Immunomodulation and suppression Flashcards by Alice Spencer

What is meant by immunomodulation?

The act of manipulating the immune system using immunomodulatory drugs to achieve a desired immune response

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What are the 3 possible outcomes of immunomodulation?

1) Immunopotentiation (enhancement of the immune response by increasing its rate or duration)
2) Immunosuppression
3) Induction of immunological tolerance

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What are the 7 mechanisms of immunomodulation?

1) Immunization
2) Replacement therapy
3) Immune stimulants
4) Immune suppressants
5) Anti-inflammatory agents
6) Allergen immunotherapy (desensitization)
7) Adoptive immunotherapy

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What are biologics?

Medicinal products produced using molecular biology techniques including recombinant DNA

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What are the 3 main classes of biologics?

1) Substances that are (nearly) identical to the body’s own key signalling proteins
2) Monoclonal antibodies
3) Fusion proteins

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Adalimumab is a Human IgG anti-TNF monoclonal Ab, what is its structure?

Human Fc portion and Human Fab portion that binds to TNF

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Etanercept is a fusion protein anti-TNF monoclonal Ab, what is its structure?

Human Fc portion bound to a human TNFR2 (TNF receptor) which in the body serves to mop up extra TNF)

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What is TNF?

An important pro-inflammatory cytokine

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Infliximab is a chimeric mouse-human anti-TNF monoclonal Ab, what is its structure and how is it produced?

Mouse Fab portion
Human Fc portion
Mice are modified to produce a human Fc portion and are given TNF so produce an Ab against TNF with a mouse Fab portion and a human Fc portion

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Cetrolizumab is a humanised monovalent Fab-PEG anti-TNF monoclonal Ab what is its structure?

Human Fab region bound to a polyethylene glycol - this makes the Fab region more stable and less digestible

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What 3 treatments or processes lead to immunopotentiation?

1) Immunisation
2) Replacement therapies
3) Immune stimulants

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What is passive immunisation?

Transfer of specific, high titre antibody from donor to recipient.

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What kind of protection does passive immunisation provide?

Immediate but transient protection

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What are the 2 main problems with passive immunisation?

1) Risk of transmission of viruses (Ab are blood borne)

2) Serum sickness (occurs when suddenly a large number of immune complexes form within the circulation)

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What are the 2 types of passive vaccinations?

1) Pooled specific human immunoglobulin

2) Animal sera

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What are the 5 main uses of passive immunisation?

1) Hep B prophylaxis and treatment
2) Botulism
3) VZV (in pregnancy)
4) Diphtheria
5) Snake bites

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What is active immunisation?

To stimulate the development of a protective immune response and immunological memory

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What are the 4 kinds of immunogenic material used in active immunisation?

1) Weakened forms of pathogens
2) Killed, inactivated pathogens
3) Purified materials (proteins, DNA)
4) Adjuvants

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What are the 3 problems associated with active immunisation?

1) Allergy to any vaccine component
2) Limited usefulness in immunocompromised
3) Delay in achieving potential

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What are the 6 types of immune replacement therapy?

1) Pooled human immunoglobulin
2) G-CSF/GM-CSF
3) IL-2
4) alpha-interferon
5) beta-interferon
6) gamma-interferon

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What is pooled human immunoglobulin replacement therapy used in the treatment of?

Immune deficient states

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What does G-CSF/GM-CSF replacement therapy do?

Acts on the bone marrow to increase production of mature neutrophils

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What does IL-2 replacement therapy do, is it used often?

Stimulates T cell activation - rarely used

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What is alpha-interferon replacement therapy used in the treatment of?

Hepatitis C

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What is beta-interferon replacement therapy used in the treatment of?

What can gamma-interferon replacement therapy be useful in the treatment of?

Certain intracellular infections (atypical mycobacteria), also used in the chronic granulomatous disease and IL-12 deficiency

What 5 types of drugs are immunosuppressants?

1) Corticosteroids 2) Cytotoxic agents 3) Anti-proliferative/activation agents 4) DMARDs 5) Biologic DMARDs

What are the 6 effects of corticosteroids on the immune system leading to immunosuppression?

1) Decreased neutrophil margination (movement into tissues) 2) Reduced production of inflammatory cytokines 3) Inhibition of phospholipase A2 (reduced arachidonic acid metabolites production) 4) Lymphopenia 5) Decreased T cell proliferation 6) Reduced immunoglobulins production

What are the 5 main side effects of corticosteroids?

1) Changes to carbohydrate and lipid metabolism (diabetes, hyperlipidaemia) 2) Reduced protein synthesis (poor wound healing) 3) Osteoporosis 4) Glaucoma and cataracts 5) Psychiatric complications

What 4 kinds of diseases/conditions are corticosteroids used to treat?

1) Autoimmune diseases (CTD (connective tissue diseases), vasculitis, RA) 2) Inflammatory diseases (Crohn's, Sarcoids, GCA/polymyalgia rheumatic) 3) Malignancies (lymphoma) 4) Allograft (human tissue graft) rejection

What are the 4 classes of drugs targeting lymphocytes?

1) Antimetabolites 2) Calcineurin inhibitors 3) M-TOR inhibitors 4) IL-2 receptor mABs

What is the mode of action of calcineurin inhibitors?

Bind to intracellular proteins Prevents activation of NFAT - factor which stimulates cytokine (ie. IL-2 and INF-gamma) transcription Reversible inhibition of T cell activation, proliferation and clonal expansion results

What intracellular protein does the calcineurin inhibitor ciclosporin A bind to?

Cyclophillin

What intracellular protein does the calcineurin inhibitor Tacrolimus bind to?

FKBP-12

Once T cells have an antigen presenting cell presented to them by an APC, what 2 stages do they go through?

1) Activation - by autocrine cytokine IL-2 2) Proliferation - IL2 stimulates signalling pathway involving mTOR which allows cells to go into the cell cycle and proliferate

What is the mode of action of sirolimus an MTOR-inhibitor?

Inhibits cell response to IL-2 by the MTOR pathway | Get cell arrest at the G1-S phase, ie. T cells are prevented from proliferating

What are the 8 side effects of calcineurin/mTOR inhibitors?

1) Hypertension 2) Hirsutism (abnormal growth of hair on a woman's face and body) 3) Nephrotoxicity 4) Hepatotoxicity 5) Lymphomas 6) Opportunistic infections 7) Neurotoxicity 8) Multiple drug interactions (induce p450)

What are the 2 clinical uses of calcineurin/mTOR inhibitors?

1) Transplantation - allograft (human tissue graft) rejections 2) Autoimmune disease

What is the mode of action of antimetabolites?

``` Inhibit nucleotide (purine) synthesis Have effects on T and B cells - impaired DNA production, prevents early stages of activated cells proliferation ```

What is the mode of action of Azathioprine - an antimetabolites - specifically?

Guanine anti-metabolite, rapidly converted in 6-mercaptopurine

What is the mode of action of Mycophenolate mofetil - an antimetabolite - specifically?

Non-competitive inhibitor of IMPDH | Prevents production of guanosine triphosphate

What is the rough mode of action of the immunosuppressant methotrexate?

Folate antagonist

What is the rough mode of action of the immunosuppressant cyclophosphamide?

Cross-link DNA

What are the 4 side effects of all cytotoxic drugs?

1) Bone marrow suppression 2) Gastric upset 3) Hepatitis 4) Susceptibility to infections (NB. they affect all rapidly dividing cells)

What is the specific side effect of methotrexate (MTX)?

Pneumonitis

What is the specific side effect of cyclophosphamide (a cytotoxic drug)?

Cystitis

What are the clinical uses of azathioprine and MMF? 2

Autoimmune disease | Allograft rejection

What are the clinical uses of methotrexate? 4

1) Rheumatoid arthritis 2) Polymyositis 3) Vasculitis 4) Graft vs Host disease in bone marrow transplant

What are the 2 clinical uses of the cytotoxic drug cyclosphamide?

1) Vasculitis (Wagner's, CSS) | 2) SLE

Biologic DMARDs fall into what 5 categories?

1) Anti-cytokines 2) Anti-B cell therapies 3) Anti-T cell activation 4) Anti-adhesion molecules 5) Complement inhibitors

Name 3 anti-cytokines?

1) Anti-TNF 2) Anti-IL-6 (Tocilizumab) 3) Anti-IL-1

What is Anti-TNF used to treat?

First to be used successfully in treatment of RA | No used in a number of other inflammatory conditions (Crohn's, psoriaisis, ankylosing spondylitis)

There increased risk of what infection when using anti-TNF drugs?

What 2 conditions are anti-IL-6 drugs used to treat?

RA, AOSD (Adult onset Still's disease - rare form of arthritis)

Anti-IL-6 drugs may cause problems with control of what substances in the body?

Serum lipids

Anti-IL-1 drugs are used in the treatment of what 2 conditions?

AOSD (Adult onset Still's disease) | Auto inflammatory sydromes

Rituximab is a chimeric mAb against what?

CD20-B cell surface

What are the 4 main uses of rituximab?

(First developed as treatment of chemotherapy resistant DLCL) 1) Lymphomas 2) Leukaemias 3) Transplant rejection 4) Autoimmune disorders

Name 2 forms of adoptive immunotherapy?

1) Bone marrow transplant | 2) Stem cell transplant

Name the 5 main uses of adoptive immunotherapies (BMT and SCT)?

1) Immunodeficiencies 2) Lymphomas 3) Leukemias 4) Inherited metabollic disorders (osteopetrosis) 5) Autoimmune disorders

Name the 4 kinds of immunomodulator treatments for allergy?

1) Immune suppressants 2) Allergen specific immunotherapy 3) Anti-IgE monoclonal therapy 4) Anti-IL-5 monoclonal treatment

What is allergen specific immunotherapy?

People are given doses of an allergen in a controlled manner to inducer tolerance to that allergen, may be give subcutaneously or sublingually

What is the mechanism of action of allergen specific immunotherapy?

Switching of immune response from Th2 (allergic) to Th1 (non-allergic) Also get development of T reg cells and tolerance

What are the possible side effects of allergen specific immunotherapy?

Localised and systemic allergic reactions

Give 2 indications for allergen specific immunotherapy?

1) Allergic rhinoconjunctivitis not controlled on max medical therapy 2) Anaphylaxis to insect venoms

Omalizumab is a mAb against what?

IgE

Omalizumab is used in the therapy of what 3 conditions?

Used in asthma | Also useful in therapy of chronic urticaria and angioedema

What is the possible major adverse effect of omalizumab?

May cause severe systemic anaphylaxis

Mepolizumab is a mAb against what?

IL-5

What is the mode of action of Mepolizumab?

Prevents eosinophil recruitment and activation

Is Mepolizumab useful in the therapy of asthma?

No has limited effect on Asthma

Is Mepolizumab used in the treatment of hypereosinophilic syndrome?

No, it has no clincal efficacy in the treatment of hypereosinophilic syndrome