Year 5 - Pathology > IMMUNO: Immune modulating therapies > Flashcards

IMMUNO: Immune modulating therapies Flashcards

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1
Q

List 4 methods for boosting the immune response.

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

List 4 methods for suppressing the immune response.

A
  • Steroids
  • Anti-proliferative agents
  • Plasmapheresis
  • Inhibitors of cell signalling
  • Agents directed at cell surface antigens
  • Agents directed at cytokines
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3
Q

What event in history showed us that immune memory exists?

A

Measles and memory – a 1781 epidemic on the Faroe Islands proved immune memory existed and protected people for the rest of their lives. It wasn’t until after this generation passed away that another measles pandemic broke out

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4
Q

Adaptive immune response to vaccination:

  1. B and T cells
  2. Wide repertoire of antigen receptors: can create 1011 to 1012 receptors
  3. Exquisite specificity
  4. Clonal expansion
  5. Immunological memory
A

APCs

APCs present peptides to T cells to initiate an acquired immune response.

APCs include:

  • DCs,
  • macrophages (incl Langerhans cells, mesangial cells,Kupffer cells, osteoclasts, microglia etc),
  • B cells
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5
Q

What are the two main components of immunological memory?

A
  1. High affinity specific antibodies - pre-formed pool
  2. Specific T and B cells - residual pool with enhanced capacity to respond if re-infection occurs
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6
Q

Describe the process of clonal expansion (including T and B cells).

A

T cells with appropriate specificity will proliferate and differentiate –> effector cells (cytokine secreting, cytotoxic)

B cells with appropriate specificity will proliferate –>

  1. T cell independent IgM plasma and memory cells
  2. T cell dependent IgG/A/E, memory and plasma cells in germinal centre reaction
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7
Q

Which cell population is most involved in immunological memory?

A

CD8 +ve T cells

Activated when antigen is presented to CD8 +ve T cells through APCs –> clonal expansion and one of two fates: death by apoptosis (MOST) or survival as memory cells.

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8
Q

In generation of immunological memory, what aids clonal expansion of CD8 +ve T cells?

A

IL-2 from T helper cells

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9
Q

B cell response

A
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10
Q

Summarise the characteristics of the T and B cell memory responses.

A

T cells:

  1. Longevity - Memory cells maintained for long time without antigen by continual low-level proliferation in response to cytokines
  2. Expression of different cell surface proteins involved in chemotaxis / cell adhesion - allow memory cells to access non-lymphoid tissues
  3. Rapid, robust response to subsequent exposure - due are more memory cells. These cells are more easily activated than naïve cells

B cell memory:

  1. Pre-formed antibody - Circulating high affinity IgG antibodies
  2. Longevity - Long lived memory B cells and plasma cells
  3. Rapid, robust response to subsequent exposure - Memory B cells more easily and rapidly activated than naïve
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11
Q

How is longevity of the T cell memory response maintained?

A

By continual low-level proliferation in response to cytokines

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12
Q

What do we want from a vaccine?

A
  1. Memory
  2. No adverse reactions
  3. Practical e.g. one shot, easy stoarge, inexpensive
  4. Response should be protective
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13
Q

What is the protective immunological factor in influenza?

A

Although CD8 T cells control the virus load in influenza, it is antibody which provides a protective response

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14
Q

What is target for vaccines in influenza and why?

A

HA (haemagglutinin) - this is the receptor-binding and membrane fusion glycoprotein of influenza and the target for infectivity-neutralising Abs

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15
Q

How do you detect antibodies to Influenza?

A

Antibodies can be detected using a haemagglutinin inhibition assay__: add patient’s serum (at various dilutions) to a plate of RBC and Influenza virus

  1. Cells clump at bottom of the plate forming a red spot = normal red cells in a dish (no HA or there are anti-HA antibodies present in the patient’s serum)
  2. Diffuse coloration across the well = HA of influenza virus making the RBCs haemagluttinate (no antibodies present)
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16
Q

What receptor on RBC is responsible for haemagluttination?

A

Sialic acid receprors on RBC bind to the HA of influenza virus

Inhibited by antibodies to HA

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17
Q

Can you measure the level of HA antibodies in influenza using this assay?

A

The higher the dilution with an inhibitory effect, the greater level of antibodies the patient has against HA

Higher antibody means lower risk of infection

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18
Q

When does protection begin and how long does it last with the influenza vaccine?

A

Antibody protection begins 7 days after vaccine and protection can last for around 6 months

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19
Q

What type of vaccine is the BCG vaccine?

A

Attenuated strain of bovine TB

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20
Q

What is the role of the BCG vaccine for TB?

A
  • Provides some protection against primary infection
  • Mainly provides protection against progression to active TB
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21
Q

Which cellular response is most important in the BCG vaccine?

A

T cell response is important in protection

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22
Q

Describe the use of the Mantoux test and its results. What does a wheal of >10mm indicate?

A

Mantoux Test – previous exposure to TB:

  • Inject a small amount of liquid tuberculin (AKA purified protein derivative / PPD) intradermally
  • Area of injection is examined 48-72 hours after tuberculin injection
  • The reaction is an area of swelling around the injection site

Positive reaction wheal:

  • >5mm (high-risk – i.e. immunocompromised, living with someone with TB)
  • >10mm (medium-risk – i.e. healthcare workers)
  • >15mm (low-risk)
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23
Q
A

B and T cells

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24
Q

Which of these vaccines should you not give to an immunosuppressed individual?

  • BCG
  • Diphtheria toxoid
  • Influenza inactivated
  • Polio injected
  • mRNA COVID
A

BCG is live; some influenza vaccines can also be live but here it was specific that it was inactivated.

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25
Nivolumab
26
List 5 different types of vaccines.
1. Live vaccines 2. Inactivated/Component vaccines - Conjugates+ Adjuvants increase immunogenicity 3. RNA vaccines 4. Adenoviral vector vaccines 5. Dendritic cell vaccines
27
List 3 examples of live attenuated vaccines.
* MMR * BCG * Yellow fever * Typhoid * Polio (Sabin) * Vaccinia
28
What are 2 advantages and disadvantages of live attenuated vaccines?
Advantages: 1. INFECTION established ideally with mild symptoms 2. BROAD immune response raised to multiple antigens (offer protection against different strains) 3. ALL phases of immunity activated (T cells, B cells – local IgA, humoral IgG, etc.) 4. LIFE-LONG immuity often conferred after one dose Disadvantages: 1. STORAGE problems 2. VIRULENCE reversion is possible 3. SPREAD to contacts (i.e. spread to immunocompromised/immunosuppressed)
29
Give an example of each of these types of vaccines: 1. Inactivated 2. Component/subunit 3. Toxoid
* Inactivated = e.g. * **influenza**, * **cholera**, * **Bubonic plague** * **polio** (Salk), * **HAV**, * **Pertussis**, * **Rabies** * Component/subunit = e.g. * **HbS** antigen (HBV) * **HPV** (capsid), * **influenza** (recombiant quadrivalent - less used now) * Toxoids (inactivated toxin) = e.g. * **diphtheria**, * **tetanus**
30
Give 2 advantages and disadvantages of inactivated/ component/ subunit/ toxoid vaccines.
Advantages: 1. NO REVERSION or mutation 2. IMMUNODEFICIENT patient safe 3. STORAGE easier 4. COST lower Disadvantages: 1. NORMAL route of infection usually not followed 2. IMMUNOGENICITY may be low 3. MULTIPLE injections may be needed 4. CONJUGATES or adjuvants may be necessary
31
What does a conjugate vaccine consist of? Give 3 examples.
Polysaccharide + protein carrier * HiB * meningococcus * pneumococcus *(All polysaccharide encapsulated)*
32
Why does a conjugate vaccine consist of both polysaccharide + protein carrier?
Polysaccharide induces a **T cell-independent B cell r**esponse _(transient)_ Protein carrier promotes **T cell-dependant B cell re**sponse _(long-term)_
33
What is the goal of adjuvants in vaccines and what natural response do they mimic?
Increase immune response **without altering specificity** Mimic action of PAMPs on TLR and other PPRs
34
Give 3 examples of adjuvants. Which is most common, safe and effective?
1. Aluminium salts/alum (used in humans) - **_most commonly used, safe and effective._** 2. Lipids (monophosphoryl lipid A, human HPV) 3. Oils (Freund's adjuvant in animals)
35
Which vaccines in alum used as an adjuvant in? What is its MOA?
Hep A, hep B and HiB **MOA not understood** but may cause slow antigen release over time to prolong stimulation or induce inflammation to trigger a greater immune response. May also activate Gr1+IL4+ eosinophils to prime naive B cells and produce an antibody response.
36
Which part of SARS-CoV2 binds to ACE2?
Spike protein - this mediates infection of cells
37
Describe the process of creating a mRNA vaccine for SARS-CoV.
1. E coli is infected with plasmids containing DNA for spike protein 2. Plasmids are harvested from the E coli cultures 3. DNA is excised from plasmids using enzymes and transcribed to mRNA 4. mRNA is complexed with lipids to envelope the mRNA into lipid nanoparticles to the to create the vaccine
38
How do mRNA vaccines work?
1. mRNA/lipid complexes are injected into muscle where it enters cells e.g. muscle, endothelial, fibroblasts, DCs 2. mRNA is translated and spike protein synthesised/expressed on surface of these cells 3. Stimulates immune response including B cells/antibodies and T cells
39
What do adenoviral vector vaccines consist of? Give 2 examples.
DNA of relevant protein (e.g. COVID spike protein) inserted into viral vector to produce vaccine 1. AZ COVID vaccine - vector: ChAdOx1-S +COVID spike protein DNA 2. Sputnik COVID vaccine - vector: adenovirus types 26 and 5 + COVID spike protein DNA
40
How do adenoviral vector vaccines work?
1. Adenovirus with specific DNA infects cells in vivo 2. This causes transcription/translation of proteins 3. Stimulates immune response including B cells, antibodies and T cells
41
What is the rationale for using dendritic cell vaccines?
Acquired defects in DCs (maturation and function) sometimes cause malignancy So perhaps using ex-vivo-generated DCs pulse with tumour antigens may be good as vaccines aimed at tumour associated antigens or mutational antigens *i.e. DCs used as APCs to present tumour antigens to immune cells*
42
Give an example of a DC vaccine and its use.
Sipuleucel-T Provenge * Personalised * Used as immunotherapy for prostatic cancer * Leukaphoresis followed by harvesting APCs and incubating them with recombinant PAP-GMCSF * APCs are infused back into the patient * Stimulates patient's own immune response \*PAP-GMCSF = Prostatic acid phosphatase-granulocyte macrophage colony stimulating factor
43
List 5 different therapies used to replace missing components of the immune system.
HSCT Specific immunoglobulin Adoptive cell transfer - T cells * Virus specific T cells * Tumour infiltrating T cells (TIL – T cell therapy) * T cell receptor T cells (TCR - T cell therapy) * Chimeric antigen receptor T cells (CAR – T cell therapy)
44
What are the indications for HSCT as a means of replacing missing components of the immune system?
Life-threatening primary immunodeficiencies e.g. SCID (Severe combined immunodeficiency) and Leukocyte adhesion defects Haematological malignancy
45
How are human normal immunoglobulin therapies prepared?
* From pools of \>1000 donors * Pre-formed IgG to a wide range of unspecified organisms * Blood products are screened for HBV, HCV and HIV and further treated to kill any live virus * Administered IV/SC e.g. Sandoglobulin, Gammar PIV, Panglobulin
46
What are the indications for antobody replacement therapy?
**Primary antibody deficiency** * X linked agammaglobulinaemia * X linked hyper IgM syndrome * Common variable immune deficiency (CVID) **Secondary antibody deficiency** * **Haematological malignancies e.g.** Chronic lymphocytic leukaemia, Multiple myeloma * **After bone marrow transplantation**
47
Give 4 examples of specific human immunoglobulins.
* **HBV Ig**– needle stick/bite/sexual contact – from HepBSag+ve individual * **Rabies Ig**– to bite site following potential rabies exposure * **VZV Ig**– women \<20 weeks pregnancy or immunosuppressed where aciclovir or valaciclovir is contraindicated * **Tetanus Ig**– no specific preparation available in UK – use IVIG for suspected tetanus
48
What are the indications for specific immunoglobulin use?
PEP (post-exposure prophylaxis) NB: the Ig is derived from donors with high tires of IgG antibodies to specific pathogens
49
How do virus specific T cell therapies work? What are the uses?
See diagram: basics are that PMBCs are stimulated with the antigen ex vivo to expand the specific cells which can then be reinfused. Use: 1. EBV related B cell lymphoproliferative disease 2. Severe persistent viral infection in immunocompromise
50
How do tumour infiltrating lymphocyte (TIL) therapies work?
51
How do TCR and CAR-T cell therapies work? e.g. targeting CD19
T cells with chimeric receptors targeting CD19: * Patient’s own T cells * Genetically engineered to express receptor * Expanded in vitro
52
What are the uses of CAR-T cell therapies?
Example: CD3xi – CD28 – scFv(CD19) * Acute lymphoblastic leukaemia in children * Non-Hodgkin lymphoma - some forms ***CAR T cells less successful in solid tumours***
53
Give 3 examples of antibodies used for blocking immune checkpoints.
* Ipilimumab - specific for CTLA-4 * Pembrolizumab and Nivolumab - specific for PD-1
54
What is the MOA of Ipilimumab?
* Antibody binds to CTLA4 * Blocks immune checkpoint * Allows T cell activation
55
What are the indications for anti-CTLA4 antibody use and what is a complication?
Indication: advanced melanoma Complication: autoimmunity
56
What is the MOA of pembrolizumab and nivolumab?
* Antibody binds to PD-1 * Blocks immune checkpoint * Allows T cell activation
57
What are the indications for use of pembrolizumab and nivolumab? What is a complication?
Indications: * Advanced melanoma * Metastatic renal cell cancer Complication: autoimmunity
58
Give 4 examples of uses of recmbinant cytokines in clinical practice.
* **Interleukin 2** – stimulate T cell response - Renal cell cancer * **Interferon alpha 2a** – immunomodulatory effect - Behcet’s * **Interferon alpha** – antiviral effect - Hepatitis B; Hepatitis C (with ribavirin) * **Interferon gamma** – enhance macrophage function; Chronic granulomatous disease
59
Which recombinant cytokines are used in these conditions? 1. Behcet's 2. Renal cell carcinoma 3. Chronic granulomatous disease 4. HBV 5. HCV
1. **Interferon alpha 2a** – immunomodulatory effect - Behcet’s 2. **Interleukin 2** – stimulate T cell response - Renal cell cancer 3. **Interferon gamma** – enhance macrophage function; Chronic granulomatous disease 4. **Interferon alpha** – antiviral effect - Hepatitis B; Hepatitis C (with ribavirin) 5. **Interferon alpha** – antiviral effect - Hepatitis B; Hepatitis C (with ribavirin)
60
[Suppressing the immune system] What are corticosteroids, their activity and comparison to endogenous secretion of such steroid?
**Synthetic glucocorticoids** based upon naturally occuring steroids **No mineralocorticoid** activity Prednisolone (or precursor prednisone then metabolised by liver into this) Endogenous secretion equivalent to 3-4 mg prednisolone
61
What are the uses of corticosteroids?
1. Allergic disorders 2. Auto-immune disease 3. Auto-inflammatory diseases 4. Transplantation 5. Malignant disease
62
What is the effect of corticosteroids on prostaglandins?
**Act to inhibit phospholipase A2** Phospholipase A2 usually breaks down phospholipids to form arachidonic acid which is converted to eicosanoids (eg prostaglandins, leukotrienes) by cyclo-oxygenases Corticosteroids therefore block arachidonic acid and prostaglandin formation and so reduce inflammation
63
What is the effect of corticosteroid on phagocytes?
Decreased traffic of phagocytes to inflamed tissue via: 1. Decreased expression of adhesion molecules on endothelium 2. Blocks the signals that tell immune cells to move from bloodstream and into tissues 3. Results in transient increase in neutrophil counts Decreased phagocytosis Decreased release of proteolytic enzymes
64
What are the effects of corticosteroids on lymphocyte function? Which lymphocytes are most affected?
Lymphopenia - Sequestration of lymphocytes in lymphoid tissue --\> affects CD4+ T cells \> CD8+ T cells \> B cells Blocks cytokine gene expression Decreased antibody production Promotes apoptosis
65
What are the SE of corticosteroids?
Metabolic - diabetes, central obesity, moon face, lipid abnormalities, osteoporosis, hirsuism, adrenal suppression Other - Cataracts, glaucoma, peptic ulceration, pancreatitis, avascular necrosis Immunosuppression - can lead to infection
66
What are cytotoxic agents? List 3 examples of drugs with this action.
= anti-proliferatiev immunosuppressants Drugs (selected) 1. Cyclophosphamide 2. Mycophenolate 3. Azathioprine
67
What is the MOA of cytotoxic agents in general? What toxicity/SE can occur?
_Action_ - **Inhibit DNA synthesi**s. Cells with rapid turnover most sensitive _Toxicity_ * Bone marrow suppression * Infection * Malignancy * Teratogenic
68
What are the SE 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
69
Which infection are those on cyclophosphamide at risk of?
PCP
70
What are 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 * Check for TPMT polymphormism! * Hepatotoxicity - uncommon * Infection **- Serious infection less common than with cyclophosphamide**
71
What should you always check for when starting azathioprine and why?
Thiopurine methyltransferase (TPMT) polymorphisms --\> **unable to metabolise azathioprine --\> bone marrow suppression** SO check TPMT activity or gene variants before treatment if possible + always check FBCafter starting therapy
72
What are the side effects of MMF?
MMF = Mycophenolate mofentil ## Footnote **Bone marrow suppression** - Cells with rapid turnover (leucocytes and platelets) are particularly sensitive **Infection** - Particular risk of herpes virus reactivation and PML risk (JC virus)
73
What is the aim of plasmapharesis?
**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’)
74
What are the problems with plasmapharesis and plasma exchange?
Rebound antibody production limits efficacy, therefore usually given with anti-proliferative agent
75
What category of hypersensitivity do most indications for plasmapharesis fall into?
type II hypersensitivity - the antibody itself is directly pathogenic
76
What are the indications for plasmapharesis?
**Severe antibody-mediated disease e.g.** 1. Goodpasture syndrome - anti-glomerular basement membrane antibodies 2. Severe acute myasthenia gravis - Anti-AChR antibodies 3. Antibody mediated transplant rejection/ABO incompatible - Ab directed at donor HLA/AB molecules
77
What is the MOA of calcineurin inhibitors? What are 3 uses?
Inhibit **T cell proliferation/function via:** * reducing IL-2 production + IL-2R expression, --\> reduction in T-cell activation after successful APC interaction * This results in reduced clonal expansion and proliferation Used in: 1. Transplantation 2. SLE 3. Psoriatic arthritis
78
Give 2 examples of calcineurin inhibitors.
* Ciclosporin * Tacrolimus
79
What is the use of mTOR inhibitors and what is their use? Give one example.
Inihibit cell signalling particularly T cell proliferation and function. Used in transplantation Example: Rapamycin (Sirolimus)
80
What is the MOA of JAK inhibitors? What conditions are they used in?
AKA Jakinibs **MOA** * Inhibit JAK-STAT signalling (associated with cytokine receptors) * Influences gene transcription * Inhibits production of inflammatory molecules **Uses**: Rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis
81
What is the use of PDE4 inhibitors? What is their MOA?
They are a cell signalling inhibitor e.g. Apremilast. _MOA_ * Inhibition of PDE4 leads to increase in cAMP * Influences gene transcription via protein kinase A pathway * Modulates cytokine production Uses: psoriasis and psoriatic arthritis
82
Give 4 examples of agents directed at cell surface antigens in suppressing the immune response.
1. Rabbit anti-thymocyte globulin 2. Basiliximab – anti-CD25 3. Abatacept – CTLA4-Ig 4. Rituximab – anti-CD20 5. Vedolizumab – anti-a4b7 integrin Actions include * Block signalling * Cell depletion * Inhibit migration
83
What component of the immune system do each of these act on? 1. Rabbit anti-thymocyte globulin 2. Basiliximab – anti-CD25 3. Abatacept – CTLA4-Ig 4. Rituximab – anti-CD20 5. Vedolizumab – anti-a4b7 integrin
* 1-3 T cells * 4 - B cells * 5 - lymphocyte migration
84
What are the uses of anti-thymocyte globulin?
Allograft rejection (renal, heart) - given with daily IV infusion
85
What is the MOA of anti-thymocyte globulin? What are the SE?
MOA: 1. Lymphocyte depletion 2. Modulation of T cell activation 3. Modulation of T cell migration SE/toxicity: * Infusion reactions * Leukopenia * Infection * Malignancy
86
What are the indications for use of antibody directed at CD25 (IL-2Ralpha chain) e.g. Basiliximab?
Prophylaxis of allograft rejection - given via IV before and after transplant surgery
87
What is the MOA of antibody directed at CD25 (IL-2Ra chain) e.g. Basiliximab? What are the SE/toxocity?
MOA- Blocks IL-2 induced signalling and inhibits T cell proliferation Toxicity * Infusion reaction * Infection * Concern re long term risk malignancy
88
What is the use of CTLA-4Ig fusion proteins e.g. Abatacept?
**Rheumatoid arthritis -** IV 4 weekly or SC weekly
89
What is the MOA and SE of CTLA-4Ig fusion protein?
MOA - reduces costimulation of T cells via CD28 SE: * Infusion rection * Infection (TB, HBV, HCV) * Caution with malignancy
90
Prednisolone
91
RhA
92
Psoriasis is T cell mediated so 4 is correct
93
What are the indications for use of Rituximab (Ab specific for CD20)
1. Lymphoma 2. Rheumatoid arthritis - 2 doses intravenous every 6-12 months (RA) 3. SLE
94
What is the MOA of rituximab? What are the SE?
_Action_ - Depletes mature B cells _Toxicity_ * Infusion reactions * Infection (PML) * Exacerbation CV disease
95
What are the indications for antibodies specific to alpha4beta7 integrin (vedolizumab)?
IBD - given IV every 8 weeks
96
What is the MOA of Vedolizumab? What are theSE/toxocity?
**Inhibits leukocyte migration** **MOA**: By inhibiting α4β7 integrin, vedolizumab inhibits adhesion of lymphocytes to mucosal addressin cell adhesion molecule-1 (MAdCAM-1), thereby preventing lymphocytic cells from entering the gut lamina propria and GALT **Toxicity:** * Infusion reaction * Hepatotoxicity * Infection (?PML) * Malignancy concerns
97
List the agents directed at cytokines and their receptors used in immune suppression.
1. Anti-TNF-alpha antibody and TNF alpha receptor IgFc fusion protein 2. Anti-IL-1beta or anti-IL1R antagonist 3. Anti-IL-6 receptor 4. Anti-IL17/23 antibodies and anti-IL12/23 (p40) antibody 5. Anti-IL4/5/13 antibodies 6. Anti-RANK ligand antibody
98
Why is TNF-alpha a pivotal cytokine in inflammation? In what conditions is TNFalpha blockade used?
Causes inflammation in many different ways (below) TNFa blockade used in RhA, psoriasis and psoriatic arthritis, IBD, Familial Mediterranean fever
99
What are the indications for anti-TNF-alpha antibody use?
Indications 1. Rheumatoid arthritis 2. Ankylosing spondylitis 3. Psoriasis and psoriatic arthritis 4. Inflammatory bowel disease **SC or IV**
100
What is the MOA of anti-TNF-alpha antibodies (e.g.Infliximab, Adalimumab, Certolizumab, Golimumab)? What are the SE?
MOA: * Inhibits TNFalpha action SE/toxicity: * Infusion/injection site reactions * Infection (TB, HBV, HCV) * Demyelination * Malignancy
101
What are the indications for Etanercept (TNFalpha antagonist)?
* Rheumatoid arthritis * Ankylosing spondylitis * Psoriasis and psoriatic arthritis **Subcutaneous** weekly
102
What is the MOA of TNF-alpha antagonists (Etanercept)? What are the SE?
**MOA**: Inhibits TNFalpha and TNFbeta **Toxicity**: * Injection site reactions * Infection (TB, HBV, HCV) * Lupus-like conditions * Demyelination * Malignancy
103
What drives IL-1 secretion? What conditions can IL-1 blockade be used in?
Inflammasome FMF, gout, adult onset Still's disease
104
Which condition is IL-6 blockade most used in? What other conditions are abs against IL-6 R used in?
* IL-6 has large role in inflammation in **RhA** and IL-6 blockade is used in its management _Also:_ * **Castleman's disease** - given SC every 1-2 weeks
105
What is the MOA? of antibodies directed at IL-6R? What are the SE?
**MOA** - reduces macrophage, T cell, B cell and neutrophil activation **SE/toxicity:** * infusion reactions * infection * hepatotoxicity * elevated lipids * caution wrt malignancy
106
In which condition is the IL23-IL-17 pathway important?
Spondyloarthritides and related conditions: * Axial spondyloarthritis (AS), * Psoriasis and psoriatic arthritis, * Inflammatory bowel disease (not anti-IL17 for IBD)
107
Which Th responses is IL-23 and IL-17 implicated in?
Th17
108
What are the two subunits of IL23? What condition is Guselkumab (ab against p19 alpha subunit of IL23) used in?
*NB: IL-23 comprises p40 and p19 subunits which inhibit IL-23 if they are blocked with antibody* **Indications**: psoriasis + psoriatic arthritis - given SC every 8 weeks
109
What are the SE of antibodies against p19 of IL-23? What is the MOA?
MOA - inhibits IL-23 Toxicity/SE - * injection site reactions * infection (TB) * concern re malignancy
110
Which Th response are cytokines IL-4, IL-5 and IL-13 implicated in?
Th2 and eosinophil responses - these are important in asthma and eczema Blockade of IL-4/5/13 can be used in the management of asthma and eczema
111
What are the uses of IL4/5/13 blockade?
Ab specific to IL4R-alpha can be used in asthma/eczema Anti-IL13 ab for eczema Anti-IL5 ab for asthma
112
What is the mechanism of the RANK ligand/RANK receptor pathway? When is anti-RANK antibody used?
Important in driving osteoclast differentiation. RANKL is a cytokine expressed on osteoblasts. OPG is a soluble RANKL decoy which is produced by osteoblasts and prevents RANKL-RANK interaction to prevent osteoclast formation. Anti-RANK antibody is used in **osteoporosis - given SC every 6 months**
113
What is the MOA of Denosumab? What are the SE?
**MOA** - inhibits RANK mediated osteoclast differentiation and function **SE/toxicity** - * injection site reactions * infection * avascular necrosis of jaw
114
What are the SE of biologics used for immunosuppression?
* **Infusion reactions** * **Injection site reactions** * **Acute infection** - x2 background risk, vaccinate/avoid contact/stop immunosuppression temporarily if occurs, consider atypicals. * **Chronic infection** - * **TB** - TB Elispot, prophylaxis if required, throrough history and examination * **HCV and HBV -** check HBV core Ab before and hep C ab. * **HIV** - check serology before * **JC virus -** a polyoma virus which can reactivate on biologics and progress to cause PML * **Malignancy** * **Auto-immunity**
115
What is the pathophysiology of infusion reactions with the use of biologics?
**IgE mediated** - urticaria, hypotension, tachycardia, wheeze **Not classical type I hypersensitivity** - headache, fevers, myalgias
116
When do infusion _site_ reactions usually occur in biologic use for immunosuppression? What is the pathophysiology?
**Timing** - Peak at 48hrs and can occur at previous infection sites ('recall reaction') **Mechanism** - mixed cellular infiltrates +/- CD8 T cells, not generally IgE or immune complex mediated.
117
What is the risk increase in acute infection for those immunosuppressed with biologics?
\>x2 background risk of acute infection
118
In the use of biologics for immunosuppression, in what cases is JC virus infection/PML more common?
In the use of multiple immunosuppressive agents (JC virus infects and destroys oligodendrocytes)
119
List 3 malignancies that are more common in biologic use for immunosuppression. Which therapies is risk of these lower in?
* Lymphoma (EBV) * Non melanoma skin cancers (Human papilloma virus) * ? Melanoma ## Footnote *Risk is lower with targeted forms of immunosuppression*
120
List 5 autoimmune conditions which may occur as a SE of biologic use for immunosuppression.
* SLE and lupus-like syndromes * Anti-phospholipid syndromes * Vasculitis * Interstitial lung disease * Sarcoidosis * Uveitis * Autoimmune hepatitis * Demyelination
Year 5 - Pathology
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