L2.2 Immunosuppressant Flashcards Preview

Pharmacology > L2.2 Immunosuppressant > Flashcards

Flashcards in L2.2 Immunosuppressant Deck (18):
1

Uses of the immunosuppressant

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

2

Problems with transplantations

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

3

Phases of transplantation rejection

  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…

4

Relationship b/w immunsuppressive targets & Anti-inflammatory drugs

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

5

How do T-cells contribute to graft rejection responses

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

6

Why are drugs usually used in combinations

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

7

Mechanism of calcineurin inhibitors

  • 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

8

Calcineurin inhibitors: Cyclosporin

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

9

Calcineurin inhibitor: Tacrolimus (FK506)

  • Binds immunophilin: FKBP
  • A.E Nephrotoxocity

10

Calcineurin inhibitor: Sirolimus (rapamycin)

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

11

Anti-metabolites: Azothioprine

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

12

Anti-metabolites: Mycophenolate mofetil

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

13

Harvesting Monoclonal AB with mice

  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

14

Havesting chimeric Monoclonal AB

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

15

Monoclonal AB action: delete lymphocytes

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

16

Monoclonal AB: Blocking R

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

17

General unwanted effects of immunosuppressants

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

18

Inducing immune tolerance

  • 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