Transplantation

Question 1

What is an allograft?

Answer 1

between different members of the same species

Question 2

What is an autograft?

Answer 2

from one part of the body to another eg skin

Question 3

What is an isograft?

Answer 3

between genetically identical individuals eg monozygotic twins

Question 4

What is a xenograft?

Answer 4

between members of different species eg porcine valves

Question 5

Which immune cell is responsible for the rejection response?

Answer 5

• T-cells recognize MHC antigen, the HLA molecules that are on the surface of most cells
• MHC antigens that stimulate strong rejection responses are encoded by MHC genes
  
  • if you are twins, you have the same MHC and low-risk of rejection
  • if you are not, you have different (non-self) MHC that will be recognized as an antigen by the T cells

Question 6

What is MHC Class I?

Answer 6

• HLA-A, B, and C loci
• expressed on all cells
• present cytoplasm-derived proteins (Ags)
  
  • presents Ag to CD8+ T-cells

Question 7

What is MHC Class II?

Answer 7

• DR, DP, and DQ loci
• presented mainly on APC and other inducible cells
• present extracellular derived proteins (Ag) to CD4+ T cells

Question 8

What is the major transplant antigen?

Answer 8

non-self MHC molecules

Question 9

What is hyperacute rejection?

Answer 9

• humoral rejection, antibody-mediated rejection
• minutes-hours
• caused by pre-formed anti-donor antibodies and complement to:
  
  • blood group
  • non-self MHC
    
    • can be developed through previous exposure (transfusions, pregnancy, transplant)
    • can have without this exposure as well

Question 10

What is acute cellular allograft rejection?

Answer 10

• occurs over days-weeks
• caused by primary activation of T cells
  
  • as self-APCs travel through the graft they pick up chunks of non-self MHC
  • self-APC and non-self-APC present to T-cells in draining lymph nodes
  • activates and proliferates T-cells against non-self MHC

Question 11

What is chronic allograft rejection?

Answer 11

• occurs over months-years
• not fully understood; wear and tear of not coping with many insults over time
• slow process where function declines
• can be caused by/a combination of:
  
  • episodes of acute rejection early on - T-cells in graft from day 1
  • association with viral infections - CMV
  • ischaemia-reperfusion injury (between bodies)
  • hyperlipidaemia
  • hypertension
  • infection
• characterized by scarring or fibrosis of organs predominantly around tubules

Question 12

How is allograft rejection prevented?

Answer 12

• matching blood type ABO antigens
• matching MHC alleles
• immunosuppressive drugs

Question 13

Immunosuppressive drugs target

Answer 13

T-cells

Question 14

How is graft rejection inhibited?

Answer 14

• immunosuppressive drugs:
  
  • azathioprine - not sufficient on its own, first developed drug
  • prednisolone (steroid) - needed high doses, dangerous
  • cyclosporin - targets recently-activated T-cells

Question 15

What are the commonly used immunosuppressive drugs?

Answer 15

cocktail of:

• calcineurin inhibitors
  
  • cyclosporin, tacrolimus
• anti-inflammatories
  
  • steroids
• anti-proliferatives
  
  • azathioprine

Question 16

How do calcineurin inhibitors work?

Answer 16

• eg cyclosporin, tacrolimus
• inhibit IL-2 gene transcription
  
  • IL-2 normally functions in a positive feedback loop from activated T-cells onto themselves to proliferate and activate more T-cells

Question 17

What are the downsides of calcineurin inhibitors?

Answer 17

• leave pt susceptible to viral infection: CMV, HSV
• major side effect of cyclosporin is nephrotoxicity