Immunomodulators Flashcards
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 are cytokines used as immune modulators?
Usually to boost immune response –> now used a lot less
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
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
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)
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)
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)
What is Virus specific T cell therapy?
Generally T-cells enhanved for specific virus (e.g. for EBV in B cell lymphoproliferatice disease)
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.
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
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)
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 )
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
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
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
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
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
What are some of the examples of antiproliferative drugs used to induce immunosuppression?
- Cyclophosphamide
- Mycophenolate
- Azathioprine
- Methotrexate
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?
- Immunodsuppression: x2 risk of acute infection
- infusion reaction - Type I hypersensitiveiy (IgE, anaphylaxis) and headache, fever myalgia
- Injection site reactions (
What are the main chronic infections that cause issues in immunosuppression?
How should they be screened for before commencement of immunosuppression?
- Tuberculosis - screen before and probably need to treat before starting (elpspot/ quantiferon test)
- HBV and HCV –> screen before treatment (Hep B core antibody, Hep C antibody)
- HIV: serology before treatement
- 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.
