L2.2 Immunosuppressant

Question 1

Uses of the immunosuppressant

Answer 1

• Prevent tissue transplant rejection
• Treat autoimmune diseases
• Treat chronic inflammation diseases

Question 2

Problems with transplantations

Answer 2

• recognise as foreign tissue → mounts immune response
• Inappropriate activation of T-lymphocytes
• Propagation of unwanted immune response

Question 3

Phases of transplantation rejection

Answer 3

1. Hyperacute (initiated rapidly following transplantation)
   
   • Patients have pre-formed AB → against graft-vascular endothelial cells → severe blood coagulation
2. Acute (weeks → months)
   
   • Driven by lymphocytes
     
     • Damage during transplant → release DAMPs → immune response mounted to clear the ‘threat’
   • Major target of immunosuppressant
3. Chronic (months → years)
   
   • Slow fibrosis & remodeling
   • e.g. Rheumatoid arthritis, type 1 diabetes…

Question 4

Relationship b/w immunsuppressive targets & Anti-inflammatory drugs

Answer 4

• Immunosuppressant and anti-inflammatory targets are on opposite ends of the spectrum

Question 5

How do T-cells contribute to graft rejection responses

Answer 5

• T-cells → activate Ca2+ → ↑IL2 & drives proliferation of clonal T-cells → activates T-cells → autoimmune response against graft

Question 6

Why are drugs usually used in combinations

Answer 6

• Drugs are usually used in combination - with lower doses of single drug required → ↓drug specific adverse effect

Question 7

Mechanism of calcineurin inhibitors

Answer 7

• APC present antigen to T-cell on MHC II surface → PLC → ↑Ca2+ → Calcineurin (IMMUNOPHILIN ACTS TO INHIBIT) → P-NFAT (becomes dephosphorylated) → NFAT (now in nucleus) → ↑[IL2] → mTOR (SIROLIMUS ACTS) → cell proliferation

Question 8

Calcineurin inhibitors: Cyclosporin

Answer 8

• From soil fungus Borel
• Binds immunophilin: cyclophilin
• Active orally
• A.E: Nephrotoxicity

Question 9

Calcineurin inhibitor: Tacrolimus (FK506)

Answer 9

• Binds immunophilin: FKBP
• A.E Nephrotoxocity

Question 10

Calcineurin inhibitor: Sirolimus (rapamycin)

Answer 10

• Binds immunophilin: FKBP but acts on mTOR instead of calcineurin
• A.E Hyperlipidemia

Question 11

Anti-metabolites: Azothioprine

Answer 11

• Inhibits cell ability to make nucleic acid (purine)
  
  • Blunts DNA syn → cell death (signals to apoptose)
• *Converted to 6-mercaptopurine → inhibits purine*

Question 12

Anti-metabolites: Mycophenolate mofetil

Answer 12

• Selective inhibition of de novo pathway
• Lymphocytes rely on de novo purine syn pathway
• Others normally rely on salvage pathway
• A.E: Blood leukopenia

Question 13

Harvesting Monoclonal AB with mice

Answer 13

1. Inject mice with protein want to form AB against
2. Havest B-cells
3. Fuse with tumour cell → hybrid cell producing AB

But may generate anti-AB response in humans

Question 14

Havesting chimeric Monoclonal AB

Answer 14

1. Isolate RNA, splice and clone part of AB involving antigen binding
2. Place into human AB backbone

Question 15

Monoclonal AB action: delete lymphocytes

Answer 15

• Delete lymphocytes (induction therapy)
• Munromonab
  
  • Tags & recruits killer T-cells
  • Triggers apoptosis
  • AB & Complement - dependent cytotoxicity

Question 16

Monoclonal AB: Blocking R

Answer 16

• Basiliximab, Daelizumab
• Competitively block R.
• Internalising R.

Question 17

General unwanted effects of immunosuppressants

Answer 17

• ↑risks of infection & cancer
• Immunosuppressant generally have to be used for life

Question 18

Inducing immune tolerance

Answer 18

• Bone marrow chimerism: Stem cells from donor → grow
  
  • Tolerance of both immune systems
• Regulatory T-cells introduction/expansion
• Modulation of lymphocyte co-stimulation
  
  • Danger signal (driven by co-stim)
    
    • B7 (on activated APC) + CD28 (on T-cells) → without interaction → T-cells not activated
  • Abatacept/Belatacept (fusion proteins) → Block B7 molecule → prevent co-stim to T-cells & develop tolerance