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Year 5 Path Immunology > Immunomodulators > Flashcards

Immunomodulators Flashcards

1
Q

What 4 immune modulating therapies are there that can boost the immune system?

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

How are cytokines used as immune modulators?

A

Usually to boost immune response –> now used a lot less

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3
Q

Name examples of therapeutic use of cytokine therapy in medicine

A
  1. IL-2 – increase T cell response, renal Cell carcinoma
  2. Interferon alpha - antiviral effect, Hep B & C (+ ribavirin)
  3. Interferon gamma: increase macrophage function, Chronic granulomatous disease
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4
Q

What are examples of replacing missing components of the immune system as a way to boost?

A
  1. Bone Marrow transplant
  2. Antibody replacment (blood product from >1000 donors –> different antibodies used in primary antibody deficiency (Common variable immune defieincy, x-linked agammaglobulinaemia,) , sometimes secondary antibody deficiency (CLL; post BM transplant)
  3. Speficic Immunoglobuling for PEP –> passive immunisation , e.g. for HepB, Rabies, vvaricella zoster in pregnancy under 20 ) , tetanus immunoglobulin
  4. T-cell (some velopment
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5
Q

What are the different options and indicationn of antibody replacement?

A

IVIg/ ScIg –> pooled blood product from >1000 donors –> different IgG antibodies against many diseases formed

Indications

  • primary antibody deficiency (Common variable immune defieincy, x-linked agammaglobulinaemia,)
  • sometimes secondary antibody deficiency (CLL; post BM transplant)
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6
Q

Name examples of where specific antibodies are used in prevention and treatment of diseases

A

Derived from plasma donors with high titres of
IgG antibodies to specific pathogens, usually used as PEP –>

  • Hepatitis B
  • Rabies
  • Varicella Zoster (for pregnanct women under 20 weeks)
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7
Q

What are the different ways of replacing missing T-cell immune responses?

A

All together: Adoptive cell transfer (ACT)

Different methods, quite specific for certain diseases

  • 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)
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8
Q

What is Virus specific T cell therapy?

A

Generally T-cells enhanved for specific virus (e.g. for EBV in B cell lymphoproliferatice disease)

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9
Q

What is tumour infiltrating lymphocytte (TIL) therapy?

A
  • TILs collected from tumour & expanded with IL-2
  • TIL infusion into lymphoid depleted patient → destroy cancer cells

Indications: Head & neck SCC, melanoma, lung and gynae ca.

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10
Q

What are TCR and CARt T cell therapy?

A

T cells get engineered to express receptors specific to tumour angigens

TCR: design of t-cell receptor against any antigen
CAR: desing of a variable segment of antibody (e.g. for CD-19) –> mainly non-H lymphomas or Lymphoblastik Leukaemia

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11
Q

Wha tis the MOA of all immune checkpoints blockads?

A

Blocking the -ve feedback loop, that usually downregulates immune cells (e.g. blocking of PD-1 thatt can be present on APC and some tumour cells –> enhance immune response against tumours)

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12
Q

What is Pembrolizumab or Nivolumab?

What are the indications and complications?

A

Monoclonal antibodies against PD-1:

PD-1 present on many tumours usually suppresses immune response against malignant tissue –> antibody = immune checkpoint blockade –> allows T-cell activation

Indications
- Advanced melanoma
- Metastatic renal cell cancer
- Increasing indications in oncology

Complications
- Autoimmunity (no -ve regulation )

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13
Q

What is Ipilimumab?
What are the indications

A

It is another immune-checkpoint inhibitor for CTLA4 that allows more T-cell activation, particularly for treatment of melanoma + metastatic Renal cell caners

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14
Q

What are the different ways of suppressing the immune sysems?

A
  • Steroids
  • Anti-proliferative agents
  • Plasmapheresis
  • Inhibitors of cell signalling
  • Agents directed at cell surface antigens
  • Agents directed at cytokines and their receptors
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15
Q

What is the MOA of steroids in the use as immunosuppression?

A

Suppress all actions of immune system

  1. Inhibit Prostaglandins synthesis : Inhibits phospholipase A2 →no breakdown of phospholipids to arachidonic acid→ prostaglandin synthesis blocked = reduced inflammation
  2. Reduced Phagocyte traffic : –> reduced prostaglandins= reduced signaling for neutrophils to move into tissue –> increase in circulatory neutrophils
    • additional reduced release of phagocytic enzymes
  4. Lymphocyte
    Lymphocytes stay in lymphoid tissue –> lymphopenia
    + additional suppression of cytokine genes, antibody formation and steroids promote apoptosis
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16
Q

What are the main side-effects of steroid use?

A
  1. Metabolic (diabetis, lipid, osteoporois, hisrsutism, adrenal suppression in long-term use)
  2. others (cataracts, glaucoma, peptic ulcers, pancreatitis, avascular necrosis
  3. and immunosuppression –> infection
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17
Q

What is the general rational behind using anti-proliferative drugs for immunosuppression?

A

Inhibit DNA synthessis
–> Cells with rapid turnover are the most sensitive –> often immune cells have a rapid turnover

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18
Q

What are some of the examples of antiproliferative drugs used to induce immunosuppression?

A
  • Cyclophosphamide
  • Mycophenolate
  • Azathioprine
  • Methotrexate
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19
Q

What is cyclophosphamide?
When is it used and what are the side effects?

A

It is an anti-proliferative drug used to induce immunosuppression –> used mainly in connective tissue disease, vasculitis

Toxic to proliferating cells

  • Bone marrow depression
  • Hair loss
  • Sterility (male»female) –> sperm storage

Haemorrhagic cystitis

  • Toxic metabolite acrolein excreted via urine

Malignancy

  • Bladder cancer
  • Haematological malignancies
  • Non-melanoma skin cancer

Infection

  • Pneumocystis jiroveci
20
Q

What is Azathioprine ?
When is it used and what are the main side-effects?

A

Anti-proliferative drug used to induce immunosuppression, often used for transplant

Bone marrow suppression

  • Cells with rapid turnover (leucocytes and platelets) are particularly sensitive
  • 1:300 individuals are extremely susceptible to bone marrow suppression (due to genetic predisposition making metabolism less likely –> check TPMT activity/ genes )
  • always check full blood count after starting therapy

Hepatotoxicity

Idiosyncratic and uncommon Infection

Serious infection less common than with cyclophosphamide

21
Q

What is mycophenolate Mofetil?
When is it used and what are the side-effects?

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)
22
Q

What is the rational behing using plasma exchange?

What are the issues?

A

It is a way of immuosuppressive therpapy

AIM: Remove of pathogenic antibodies (e.g. severe myasthenia gravis)

–> blood filtered

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

23
Q

What are the indications for using plasma exchange?

A

Severe antibody-mediated disease

  • Goodpasture syndrome
  • Anti-glomerular basement membrane antibodies
  • Severe acute myasthenia gravis
  • Anti-acetyl choline receptor antibodies
  • Antibody mediated transplant rejection/ABO incompatible
  • Antibodies directed at donor HLA/AB molecules
24
Q

How do inhibitors of cell signalling change immune response?

What are some examples of using them?

A

Class of drugs used for the induction of immunoosuppression

  1. Example: Calcineurin inhibitors
    MOA: calcineurin usually involved in T-cell activation and signaling –> inhibitor supresses T-cell response
25
Q

What is the MOA of calcineurin inhibitors?

When are they used?

A

calcineurin usually involved in T-cell activation and signaling –> inhibitor supresses T-cell response

  • Transplantation
  • SLE
  • Psoriatic arthritis
26
Q

What type of drug is a JAK inhibtor?

When can it be used?

A

It is a immune-modulator –> suppression of immune system via inhibition of cell signaling

Inhibition of JAK-STAT signaling (associated with cytokine production) –> inhibits production of inflammatory molecules

  • Rheumatoid arthritis
  • psoriatic arthritis
  • axial spondyloarthritis
27
Q

What are PDE4 inhibitors? When are they used?

A

Immunosuppressants that change cell-signaling pathways

–> Modulates cytokine response

Used in management of

  • psoriasis and psoriatic arthritis
28
Q

What is the general rational of using monoclonal antibodies to targeted to surface antigens in order to induce immune suppression?

A

Receptors/ surface antigens are needed for different task. By inhibiting/ stimmulating them they can
1. Block signalling
2. Cell depletion
3. Inhibit migration

for different immune cells (T, B and other migration)

29
Q

What are the side-effects of generall using therapies, targeted to T-cell surface antigens?

A

Malignancy
Toxicity

30
Q

What are drugs antibodies direacted at CD25?

When are they sused?

A

Immunosuppressive drug working by blocking of cell membrane/ antigens

–> Blocks IL-2 induced signalling and inhibits T cell proliferation

Indications and dosing
Prophylaxis of allograft rejection
Intravenous given before and after transplant surgery

Toxicity
Infusion reactions
- Infection
- Concern re long term risk malignancy

31
Q

What is CTLA4 fusion protein as a drug?

What is the indication and rationale of using it?

A

Indications and dosing

  • Rheumatoid arthritis
  • Intravenous 4 weekly
  • Subcutaneous weekly

Action

Reduces costimulation of
T cells via CD28

Toxicity

  • Infusion reaction
  • Infection (TB, HBV, HCV)
  • Caution with malignancy
32
Q

What is the target of Rituximab?

A
  • Monoclonal antibody against CD 20 - mature B-cells

realaitvely little immunosuppression –> as only B-cells, not plasma cells are supressed (over time loss of plasma cells)

2 infusions 2 weekas apart –> top up every 26-8 months

33
Q

How do agents directed against cytokines and cytokine receptors work?

A

Generally suppress/ block pro-inflammaory cytokine pathway –> immunosuppression in many diseases

34
Q

What is TNF -alpha?

What disease is importnat to connsider with using TNF-alpha inhibitors?

A
  • Cytokine and it pivotal in inflammation in many many conditions –> activates all inflammatory cells

Clinically use to block with TNF alpha blockers:

Rheumatoid arthritis, Psoriasis and psoriatic arthritis, Inflammatory bowel disease, Familial Mediterranean fever

35
Q

What are the side-effects of using TNF .alpha inhibitors

A
  • Infusion or injection site reactions
  • Infection (TB (particularly important - screen before) , HBV, HCV)
  • Lupus-like conditions
  • Demyelination
  • Malignancy (currently no evidence for solidary tumour malignantcy, maybe borderline increase in skin cancers)
36
Q

What is IL-1?
What condiitons is an IL-1 antibody / drug usually used in?

A

Cytokine that often n activates the inflammasome –> immunosuppression with IL-1 inhibitors

Used therapeutically in
Gout Familial Mediterraneial fever, Adult onset stills disease

37
Q

What is IL-6 ?

What are the clincal uses of IL-6 inhibitors?

A

Cytokine involved in driving inflammation in

Mainly used in Rheumatoid arthritis (e.g. Tociliuzumab) , now maybe more in GCA)

38
Q

What are IL-23 and IL17?

In what diseases profit from IL-23 and IL-17 inhibitors?

A

Cytokines involved in pro-innflammatory process of
1. spondyloarthritides and related conditions incl.

  • Axial spondyloarthritis
  • psoriasis and psoriatic arthritis
  • IBD
39
Q

What are IL-4, IL-5 and IL13?

What conditions can benefit therapeutically from inhibitors of these cytokines?

A

Cytkines important in Th2 and eosinophile response

–> Useful for Eczema and asthma

40
Q

Explain the role of RANK and the use of anti-RANK ligand antibody

A

RANK imporant in osteoclast activation

With RANK ligant antibody (denosumab):

Stops osteoclast actication – > decreases bone reabsorbtion (usually promoted by RANK) –> good for osteoporosis

41
Q

What are the main side-effects in using biological agents?

A
  1. Immunodsuppression: x2 risk of acute infection
  2. infusion reaction - Type I hypersensitiveiy (IgE, anaphylaxis) and headache, fever myalgia
  3. Injection site reactions (
42
Q

What are the main chronic infections that cause issues in immunosuppression?

How should they be screened for before commencement of immunosuppression?

A
  1. Tuberculosis - screen before and probably need to treat before starting (elpspot/ quantiferon test)
  2. HBV and HCV –> screen before treatment (Hep B core antibody, Hep C antibody)
  3. HIV: serology before treatement
  4. JCV (Johan Cunningham virus)
43
Q

What is John Cunningham Virus?

A

Generally rare infection, but commensal virus thatn can reactivate with strong (several ) immunosuppression

Destroys oligodendrocytes –> progressive multifocal leukoencepahlopathy

44
Q

What are the risk of malignancy with use of immunosuppression?

A

Not for solid tumours but

  • Lymphoma (EBV) (x3, but increase in with many autoimmune, so ? if the risk changes but the risk is higher)
  • increase in Non melanoma skin cancers (Human papilloma virus)
  • ? increase Melanoma (likely, not yet strong evidence)

Generally lower in targeted treatments than generlaised regimes

45
Q

Explain the relationship between use of immunosuppressive treatment and development of auto-immune conditions

A

Can cause dysregulation of immune system →

  • SLE & lupus-like syndromes
  • anti- phopsolipid syndromes
  • vasculitis
  • interstitial lung disease
  • sarcoidosis
  • uveitis
  • AI hepatitis
  • demyelination.

Year 5 Path Immunology (6 decks)

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