Immunomodulation

Question 1

What is immunomodulation?

Answer 1

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

Question 2

What are the various mechanisms that can be used to bring about immunomodulation?

Answer 2

• Immunization
• Replacement therapy
• Immune stimulants
• Immune suppressants
• Anti-inflammatory agents
• Allergen immunotherapy (desentization)
• Adoptive immunotherapy

Question 3

What are biologic immunomodulators?

Answer 3

Medicinal products produced using molecular biology techniques including recombinant DNA technology.

Question 4

What are the main classes of biologic immunomodulators?

Answer 4

• Substances that are (nearly) identical to the body’s own key signaling proteins
• Monoclonal antibodies
• Fusion proteins

Question 5

What is the problem with biologic immunomodulators?

Answer 5

Humans can develop autoantibodies against them.

Question 6

What is is immunopotentiation?

Answer 6

Immunisation

Question 7

What is the definition of passive immunisation?

Answer 7

Transfer of specific, high-titre antibody from donor to recipient. Provides immediate but transient protection

Question 8

What are the risks associated with passive immunisation?

Answer 8

• Risk of transmission of viruses

- Serum sickness

Question 9

What types of passive immunisation are available?

Answer 9

• Pooled specific human immunoglobulin

- Animal sera (antitoxins an antivenins)

Question 10

What are the clinical indications for passive immunisation?

Answer 10

Hep B prophylaxis and treatment

Botulism, VZV (pregnancy), diphtheria, snake bites

Question 11

What is the definition of active immunisation?

Answer 11

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

Question 12

What kind of immunogenic material is used in vaccines?

Answer 12

• Weakened forms of pathogens
• Killed inactivated pathogens
• Purified materials (proteins, DNA)
• Adjuvants

Question 13

What problems are associated with vaccination?

Answer 13

• Allergy to any vaccine component
• Limited usefulness in immunocompromised
• Delay in achieving protection

Question 14

What is pooled human immunoglobulin used for?

Answer 14

Rx of antibody deficiency states

Question 15

What are the various actions of corticosteroids?

Answer 15

• Decreased neutrophil margination
• Reduced production of inflammatory cytokines
• Inhibition phospholipase A2 (reduced arachidonic acid metabolites production)
• Lymphopenia
• Decreased T cells proliferation
• Reduced immunoglobulins production

Question 16

What are the side-effects of corticosteroids?

Answer 16

• Carbohydrate and lipid metabolism
  
  • Diabetes
  • Hyperlipidaemia
• Reduced protein synthesis
  
  • Poor wound healing
• Osteoporosis
• Glaucoma and cataracts
• Psychiatric complications

Question 17

What are the uses of corticosteroids?

Answer 17

• Autoimmune diseases
  
  • CTD, vasculitis, RA
• Inflammatory diseases
  
  • Crohn’s, sarcoid, GCA/polymyalgia rheumatica
• Malignancies
  
  • Lymphoma
• Allograft rejection

Question 18

What is calcineurin?

Answer 18

Calcineurin (CN) is a calcium and calmodulin dependent serine/threonine protein phosphatase. Activates T cells and stimulates growth and differentiation.

Question 19

Name two calcineurin inhibitors.

Answer 19

• Ciclosporin A (CyA)

- Tacrolimus (FK506)

Question 20

How does ciclosporin work?

Answer 20

• Binds to intracellular protein cyclophilin
• Prevents activation of NFAT
  Factors which stimulate cytokines (i.e IL-2 and INFγ) gene transcription
• Reversible inhibition of T-cell activation, proliferation and clonal expansion

Question 21

How does sirolimus work?

Answer 21

• Also binds to FKBP12 but different effects
• Inhibits mammalian target of rapamycin (mTOR)
• Inhibits response to IL-2
• Cell cycle arrest at G1-S phase

Question 22

How does Azathioprine (AZA) work?

Answer 22

• Guanine anti-metabolite (i.e. purine analogue)
• Rapidly converted into 6-mercaptopurine
• Impaired T cell DNA production

Question 23

How does Mycophenolate mofetil work?

Answer 23

• Non-competitive inhibitor of IMPDH
• Prevents production of guanosine triphosphate
• Interferes with proliferation of T and B cells

Question 24

What are the clinical uses of cytotoxic drugs?

Answer 24

• AZA/MMF
  
  • Autoimmune diseases (SLE, vasulitis, IBD)
  • Allograft rejection
• MTX
  
  • RA, PsA, Polymyositis, vasculitis
  • GvHD in BMT
• Cyclophosphamide
  
  • Vasculitis (Wagner’s, CSS)
  • SLE

Question 25

What are the features of anti-TNF drugs?

Answer 25

- First biologics to be successfully used in therapy of RA (5 different agents now licensed) - Used in a number of other inflammatory conditions (Crohn’s, psoriasis, ankylosing spondylitis) - Caution: increase risk of TB

Question 26

What are the features of IL-6 drugs?

Answer 26

- Blocks IL-6 receptor - Used in therapy of RA and AOSD - May cause problems with control of serum lipids

Question 27

What is rituximab?

Answer 27

- Chimeric mAb against CD20- B cell surface - Can get rid of B cell producing autoreactive antibodies - Used in: - Lymphomas, leukaemias - Transplant rejection - Autoimmune disorders

Question 28

What are the indications for allergen-specific immunotherapy?

Answer 28

- Allergic rhinoconjutivitis not controlled on maximum medical therapy - Anaphylaxis to insect venoms

Question 29

What are the mechanisms behind allergen-specific immunotherapy?

Answer 29

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