(12) Immunomodulation and Suppression Flashcards
What is the definition of immunomodulation?
The act of manipulating the immune system using immunomodulatory drugs to achieve a desired immune response
A therapeutic effect of immunomodulation may lead to what?
- immunopotentiation
- immunosuppression
- induction of immunological tolerance
What are the possible mechanisms of immunomodulation?
- immunisation
- replacement therapy
- immune stimulants
- immune suppressants
- anti-inflammatory agents
- allergen immunotherapy (desentisation)
- adoptive immunotherapy
What are biologics?
Medicinal products produced using molecular biology techniques including recombinant DNA technology
An immunomodulator
What are the main classes of biologics?
- substances that are (nearly) identical to the body’s own key signalling proteins
- monoclonal antibodies
- fusion proteins
What is adalimumab?
Human IgG1
Monoclonal antibody
Has a human constant domain (Fc) and a human variable domain (Fab region)
What is infliximab?
Chimeric mouse-human
IgG1 monoclonal antibody
Has a human constant domain and a murine variable domain
What is entanercept?
Fusion protein
Fc-TNFR2 extracellular domain
Has a human constant domain and a human TNFR2 extracellular domain
What is cetrolizumab?
Humanised monovalent Fab-PEG
Has a polyehtylene glycol (PEG) moiety, a human constant domain and a human variable domain
What is immunopotentiation?
Accentuation of the response to an immunogen by administration of another substance
- immunisation - active and passive
- replacement therapies
- immune stimulants
What is the definition of passive immunisation?
Transfer of specific, high-titre antibody from donor to recipient
Provides immediate but transient protection
What are the problems with passive immunisation?
- risk of transmission of viruses
- serum sickness
What is serum sickness?
An allergic reaction to an injection of serum, typically mild and characterised by skin rashes, joint stiffness, and fever
What are types of passive immunisation?
- pooled specific human immunoglobin
- animal sera (antitoxins and antivenins)
What are the uses of passive immunisation?
- hep B prophylaxis and treatment
- botulism, VZV (pregnancy), diphtheria, snake bites
What is the definition of active immunisation?
To stimulate the development of a protective immune response and immunological memory
What are the immunogenic materials used in active immunisation?
- weakened forms of pathogens
- killed inactivated pathogens
- purified materials (proteins, DNA)
- adjuvants
What are the problems with active immunisation?
- allergy to any vaccine component
- limited usefulness in immunocompromised
- delay in achieving protection
Give some examples of replacement therapies and immune stimulation
- pooled human immunoglobin (IV or SC)
- G-CSF/GM-CSF
- IL-2
- a-interferon
- b-interferon
- y-interferon
Pooled human immunoglobins can be used in replacement therapies/immune stimulation. When are they used?
Used in Rx of antibody deficiency states
G-CSF and GM-CSF can be used in immune stimulation. What are they and what do they do?
Granulocyte-colony stimulating factor
Granulocyte macrophage-colony stimulating factor
Glycoprotein that stimulates bone marrow to increase production of mature neutrophils
IL-2 can be used in immune stimulation. What does it do?
Stimulates T cell activation - rarely used
a-interferon can be used in replacement therapy/immune stimulation. What is it used for?
Main use in treatment of Hep C
b-interferon can be used in replacement therapy/immune stimulation. What is it used for?
Used in therapy of MS
y-interferon can be used in replacement therapy/immune stimulation. What can it be used for?
Can be useful in treatment of certain intracellular infections (atypical mycobacteria), also used in chronic granulomatous disease and IL-12 deficiency
What substances cause immunosuppression?
- corticosteroids
- cytotoxic agents
- anti-proliferative/activatio agents
- DMARDs
- biologic DMARDs
What are DMARDs?
Disease-modifying antirheumatic drugs - commonly used in rheumatoid arthritis.
Decrease pain and inflammation, reduce or prevent joint damage, and preserve the structure and function of the joints
What is the action of corticosteroids (immunosuppression)?
- decreased neutrophil margination
- reduced production of inflammatory cytokines
- inhibition of phospholipase A2 (reduced arachidonic acid metabolites production)
- lymphopenia
- decreased T cells proliferation
- reduced immunoglobulins production
What is lymphopenia?
Lymphocytopenia, or lymphopenia, is the condition of having an abnormally low level of lymphocytes in the blood
What is thrombocytopenia?
Deficiency of platelets in the blood - causes bleeding into the tissues, bruising, and slow blood clotting after injury
What are the side effects of corticosteroids?
- carbohydrate and lipid metabolism (diabetes, hyperlipidaemia)
- reduced protein synthesis (poor wound healing)
- osteoporosis
- glaucoma and cataracts
- psychiatric complications
What are the uses of corticosteroids?
- Autoimmune disease (CTD, vasculitis, RA)
- Inflammatory diseases (Crohn’s, sarcoid, GCA/polymyalgia rheumatica)
- malignancies (lymphoma)
- allograft rejection
T cells can be a target for immunosupression. What is the normal T cell pathway?
- antigen presenting to T cell by APC
- T cell binds the you get activation
- IL-2 released and acts in an autocrine fashion, allowing T cell to further up regulate
- mTOR allows cell cycle progression
- T cell proliferation
CyA and tacrolimus are drugs used in T cell targeted immunosuppression. Where in the pathway do they act?
At T cell activation
Anti-IL-2 receptor antibodies are drugs used in T cell targeted immunosuppression. Where in the pathway do they act?
On the IL-2 receptor on the T cell to prevent further up regulation etc.
Sirolimus is a drug used in T cell targeted immunosuppression. Where in the pathway does it act?
Interferes with mTOR activation and therefore T cell cycle progression
Azathioprine and MMF are drugs used in T cell targeted immunosuppression. Where int the pathway does it act?
It interferes with T cell proliferation
Which 4 types of drugs are used in T cell targeted immunosuppression at different stages of the T cell pathway?
- CvA, Tacrolimus
- anti-IL-2 receptor mAbs
- sirolimus
- azathioprine, MMF
Ciclosporin A (CyA) and Tacromilus (FK506) are drugs targeting lymphocytes. What type of drug are they?
Calcineurin inhibitors
IL-2 receptor mAbs are drugs targeting lymphocytes. Give examples
- basiliximab
- daclizumab
Sirolimus is a drug targeting lymphocytes. It is a type of what type of drug?
M-TOR inhibitors
Azathioprine (AZA) and mycophenolate mofetil (MMF) are drugs targeting lymphocytes. They are types of which type of drug?
Antimetabolites
What are the 4 classifications of drugs targeting lymphocytes?
- antimetabolites
- calcineurin inhibitors
- M-TOR inhibitors
- IL-2 receptor mAbs
What do the 2 calcineurin inhibitors bind to?
CyA = binds to intracellular protein cyclophilin
Tacrolimus (FK506) = binds to intracellular protein FKBP-12
What is the mode of action of calcineurin inhibitors?
- prevents activation of NFAT
- factors which stimulate cytokines (ie. IL-2 and INFy) gene transcription
What are the T cell effects of calcineurin inhibitors?
Reversible inhibition of T cell-activation, proliferation and clonal expansion
Sirolimus (rapamycin) is a macrolide antibiotic that does what?
- also binds to FKB12 but has different effects
- inhibits mammalian target of rapamycin (mTOR)
What is the mode of action of sirolimus?
- inhibits response to IL-2
What are the T cell effects of sirolimus?
- cell cycle arrest at G1-S phase
What are the calcineurin/mTOR side effects?
- hypertension
- hirsutism
- nephrotoxicity
- heptotoxicity
- lymphomas
- opportunistic infections
- neurotoxicity
- multiple drug interactions (induce P450)
What is hirsutism?
Excessive hair growth in women
What are clinical uses of calcineurin and mTOR inhibitors?
- transplantation (allograft rejection)
- autoimmune diseases
Generally, what do the antimetabolites do?
Inhibit nucleotide (purine) synthesis
What does AZA (an antimetabolite) do?
- guanine anti-metabolite
- rapidly converted into 6-mercaptopurine
What does MMF (an anti-metabolite) do?
- non-competitive inhibitor of IMPDH
- prevents production of guanosine triphosphate
What are the T and B cell effects of AZA and MMF (anti-metabolites)?
- impaired DNA production
- prevents early stages of activated cells proliferation
Give some other examples of anti-metabolites and cytotoxic drugs
- methotrexate (MTX) - folate antagonist
- cyclophosphamide - cross-link DNA
What are the side effects of all cytotoxic drugs?
- bone marrow suppression
- gastric upset
- hepatitis
- susceptibility to infection
What are side effects of cytotoxic drugs, specifically MTX?
pneumonitis
What are the side effects of cytotoxic drugs, specifically cyclophosphamide?
cystitis
What is cystitis?
Inflammation of the bladder, usually caused by a bladder infection
What are the clinical uses of cytotoxics - AZA/MMF?
- autoimmune diseases (SLE, vasculitis, IBD)
- allograft rejection
What are the clinical uses of cytotoxics - MTX?
- RA, PsA, polymyositis, vasculitis
- GvHD in BMT
What are the clinical uses of cytotoxics - cyclophosphamide?
- vasculitis (Wagner’s, CCS)
- SLE
What are the different types of biologic DMARDs?
- anti-cytokines (TNF, IL-6 and IL-1)
- anti-B cell therapies
- anti-T cell activation
- anti-adhesion molecules
- complement inhibitors
Give 3 types of anti-cytokines
- anti-TNF
- anti-lL-6 (Tocilizumab)
- anti-IL-1
What is anti-TNF used for? (a biologic)
- first biologics to be successfully used in the therapy of RA
- used in other inflammatory conditions eg. Crohn’s, psoriasis, ankylosing spondylitis
What is a caution of use of anti-TNF? ( a biologic)
Increased risk of TB
What is anti-IL-6 (Tocilizumab) used for?
- blocks IL-6 receptor
- used in therapy of RA and AOSD
What is AOSD? (adult onset Still’s disease)
Rare systemic inflammatory disease characterized by the classic triad of persistent high spiking fevers, joint pain and a distinctive salmon-colored bumpy rash
What problems may anti-IL-6 cause?
Problems with control of serum lipids
What are 3 different agents of IL-1 that are available?
- anakinra
- rilonacept
- canakinumab
What is anti-IL-1 used for?
Used in treatment of AOSD and autoinflammatory syndromes
What is rituximab?
Chimeric mAb against CD20-B cell surface
First approved in ‘97 for treatment of chemotherapy resistant DLCL
What are the uses for rituximab?
- lymphomas, leukaemias
- transplant rejection
- autoimmune disorders
Give 2 examples of adoptive immunotherapy
- bone marrow transplant (BMT)
- stem cell transplant (SCT)
What are the uses of adoptive immunotherapy (BMT and SCT)?
- immunodeficiencies (SCID)
- lymphomas and leukaemias
- inherited metabolic disorders (osteopetrosis)
- autoimmune diseases
What is osteopetrosis?
“stone bone”
an extremely rare inherited disorder whereby the bones harden, becoming denser - can cause bones to dissolve and break
What types of immunomodulators are used in allergy?
- immune suppressants
- allergen specific immunotherapy
- anti-IgE monoclonal therapy
- anti-IL-5 monoclonal treatment
What are indications for allergen specific immunotherapy?
- allergic rhinoconjunctivitis not controlled on maximum medical therapy
- anaphylaxis to insect venoms
What are the mechanisms of allergen specific immnunotherapy?
- switching of immune response from Th2 (allergic) to Th1 (non-allergic)
- development of T reg cells and tolerance
What are the routes of allergen specific immunotherapy?
SC or sublingual for aero-allergens
What are the side effects of allergen specific immunotherapy?
Localised and systemic allergic reactions
Which two monoclonal antibodies are used in immunomodulation for allergy?
- omalizumab (mAb against IgE)
- mepolizumab (mAb against IL-5)
Omalizumab is a monoclonal antibody against IgE. Which allergies is it used in?
- asthma
- chronic urticaria
- angioedema
What problems may arise when using omalizumab (a monoclonal antibody against IgE)?
May cause severe systemic anaphylaxis
Mepolizumab is a monoclonal antibody against IL-5. What does it do?
Prevents eosinophil recruitment and activation
What is mepolizumab (a monoclonal antibody against IL-5) not useful for?
- limited effect on asthma
- no clinical efficacy in hypereosinophilic syndrome
