Immunosuppression

Question 1

3 signal model

Answer 1

• An antigen-presenting cell binds to the T cell receptor and triggers the T cell at signal 1
• Costimulatory molecules and ligands bind at signal 2
• The activation of both signals 1 and 2 are needed to result in the expression of IL-2 and other factors
• At signal 3, stimulation of the IL2 receptor on the T-cell surface triggers T-cell proliferation

IL2 is a cytokine made by white blood cells

If you can stop any of these signals you stop t-cell proliferation and you stop immunosuppression

Question 2

The 3 phases of immunosuppression

Answer 2

The 3 phases of immunosuppression are:
• Induction
• Maintenance
• Treatment of rejection

Question 3

Induction

Answer 3

Induction is immunosuppressive therapy before transplant

Antibody therapy includes T-cell depleting and non-depleting agents
Depleting agents: polyclonal and monoclonal agents

Polyclonal antithymocyte antibodies:
•	Rabbit antithymocyte globulin rATG
•	Horse antithymocyte globulin hATG
•	These antibodies work against T-cells
•	As you infuse patients with polyclonal antibodies patient become really sick

Question 4

Maintenance

Answer 4

Drugs for maintenance:
•	Calcineurin inhibitors 
•	Antiproliferative/antimetabolites
•	Corticosteroids
•	Mammalian target of rapamycin inhibitors (MTOR)
•	T-cell co-stimulation blockers

Question 5

Calcineurin inhibitors
Stop signal 1 and 3
mechanism of action

Answer 5

• Calcineurin catalyses some of the intracellular processes associated with the activation of T-cell lymphocytes
• When calcineurin inhibitors bind to intracellular proteins called immunophilins they block the effect of calcineurin
• This results in reduced production of IL2 and reduced proliferation of T-cells
• (IL2 plays a role in activation of T-cell)

Question 6

Calcineurin inhibitors - examples

Answer 6

• Cyclosporin – binds with cyclophilin (an immunophilin) to inhibit calcineurin
• Tacrolimus – more potent than cyclosporin and binds to a different immunophilin (FK binding protein) to inhibit calcineurin

Question 7

Calcineurin inhibitors - adverse events

Answer 7

Concentration related adverse effects include nephrotoxicity (problem in kidney function)

Pathogenesis is multifactorial:
• Calcineurin inhibitors induce release of endothelin-1) a potent vasoconstrictor – causes renal artery vasoconstriction resulting in reduced renal blood flow and reduced GFR – toxic to kidney basically
• Low GFR means increased potassium levels which can kill you
• Decreased production of vasodilator nitric acid
• Increased expression of transforming growth factor beta (a key cytokine associated with interstitial fibrosis)

Side effects:
•	Hypertension
•	High potassium 
•	Nephrotoxicity 
•	Gingival hyperplasia – overgrowth of gum
•	Hirsutism – hair growth 
•	Tremor
•	Hyperlipidaemia
•	Diabetes

Tacrolimus compared to ciclosporin less likely to cause hyperlipidaemia, hirsutism and gum problem but diabetes is commonly associated

Question 8

Antiproliferative/
antimetabolite agents
Affects SIGNAL 3
examples

Answer 8

• Sirolimus
• Everolimus
• Mycophenolate
• Azathioprine – don’t use it in transplants much

Question 9

Sirolimus and everolimus mechanism of action

Answer 9

1. They bind to the FK-binding protein but have no effect on calcineurin
2. The binding complex inhibits a protein kinase that is critical for cell cycle progression
3. This kinase is known as the mammalian target of rapamycin (mTOR)
4. Inhibition of mTOR suppresses cytokine driven T-lymphocyte proliferation and activation resulting in immunosuppression

Question 10

MYCOPHENOLATE (MMF) (antimetabolite) mechanism of action

Answer 10

• Mycophenolate is the prodrug of mycophenolic acid (active metabolite) which inhibits purine synthesis by inhibiting inosine monophosphate dehydrogenase
• Inosine monophosphate dehydrogenase involved in guanine nucleotide synthesis required for T-cell and B-cell proliferation

Question 11

MYCOPHENOLATE (MMF) sife effects

Answer 11

MMF causes:
• GI complication: Nausea, Vomiting, ulcers, diarrhoea and abdominal pain
• Dose dependent toxicity

Question 12

Azathioprine (antimetabolite) MOA

Answer 12

A prodrug which breaks down into 6MP and then metabolised further - inhibits DNA synthesis
Not used much in transplants but used in immune disorders

Question 13

Corticosteroids
Stop signal 3 and other areas
MOA

Answer 13

Block T-cell derived, and antigen precenting cell derived cytokine expression
Basically, dampen down cytokine expression

Question 14

Corticosteroids adverse effects

Answer 14

• Steroid induced diabetes
• Hypertension
• Weight gain
• Ulcers

Some doctors don’t even use steroids they just use high dose ATG (induction drug)