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Immunology Y5 > Immunology 7 - Immune-modulating therapies 1 & 2 > Flashcards

Immunology 7 - Immune-modulating therapies 1 & 2 Flashcards

1
Q

What mediates immunological memory?

WHat are the characteirstics of memory T cells and memory B cells?

A

T and B cells

T cells

  • different expression of cell surface markers - allows migration to non-lymphoid tissue where microbes may enter
  • longevity
  • rapid, robust response to subsequent antigen exposure

B cells

  • lonevity
  • pre-formed antibody - IgG, high affinity
  • rapid, robust response to subsequent antigen exposure
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2
Q

By what mechanism can B cells provide immunological memory?

A

High affinity IgG remains circulating in blood

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3
Q

What antibody is used in influenza vaccine?

WHen does the vaccine start to work and how long is it effective for?

A

Antibody against haemagluttinin - this is the protein used by influenza to enter the cell

Starts working after 7 days; provides protection for up to 6 months

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4
Q

What is the best predictor of immunity to influenza following a vaccine?

A

IgG against haemaglutinnin (moreso than CD8 T cells)

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5
Q

Why is adjuvant used in some vaccines?

A

It stimulates an innate immune response

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6
Q

What are the indications for antibody replacement in a patient (general antibody replacement) and what is the process?

A
  1. Prepare from a pool of donors
  2. Infusion will contain IgG to a wide range of unspecified organisms
  3. Administer either IV or subcutaneously

Indications:

  • Primary antibody deficiency (3):
    • X-linked agammaglobulinaemia
    • X-linked hyper IgM syndrome
    • Common variable immune deficiency
  • Secondary antibody deficiency (3):Haematological malignancies:
    • CLL
    • Multiple myeloma
    • After bone marrow transplantation
  • Ohers
    • ITP
    • kawasaki’s disease
    • guillan barre syndrome
    • measles
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7
Q

Give examples of specific immunoglobulins that can be given to patients

A

Hep B

tetanus

rabies

VZV

HIV - post exposure prophylaxis contains HIV immunoglobulin

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8
Q

explain the 4 main ways of adoptive cell transfer

A
  1. virus specific T cell expansion
    - used to prevent EBV associated post transplant lymphoproliferative disease
    - you take out T cells from Patient/another donor and inject virus (EBV) so the T cells are now able to mount an immune response against EBV
    - the active T cells can then be transferred back to the patient so after the transplant they can mount a response against EBV
  2. Tumour infiltrating lymphocyte (TIL) T cell therapy
    - take tumour out and culture with IL2
    - this stimulates T cell expansion within population
    - isolate the T cells and inject them back into the patient
  3. T cell receptor T cell therapy
    - take out T cells from patient with malignancy
    - insert gene that codes for specific TCR - targeting tumour surface antigen

eg CD19 to target ALL

  1. Chimeric antigen receptor T cell therapy
    - like T cell receptor T cell therapy but with chimeric antigen receptor (made of an antibody and TCR)
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9
Q

What monoclonal antibody can be used in melanoma treatment?

A

Ipilimumab (anti-CTLA4) or Nivolumab, an antibody specific for PD-1

These are immune checkpoint inhibitors - enhance the T cell response

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10
Q

In what disease can IFN gamma be given therapeutically?

A

Chronic granulomatous disease

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11
Q

In what disease can IL2 be given therapeutically?

A

Renal cell carcinoma
IL-2 expands NK and T cell responses via the IL-2 surface receptor

**think you have 2 kidneys; IL2**

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12
Q

In what diseases can INF alpha be given therapeutically?

what about interferon beta?

A
  1. Interferon alpha

ABC

Alpha for hepB

CML

+ multiple myeloma

+ hairy cell leukamiea

  1. interferon beta
    - relapsing MS (past)
  2. bechet’s (B FOR BECEHETS)
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13
Q

How do steroids inhibit the immune response?

Side effects of corticosteroids

A

Inhibit phospholipase A2 which is a key enzyme in prostaglandin formation
Also decrease phagocyte trafficking (hence there is a transient increase in neutrophil count)

Also cause lymphopenia - as lymphocytes get sequestered in lymphoid tissue

Side effects

Metabolic effects:

  • Cushingoid Sx
    • Diabetes
    • central obesity
    • moon face
    • lipid abnormalities
    • osteoporosis
    • hirsutism
    • adrenal suppression
  • Other effects:
    • Cataracts
    • glaucoma
    • peptic ulceration
    • pancreatitis
    • avascular necrosis of hip and knee
  • Immunosuppression

Can use the mnemonic BECLOMETHASONE

Buffalo hump

Easy bruising

Cataracts

Larger appetite

Obesity

Moonface

Euphoria

Thin arms & legs

Hypertension/ Hyperglycaemia

Avascular necrosis of femoral head

Skin thinning

Osteoporosis

Negative nitrogen balance

Emotional lability

*causes transient leukocytosis and neutrophilia

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14
Q

Recall 4 examples of anti-proliferative agents

A

Cyclophosphamide
Azothioprine
Mycophenalate

METHOTREXATE

CAMM

**not calcineurin inhibitors

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15
Q

What is the mechanism of action of cyclophosphamide?

A

Alkylating agent.

Alkylation of guanine –> inhibition of DNA synthesis (damages DNA)

*can’t use for too long due to toxicity

B cells > T cells

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16
Q

Side effects of cyclophosphamide

A
  • Toxic to proliferating cells:
    • Bone marrow suppression
    • Hair loss
    • Sterility (male >> female)
  • Haemorrhagic cystitis
  • Malignancy:
    • Bladder cancer
    • Haematological malignancies
    • Non-melanoma skin cancer
  • Infection:
    • Pneumocystis jirovei

MAIN ONES TO. BE AWARE OF: HAEMORRHAGIC CYSTITIS

(C AND C)

as it is excreted by the kidneys

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17
Q

What is the mechanism of action of azothioprine?

A

6-mercaptupurine : it’s a purine analogue

That interferes with normal purine synthesis

Affects T cells > B cells

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18
Q

What must always be checked before prescribing azothioprine?

A

TPMT activity

polymorphism means that they cannot metabolise azathioprine which leads to excess bone marrow toxicity

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19
Q

Explain how methotrexate works, main side effects to be aware of

A
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20
Q

How can plasma exchange be used to treat autoimmune diseases?

A

Removes problematic antibody (in exchange - you exchange it for albumin)
Need to give alongside an antiproliferative agent as it can cause a rebound increase in antibody production…
Only for severe disease

Indications: type II hypersensitivity reactions eg goodpasture’s, myasthenia gravis, vascular rejection, antibody mediated rejection

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21
Q

How do calcineurin inhibitors work?

A

Calcineurin causes an upregulation of IL2 - inhibition of this allows cell proliferation

**rmb il2 is a key cytokine that drives T cell proliferation**

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22
Q

Examples of inhibitors of cell signalling

A
  1. calcineurin inhibitors
  2. JAK inhibitors
  3. PDE4 inhibitors

(also mTor inhibitor - sirolimus- inhibits IL2 pathway)

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23
Q

Give examples of a calcineurin inhibitor?

Mechanism?

Tacrolimus vs ciclosporin

A

Ciclosporin and tacrolimus

*inhibit calcineurin production which inhibits IL2 production (T cell activation and proliferation is blocked)

Indications: rejection prophylaxis in transplantation

Side effects: Nephrotoxic, hypertension, neurotoxic (+ dysmorphic features + gingival hyperrophy with ciclosporin)

CICLOSPORIN HAS MORE SIDE EFFECTS THAN TACROLIMUS

**cycling is dangerous** **taxi is safe**

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24
Q

Give 2 diseases in which JAK2 inhibitors can be useful?

Example

A

Rheumatoid and psoriatic arthritis

Tofacitinib- Jak1/3 inhibitor

**none of the haematological malignancies!!

rmb PCV is treated with venesection

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25
By what mechanism do PDE4 inhibitors work, and in what disease are they useful?
Inhibition of PDE4 --\> inceased cAMP cAMP modulates cytokine production --\> fewer cytokines **Useful in psoriasis and psoriatic arthritis** **Example: Apremilast**
26
Recall 2 immune-modulating therapies that are useful in the prophylaxis of allograft rejection
Anti-thymocyte globulin - blocks T cell proliferation Anti-CD25- daclizumab
27
Wha type of antibody is rituximab?
Anti-CD20 attacks mature B cells, but leaves plasma cells intact, so antibody production is not affected much Uses: * lymphoma * rheumatoid arthritis * SLE * vasculitis
28
What monoclonal antibody can be used in IBD treatment?
Vedolizumab Anti - alpha4beta7 integrin
29
What is infliximab? Indications
Anti-TNF alpha Indications: \ Rheumatoid arthritis Ankylosing spondylitis IBD Psoriasis and psoriatic arthritis Familial Mediterranean feve
30
What monoclonal therapy can be used in osteoporosis?
anti-RANK/RANK-ligand Denosumab
31
What is the mechanism of action of tofacitinib
JAK inhibition (jak 1 or jak 3)
32
What is the mechanism of action of apremilast?
Anti-PDE4
33
What is the mechanism of action of basilixumab?
Anti-CD25 (alpha chain of interleukin 2 receptor)
34
What is the mechanism of action of Abatacept? when is it used?
CTLA4 infused immuonglobulin it enhances the activity of CTLA4 (opposite of imilimumab) used in rhuemtaoid arthritis
35
What is the mechanism of action of rituximab?
Anti-CD20
36
What is the mechanism of action of natalizumab?
Anti-alpha4 integrin
37
What is the mechanism of action of tocilizumab?
Anti-IL6-R
38
What is the mechanism of action of muromonab
Mouse monoclonal against CD3 3 vowels in this
39
What is the mechanism of action of dacilizumab?
Anti-CD25 (alpha chain of interleukin 2)
40
What is the mechanism of action of alemtuzumab?
Anti-CD52 used in chronic lymphoid leukaemia and MS side effect: CMV infection alemtuzimab- ALL- targets all lymphocytes (cd52 is on all lymphocytes) lymphocytes--\>chronic lymphoid leukaemia and ms (which is type 4 hypersenstiivty) ms
41
What is the mechanism of action of adalizumab?
Anti-TNF alpha
42
What is the mechanism of action of certolizumab?
Anti-TNF alpha
43
What is the mechanism of action of golimumab?
anti-TNF alpha
44
What is the mechanism of action of etanercept?
anti-TNF alpha/TNF beta fusion protein
45
What is the mechanism of action of ustekinumab?
Anti-IL12/23
46
What is the mechanism of action of Secukinumab?
Anti-IL17a
47
What condition can be treated with apremilast?
Psoriasis
48
What conditions can be treated with natalizumab?
MS Crohn's
49
What conditions can be treated with abatacept?
Rheumatoid arthritis
50
What type of vaccine is BcG vaccine? How do you test for response to BcG vaccine?
Live attenuated Relies on T cell response Protects against primary infection and prevents progression to secondary infection as well protection lasts about 10-15 years Mantoux test - tests development of immunity against TB. must be interpreted with caution - can suggest active TB, latent TB or previous immunisation
51
Examples of live attenuated vaccines C/I
* MMR-VBOY * MMR- HIV safe * VZV * BCG- not HIV safe * ORAL * Polio (Sabin oral) * Typhoid (oral) * Yellow fever- not HIV safe C/I: immunosuppressed/pregnant
52
Examples of inactivated vaccines
* **Influenza** * **Cholera** * Bubonic plague * Polio (Salk) * **Hepatitis A** * **Pertussis** * Rabies rich bpp \*rich ppl; high bp
53
Examples of subunit vaccines
* HepB * HPV * Influenza (HA, NA (Neuraminidase)) HHI
54
Examples of toxoid vaccines
tetanus diphtheria
55
Conjugate vaccines
* Neisseria meningitidis * Haemophilus influenza B * Streptococcus pneumoniae Conjugate aids production of T cell response- allows germinal centre reaction to occur.
56
What is a heteortypic pathogen?
Pathogen that infects other animals but does not cause disease or causes mild disease in humans
57
Indications for stem cell transplant
* Life-threatening primary immunodeficiencies * SCID * Leukocyte adhesion defect * Haematopoietic malignancy
58
Types of antibody replacement
1. normal human immunoglobulin - used for antibody deficiency (primary or secondary) 2. specific - eg VZ Ig, HBV Ig etc. used for post exposure prophylaxis when person has not been exposed to the organism before
59
which cytokine is responsible for T cell clonal expansion?
IL-2
60
61
Indications for CAR-T cell therapy Main side effect
- not effective for solid malignancies * B cell lymphoma * ALL in kids * non - hodgkin's lymphoma \*\*think cars are moving/mobile--\>not useful for solid malignancies, only for haematologicla malignancies\*\* Cytokine release syndrome
62
Side effects of azathioprine
BM suppression hepatotoxicity Infection
63
MOA of mycophenolate mofetanil What is the main risk associated with this?
A purine anti-metabolite It blocks de novo guanosine nucleotide synthesis → \*\*\*\*prevents DNA replication Also affects T cells\>B cells Main risk: bone marrow suppression, infection - HERPES VIRUS REACTIVATION, PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY, malignancy, teratogenic **_mycoPhenolate- Pml_**
64
Antibodies against IL-6 receptor
Tocilizumab, Sarlimumab Inhibits action of macrophages, neutrophils, B cells and T cells Used in rheumatoid arthritis, castleman's disease (IL6 producing tumour)
65
Example of TNF alpha antagonist
Etanercept Blocks action of TNF alpha by blocking the receptor Used in: * Rheumatoid arthritis * Ankylosing spondylitis * Psoriasis/ Resistant Psoriasis and psoriatic arthritis RAP (rapping has INTERCEPTED the music industry) rheumatoid arthritis ankylosing spondilitis psoriasis
66
Importance of IL12 and IL23
IL12: promotes Th1 differentiation IL23: promotes Th17 cell production
67
Example of drug against IL12 and IL23
Ustekinumab ## Footnote Psoriasis and psoriatic arthritis Crohn’s disease **u-stick- --\> needlestick injjury to SKIN--\>psoriasis/psoriatic arthritis**
68
Example of drug against IL-12
Guselkumab
69
Drug against IL-17 alpha
Psoriasis and psoriatic arthritis Ankylosing spondylitis
70
Which vaccines must be given to people on immunosuppressive treatment?
Pneumococcal and influenza
71
Which organism are you more susceptible to if on TNF blockers?
Tuberculosis
72
Which monoclonal antibody is associtaed with HepB reactivation?
Rituximab cd20- is on **B cells** hep**B**
73
Which virus leads to progressive multifocal leukoencephalopathy?
JC virus \*commonly reactivates following treatment with natalizumab for multiple sclerosis
74
Summarise the ways in which the immune system can. be boosted
75
Summary of ways in whcih the immune system can be suppressed
76
Live attenuated vaccines: advantages and disadvanatgaes and examples
77
which is the only live attnuated vaccine that is safe to give in HIV?
MMR
78
Inactivated vaccines: advantages and disadvantages and examples
inactivated: SHIA Salk Hep A Influenza Anthrax
79
Conjugate vaccines
80
DNA/RNA vaccines
81
What are the ky adjuvants used in vaccines?
\*\*key one to remember is aluminium
82
83
What are the key passive vaccines to know about? how long do they usually last?
HNIG- human noromal immunoglobulin - given for hep A and measles HBIG HRIG- rabies varicella zoster pavilizumab- against RSV regeneron- experimental for covid 19 \*\*usuallyy last about 3 weeks so don't give longterm protection
84
Which vaccines do at risk groups need to get?
influenza pcv bcg
85
which vaccine sneed to be given to epopel who travel?
cholera hep A hep B ja encephalphilitis tick bourne encephalitis typhoid yellow fever
86
which vaccines do pregnant women need to get?
pertusssis
87
which vaccine is important in people aged 70-79
shingles vaccine
88
89
what is the full form of bcg?
bacilli calmette guerin
90
Describe how dendritic vaccines against tumours work (nB these are still being trialeld and have not been rolled out)
* Acquired defects in DC maturation and function is associated with some malignancies * This suggests a rationale for using \*ex vivo-\*generated DC pulsed with tumour antigens as vaccines * You can take the dendritic cells out of a patient and load them with the appropriate antigen in vitro * Then insert them back into the patient so there is an immune response towards it * It focuses on tumour associated antigens or mutational antigens Process: * Blood draw * Leukapheresis- remove WBCs from patient's blood * Incubate APCs with prostatic acid phosphatase (present in prostate cancer) * AND GM-CSF (promoted dendritic cell proliferation) * APCs are infused back into patient * Loaded dendritic cells stimulate the patient's immune response against prostatic acid phosphatase → killing the prostate cancer cells
91
Why doesn't vaccination work effectively in the elderly?
Immune senescence: Increased frequency of terminally differentiated effector memory T cells in the elderly; Increased expression of senescence markers; Much reduced production of recent thymic emigrants which drive the naïve T-cell repertoire. Nutrition: insufficient energy because of poor nutrition; Reduced availability of trace elements and minerals (reduced gut absorption)
92
What are some indications of CAR-T cell therapy? what is a key risk?
1. B cell lympoma - can engineer chimeric antigen receptor to express CD19 receptor - binds to CD19 on malignant B cells and kills them 2. ALL in kids 3. some forms of NHL key risk: cytokine release syndrome
93
what is the normal physiological function of CTLA4 and how is it used for therapeutic purposes? what about PD1?
**CTLA4** - normally it is expressed on T cells (eg CD8 positive T cells) - it competes with CD28 for binding to B7 on antigen presenting cells - i.e. it inhibits the activation of T cells by Antigen presenting cells - if you block it, there will be more antigen presentation to T cells --\>ipilimumab - antibody specific for CTLA4 --\>used in advanced melanoma **PD1/PDL1** - PD Ligand 1 and 2 found on APCs/tumour cells - they bind to PDL1 on T cells to inactivate them - if you block PD1 then T cells can be activated --\> kill tumour cells Side effects - risk of autoimmune disease
94
What is rabbit anti thymocyte globulin?
Blocks T cell proliferation (Thymus- T cells) used in allograft rejection
95
What is daclizumab?
IL-2 receptor antibody, targets CD25 Organ transplant rejection
96
What are all the anti TNF alpha antibodies?
97
Injection site reactions vs infusion reactions
infusions are deeper into the body IgE is a worse reaction - more systemic
98
ankylosing spondilitis: you have tried NSAIDS and have tried anti TNFalpha, what else can you give?
anti IL17

Immunology Y5 (11 decks)

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