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MIIM30003 - Medical & Applied Immunology > Lecture 13 - Transplant Immunology II > Flashcards

Lecture 13 - Transplant Immunology II Flashcards

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USMLE® Step 1 flashcards
1
Q

List the things taken into consideration in pre-transplant assessment

A
  • ABO matching
  • Tissue typing - HLA matching

• Assessment of risk of rejection
- Pre-existing Ab

• Pre-tx cross matching

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2
Q

Compare A1 and A2 bloodtypes

A

A1:
• 80-90% of A individuals are A1
• RBCs express high density of terminal residues on the oligosaccharides

A2:
 • 10-20% of A individuals
 • Low density of terminal sugars on RBC oligosaccharides
 • Fewer and less potent Ags
 • Behaves like group O
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3
Q

Describe what can occur in transplants when there is ABO group mismatch

A

Hyperacute rejection:

• Depending on blood group, an individual will have pre-formed IgM Abs against allogeneic RBCs

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4
Q

How can pre-formed Ab be reduced pre-transplant?

A

Removal:
• Plasma exchange
• Catheter in arm; blood cleared of Ab, blood flows back in through catheter in the other arm

Neutralisation:
• Intravenous Ig

Decreased Ab prod’n:
• Splenectomy
• Rituximab

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5
Q

Describe ‘tissue typing’ stage of pre-transplant assessment

A

Tissue type : HLA type

Donor and host tissues are typed for HLA Ags using:

  1. Serology
    • CDC
    • Panel of defined sera
  2. Molecular analysis
    • PCR based
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6
Q

Why is tissue typing important?

A

With increasing HLA mismatches between donor and recipient, there is greater risk of transplant rejection

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7
Q

Describe assessment for pre-formed Abs

A

Clinical history:
• Pregnancy
• Previous blood transfusion
• Previous transplant

Check serum sensitisation to HLA:
• Panel of donor Ags (PRA)

Most patients with pre-formed Abs have no clinical history of sensitisation

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8
Q

What is PRA?

Describe its use

What does it indicate?

A

Panel reactive Ab

Process:
1. Pre-made trays with live lymphocytes from 40-60 individuals
(represents widest range of HLA possible)

  1. Recipient’s serum added
  2. If there are pre-formed Abs against particular HLA in serum, the cells will die
  3. Dead cells stain red

Indications:
• Indirect indication of ‘transplantability’
• Determines probability of ‘crossmatch’ negative with a particular donor
• Can identify specific Ags to avoid

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9
Q

What happens if there is a high PRA result?

A
  • Longer waiting time
  • Increased rejection episodes
  • Greater immunosuppression required
  • Decreased graft survival
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10
Q

Describe the process of pre-transplant crossmatch

A

“Transplant in a test-tube”

  1. Blood samples taken from donor and recipient
  2. Donor cells and recipient serum plated out into wells
  3. Rabbit C’ added
  4. Membrane injury visualised using light microscope
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11
Q

List drugs that act through calcineurin inhibition

Describe the MOA and the immunological effects

A

Cyclosporin
• Inhibits IL-2 gene transcription in T cells
• T cells cannot proliferate after becoming activated
• Reduced T cell and granulocyte exocytosis of granule-associated serine esterases
• B cells have reduced proliferation
• B cells undergo apoptosis following activation

Tacrolimus
• Similar activation to cyclosporin
• Binds FK-binding protein which binds calcineurin
• Same immunological effects

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12
Q

What are the AE of cyclosporin?

A

Nephrotoxicity

5-10 after renal transplant, an individual will need another transplant due to the effects of cyclosporin on the kidney

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13
Q

What are the side effects of steroids?

A
  • Fluid retention
  • Hypertension
  • Increased susceptibility to infection
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14
Q

List an important steroid drug

A

Prednisolone

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15
Q

Where is the steroid receptor?

A

In the cytoplasm

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16
Q

Describe the effects of steroids

A

Anti-inflammatory:
↓ circulating lymphocytes
↓ neutrophil enzyme release
↓ monocyte activity

Immunosuppressive:
↓ lymphocyte proliferation
↓ Ag presentation by monocytes

17
Q

Describe the signalling of steroids

A
  1. Steroids cross plasma membrane and bind with receptor in cytoplasm
  2. Heat shock protein dissociates from steroid receptor
  3. Steroid-receptor complex moves into nucleus and binds regulatory regions on DNA
  4. Activation of gene transcription
18
Q

Describe how anti-proliferative drugs act

List some

A
  • Azathioprine
  • Mycophenalate
  • Rapamycin

MOA:
• Inhibit DNA and RNA synthesis

Effect:
• Blocks IL-2 production and lymphocyte expansion

19
Q

Describe the rationale of the use of combined immunosuppressive drugs

A

Allows use of lower doses of individual drugs to minimise side effects

20
Q

What things will we see in the future of transplantation?

A
  • Better immunological matching
  • More specific immunosuppression
  • Xenotransplantation
  • Induction of specific tolerance to transplanted organ
  • Stem cell transplants
21
Q

Give an overview of immunological tolerance

A

The removal, suppression or isolation of auto-reactive lymphocytes

Central and peripheral mechanisms

  • Deletion
  • Receptor editing
  • Anergy
  • Suppression w/ Tregs
  • Ignorance
22
Q

Describe approaches to donor specific tolerance

A

Interrupt signalling:
• Cyclosporine

Co-stimulation blockade:
• Ipilimumab (anti-CTLA4 Ab); blocks CD28

Donor haematopoietic chimerism
• BM transplant

Tregs
• Tregs inhibit aggressive T cells in their response against the graft

23
Q

What is stem cell transplantation?

A

In vitro differentiation of human ESCs into specialised tissues and then transplantation into people

Prospects:
Regeneration of whole tissues:
 • Lungs
 • Blood
 • Heart
 • Neurons
 • Pancreas

Use of scaffold to grow organ

24
Q

What ethical considerations need to be taken into account with transplantation?

A

Donor supply is the limiting factor in the growth of transplantation

The various sources of organs raises ethical issues:

Status of donors:
 • Brain dead, receiving cardiac / lung support
 • Not in coma
 • Not in persistent vegetative state
 • Not in 'locked-in' state

Tourism transplantation

Executed prisoner donors

25
Q

List other names for Hyperacute rejection

A

Antibody mediated rejection
/
Humoral rejection

26
Q

Describe the protocol for ABO matching in organ transplantation

A

Organs are only transplanted across blood group lines

Exceptions:
• O to A2 individual
• Pre-transplant reduction of Ab

27
Q

Which HLA loci are most important in terms of pre-transplant tissue typing

A

Differences and A, B and DR are far more important than differences at C, DP and DQ.

28
Q

Outline the cocktail of immunosuppressive drugs used for transplants

A
  1. Calcineurin inhibitors
    • Cyclosporin
    • Tacrolimus
  2. Anti-inflammatories
    • Steroids
  3. Anti-proliferatives
    • Azathioprine
29
Q

What is CD25?

A

The alpha subunit of the IL-2 receptor

MIIM30003 - Medical & Applied Immunology (30 decks)

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