disease will be activated.

Indications: advanced melanoma

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23
Q

How does anti-PD1 antibodies work in terms of blocking immune checkpoints?

Indication of use?

A

PD-1 on T cells typically interacts with PDL-1 or PDL-2 => Programmed cell death

with anti-PD-1 abs (pembrolizumab, nivolumab), we block these receptors => block immune checkpoint => T cells activate!!

Indication: advanced melanoma

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24
Q

The purpose of vaccination is to stimulate and enhance immunological memory. Which cells mediate immunological memory?

A

B and T cells

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25
Q

Which of the following vccines should not be given to an immunosuppressed individual?

A) BCG

B) Diphteria toxoid

C) Quadrivalent inactivated influenza vazzine

D) Polio (Salk)

E) Pfizer COVID vaccine

A

A) BCG

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26
Q

A 23 year old has metastatic melanoma. Which of the following my reduce disease progression?

A) BCG vaccination

B) BM transplantation

C) CAR-T cell with specificity for CD19

D) Nivolumab, an abs specific for PD-1

D) Normal human IVIG

A

D) Nivolumab, an abs specific for PD-1

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27
Q

DC vaccines - what cancer is it used in?

A

Prostate cancer (Provenge vccine)

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28
Q

What conditions (2) is CAR T cell therapy used in?

A

1. ALL

2. NHL

NB: CAR T cells less successful in solid tumours

29
Q

There are some methods to suppress the immune system - name them (6)

A

Suppressing the immune response:

  1. Steroids
  2. Anti-proliferative agents
  3. Plasmapheresis
  4. Inhibitors of cell signalling
  5. Agents directed at cell surface antigens
  6. Agents directed at cytokines and their receptors
30
Q

Steroids are synthetic ___________ with no ________ activity

A

Steroids are synthetic glucocorticoids with no mineralocorticoid activity

31
Q

Endogenous glucocorticoid secretion is equivalent to roughly _______ prednisolone

A

5 - 7.5 mg

32
Q

Name 3 ways in which steroids (i.e. prednisolone) affect the immune system

A
  1. Inhibit phospholipase A2 => block inflammation by affecting both innate and adaptive immune response
  2. Decreased phagocytes (macrophages) => decrease trafficking, decrease phagocytosis, decrease release of proteolytic enzymes
  3. lymphopenia (reduced T and B cells, reduced cytokine gene expression, reduced ab production)
33
Q

Side effects of corticosteroids:

  • metabolic:
  • other effects:
  • immune system:
A

Side effects of corticosteroids:

  • metabolic: diabetes, central obesity, moon face, lipid abnormalities, osteoporosis, hirsutism, adrenal suppression
  • other effects: cataracts, glaucoma, peptic ulceration, pancreatitis, avascular necrosis
  • immune system: immunosuppression => infection
34
Q

Anti-proliferative immunosuppressants:

  • name 3 drugs of this class
  • MOA
A

Anti-proliferative immunosuppressants:

  • name 3 drugs of this class:

1. cyclophosphamide

2. mycophenolate

3. azathioprine

  • MOA = inhibit DNA synthesis => cells with rapid turnover most sensitive
35
Q

Describe the toxicities associated with anti-proliferative immunosuppressants

A

Toxicity:

  • BM suppression
  • Infection
  • Malignancy
  • Teratogenic
36
Q

Cyclophosphamide - MOA

A

Cyclophosphamide - alkylating agent which alkylates guanine base of DNA => DNA damage => prevents replication (affects B cells > T cells)

37
Q

Cyclophosphamide - major indications (2)

A

Cyclophosphamide - major indications (2):

  1. Multisystem connective tissue disease or vasculitis (SLE, Wegener’s granulomatosis)

2. Cancers

38
Q

Azathioprine - MOA

A

Azathioprine - anti-metabolite => purine metabolised by liver to 6-mercaptopurine => azathioprine is a purine analogue => interferes with DNA Production => inhibits proliferating cells

(affects T cells > B cells)

39
Q

Azathioprine - indications (3)

A

Azathioprine - indications (3):

  1. Transplantation
  2. Autoimmune disease
  3. Auto-inflmmatory disease (CD, UC)
40
Q

What must you always check before prescribing someone azathioprine? and why?

A

Check TPMT activity or gene variants before treatment if possible; always check full blood count after starting therapy

  • should NOT GIVE if homozygous for a dysfunctional gene due to risk of BM suppression
41
Q

Plasmapharesis and plasma exchange - MOA

A

Plasmapharesis and plasma exchange - removal of pathogenic antibody by putting patient’s blood through cell separator

  • cellular constituents reinfused
  • plasma treated to remove Igs
42
Q

Indications for plasmapheresis (3)

A

Indications for plasmapheresis:

  1. Goodpasture’s syndrome (anti-glomerular BM abs)
  2. Severe acute myasthenia gravis (anti-AChR abs)
  3. Severe vascular rejection (anti-donor HLA abs)
43
Q

Inhibitors of cell signalling - name 4 drug types

A

Inhibitors of cell signalling:

  1. Calcineurin inhibitors
  2. mTOR inhibitors
  3. JAK inhibitors
  4. PDE4 inhibitors
44
Q

Calcineurin inhibitors:

  • 2 drug names
  • MOA
  • indications (3)
A

Calcineurin inhibitors:

  • 2 drug names = ciclosporin, tacrolimus
  • MOA = inhibit T cell proliferation/function
  • indications (3) = transplantation, SLE psoriatic arthritis
45
Q

mTOR inhibitors:

  • 1 drug name
  • MOA
  • Indications (1)
A

mTOR inhibitors:

  • 1 drug name = sirolimus
  • MOA = blocks T cell proliferation/function
  • Indications (1) = transplantation
46
Q

JAK inhibitors:

  • MOA
  • Indications (3)
A

JAK inhibitors:

  • 1 drug name = tofacitinib (JAK1 nd JAK3 inhibitor)
  • MOA = block JAK-STAT signalling
  • Indications (3) = RA, psoriatic arthritis, axial spondyloarthritis
47
Q

PDE4 inhibitors:

  • MOA
  • Indications (2)
A

PDE4 inhibitors:

  • MOA = inhibits PDE4 => increased cAMP => prevents activation of TFs => decrease cytokine function
  • Indications (2) = psoriasis, psoriatic arthritis
48
Q

Agents directed at cell surface antigens are divided into 3 groups - what are they?

A

Agents directed at cell surface antigens:

those that target

  1. T cell surface ags
  2. B cell surface ags
  3. Lymphocyte migration
49
Q

Anti-thymocyte globulin:

  • MOA
  • Indications (1)
A

Anti-thymocyte globulin:

  • MOA = lymphocyte depletion, modulation of T cell ctivation, modulation of T cell migrtion
  • Indications (1) = allograft rejection (renal, heart)
50
Q

Anti-CD25 (IL-2Ra chain) abs:

  • MOA
  • Indications (1)
A

Anti-CD25 (IL-2Ra chain) abs:

  • MOA = block IL-2R => inhibit T cell proliferation
  • Indications (1) = prophylaxis of allograft rejection (given before and after transplant surgery)
51
Q

CTLA-Ig infusion protein (abatacept):

  • MOA
  • Indications (1)
A

CTLA-Ig infusion protein (abatacept):

  • MOA = CTLA-Ig will bind to CD80 and CD86 on APCs => block the interaction of APCs with T cells => reduce T cell activation
  • Indications (1) = Rheumatoid arthritis
52
Q

Anti-CD20 (rituximab):

  • MOA
  • Indications (3)
A

Anti-CD20 (rituximab):

  • MOA = block CD20 on B cells => deplete mature B cells
  • Indications (3) = B cell lymphoma, RA, SLE
53
Q

Anti-alpha4beta7 integrin:

  • MOA
  • Indications
A

Anti-alpha4beta7 integrin:

  • MOA = inhibits leukocyte migration by blocking rolling/arrest
  • Indications: IBD
54
Q

Name some (6) agents directed at cytokines for immunosuppression

A

anti-TNF alpha

anti-IL-1

anti-IL-6

anti-IL17/23

anti-IL4/5/13

anti-RANK ligand

55
Q

Anti-TNF-alpha therapy:

  • MOA
  • Indications (5)
A

Anti-TNF-alpha therapy:

  • MOA = depends on whether ab or antagonist is used, but essentially both inhibit TNF-a
  • Indications (5) =

1. RA

2. Ankylosing spondylitis

3. Psoriasis

4. Psoriatic arthritis

5. IBD

56
Q

Anti-IL-1 abs:

  • MOA
  • Indications (3)
A

Anti-IL-1 abs:

  • MOA = block downstream actions of inflammasome
  • Indications (3):

1. Fmilial Mediterraenean Fever

2. Gout

3. Adult onset Still’s Disease

57
Q

Anti-IL-6 abs:

  • MOA
  • Indications (1)
A

Anti-IL-6 abs:

  • MOA = block IL-6 which is an important plyer in inflammtion in RA
  • Indications (1) = RA
58
Q

Anti-IL23 and anti-IL17:

  • Indications (4)
A

Anti-IL23 and anti-IL17:

  • Indications (4):

1. Axial spondyloarthritis

2. Psoriasis

3. Psoriatic arthritis

4. IBD (not IL-17)

59
Q

Anti-IL4, anti-IL5, anti-IL13

  • Indications (2)
A

Anti-IL4, anti-IL5, anti-IL13

  • Indications:

1. Asthma

2. Eczema

60
Q

anti-RANKL ab:

  • MOA
  • Indications
A

anti-RANKL ab:

  • MOA = RANKL expressed on osteoblasts, RANK on osteoclasts and the interaction leads to osteoclast activation! these abs act ike OPG and block the interaction, reducing osteoclast function
  • Indications = osteoporosis
61
Q

Side-effects of biologic agents:

  • infusion reaction S/Es
  • Injection site reaction S/Es
A

Side-effects of biologic agents:

  • infusion reaction S/Es = urticaria, hypotension, tachycardia, wheeze, headaches, fevers, myalgia
  • Injection site reaction S/Es = rash
62
Q

Before immunosuppressive therapy is initiated, which chronic (latent) infections could reactivate?

A
  1. TB
  2. HBV HCV
  3. HIV
  4. John Cunningham virus (JCV)
63
Q

What disease arises from reactivation of John Cunningham virus (JCV)?

A

Progressive multifocal leukoencephalopathy (PMFL)

64
Q

Side effects (4) of long-term immunosuppression

A

Side effects (4) of long-term immunosuppression:

  1. Infection
  2. Reactivation of latent infections (TB) and worsening of chronic infections (HIV)
  3. Malignancy
  4. Autoimmunity (SLE)
65
Q

A young woman with SLE is experiencing wieght gain, easy bruising, poor sleep, a raised HbA1c, and falling bone density. Which drug is she taking?

A) Azathioprine

B) Anti-CD20 ab

C) Mycophenolate

D) Prednisolone

A

D) Prednisolone

66
Q

Rituximb is a monoclonal ab specific for CD20 on B cells. For which f the following is it an effective treatment?

A) Ankylosing spondylitis

B) Malignant melanome

C) Multiple Sclerosis

D) Osteoporosis

E) Rheumatoid arthritis

A

E) Rheumatoid arthritis

67
Q

Which of the following are true about psoriasis and psoriatic arthritis?

A) Responds to inhibition of RANKL

B) Responds to CAR-T cells

C) Treatment options include IL-6 blockade or B cell depletion with rituximab

D) Treatment options include inhibition of TNF-a, inhibition of IL-12/23, or IL-17A, or use of a PD4 blocker or ciclosporin

E) Responds to use of checkpoint inhibitors such as nivolumab

A

D) Treatment options include inhibition of TNF-a, inhibition of IL-12/23, or IL-17A, or use of a PD4 blocker or ciclosporin

Pathology by week (70 decks)

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