Immunomodulators Flashcards by Jule Hoelscher

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

Vaccination
Replacement of missing components
Cytokine therapy
Blocking immune checkpoints - for
advanced melanoma

How well did you know this?

Not at all

Perfectly

How are cytokines used as immune modulators?

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

How well did you know this?

Not at all

Perfectly

Name examples of therapeutic use of cytokine therapy in medicine

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

How well did you know this?

Not at all

Perfectly

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

Bone Marrow transplant
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)
Speficic Immunoglobuling for PEP –> passive immunisation , e.g. for HepB, Rabies, vvaricella zoster in pregnancy under 20 ) , tetanus immunoglobulin
T-cell (some velopment

How well did you know this?

Not at all

Perfectly

What are the different options and indicationn of antibody replacement?

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)

How well did you know this?

Not at all

Perfectly

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

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)

How well did you know this?

Not at all

Perfectly

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

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)

How well did you know this?

Not at all

Perfectly

What is Virus specific T cell therapy?

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

How well did you know this?

Not at all

Perfectly

What is tumour infiltrating lymphocytte (TIL) therapy?

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.

How well did you know this?

Not at all

Perfectly

What are TCR and CARt T cell therapy?

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

How well did you know this?

Not at all

Perfectly

Wha tis the MOA of all immune checkpoints blockads?

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)

How well did you know this?

Not at all

Perfectly

What is Pembrolizumab or Nivolumab?

What are the indications and complications?

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 )

How well did you know this?

Not at all

Perfectly

What is Ipilimumab?
What are the indications

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

How well did you know this?

Not at all

Perfectly

What are the different ways of suppressing the immune sysems?

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

How well did you know this?

Not at all

Perfectly

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

Suppress all actions of immune system

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

How well did you know this?

Not at all

Perfectly

What are the main side-effects of steroid use?

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

How well did you know this?

Not at all

Perfectly

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

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

How well did you know this?

Not at all

Perfectly

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

Cyclophosphamide
Mycophenolate
Azathioprine
Methotrexate

How well did you know this?

Not at all

Perfectly

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

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

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

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

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

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)

What is the rational behing using plasma exchange?

What are the issues?

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

What are the indications for using plasma exchange?

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

How do inhibitors of cell signalling change immune response?

What are some examples of using them?

Class of drugs used for the induction of immunoosuppression

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

What is the MOA of calcineurin inhibitors? When are they used?

calcineurin usually involved in T-cell activation and signaling --> inhibitor supresses T-cell response * Transplantation * SLE * Psoriatic arthritis

What type of drug is a JAK inhibtor? When can it be used?

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

What are PDE4 inhibitors? When are they used?

Immunosuppressants that change cell-signaling pathways --> Modulates cytokine response Used in management of * psoriasis and psoriatic arthritis

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

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)

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

Malignancy Toxicity

What are drugs antibodies direacted at CD25? When are they sused?

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

What is CTLA4 fusion protein as a drug? What is the indication and rationale of using it?

**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

What is the target of Rituximab?

* 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

How do agents directed against cytokines and cytokine receptors work?

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

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

* 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

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

* 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)

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

Cytokine that often n activates the inflammasome --> immunosuppression with IL-1 inhibitors Used therapeutically in **Gout** Familial Mediterraneial fever, Adult onset stills disease

What is IL-6 ? What are the clincal uses of IL-6 inhibitors?

Cytokine involved in driving inflammation in Mainly used in **Rheumatoid arthritis** (e.g. Tociliuzumab) , now maybe more in GCA)

What are IL-23 and IL17? In what diseases profit from IL-23 and IL-17 inhibitors?

Cytokines involved in pro-innflammatory process of 1. spondyloarthritides and related conditions incl. * Axial spondyloarthritis * psoriasis and psoriatic arthritis * IBD

What are IL-4, IL-5 and IL13? What conditions can benefit therapeutically from inhibitors of these cytokines?

Cytkines important in Th2 and eosinophile response --> Useful for Eczema and asthma

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

RANK imporant in osteoclast activation With RANK ligant antibody (denosumab): Stops osteoclast actication -- > decreases bone reabsorbtion (usually promoted by RANK) --> good for osteoporosis

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

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

What are the main chronic infections that cause issues in immunosuppression? How should they be screened for before commencement of immunosuppression?

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)

What is John Cunningham Virus?

Generally rare infection, but commensal virus thatn can reactivate with strong (several ) immunosuppression Destroys oligodendrocytes --> progressive multifocal leukoencepahlopathy

What are the risk of malignancy with use of immunosuppression?

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

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

Can cause dysregulation of immune system → * SLE & lupus-like syndromes * anti- phopsolipid syndromes * vasculitis * interstitial lung disease * sarcoidosis * uveitis * AI hepatitis * demyelination.