Transplantation

Question 1

What is a transplant?

Answer 1

The replacement of tissues or organs that have undergone an irreversible pathological process which threatens the patient’s life or to a significant degree considerably hampers their quality of life

Question 2

What can be transplanted?

Answer 2

• Organs including lungs, kidneys, heart, liver, pancreas and womb
• Tissues including nerve, skin, bones and corneas

Question 3

What types of transplant/graft are there?

Answer 3

• Xenograft
• Allograft
• Isograft
• Autograft

Question 4

What is a xenograft?

Answer 4

• From a different species

- MHC, ABO and IgM incompatible

Question 5

What are unmodified xenografts guaranteed to lead to?

Answer 5

Immediate failure= hyperacute rejection

Question 6

What is an allograft?

Answer 6

• Transfer between genetically non-identical members of the same species
• Most common graft

Question 7

What must take place before allografting?

Answer 7

Careful tissue matching including ABO blood group and HLA(A,B,DR)

Question 8

What is an autograft?

Answer 8

• Transfer of tissue between different sites within the same organism
• Example: skin graft

Question 9

What is an isograft?

Answer 9

• From a monozygotic twin

- Same HLA match but theoretically could have different antibodies

Question 10

What is histocompatibility?

Answer 10

Property of having the same or sufficiently similar, alleles of a set of genes on chromosome 6 (HLA)
-These genes co-dominantly expressed meaning every individual expresses each of the inherited alleles, both paternal and maternal.

Question 11

What are the features of HLA class 1?

Answer 11

• HLA-A, B and C
• Present on all nucleated cells
• CD8/Tc cells recognise
• Present antigen peptides from within the cells (examples viruses)

Question 12

What are the features of HLA class 2?

Answer 12

• HLA-DR,DP,DQ
• Only present on APCs
• CD4/Th cells recognise
• Present extracellular antigens such as extracellular bacteria

Question 13

What are privileged sites?

Answer 13

Sites where there is no blood flow so no sensitisation

• No requirement for tissue matching
• No immunosuppression required

Question 14

What are the advantages of living donors?

Answer 14

• Less rejection
• Quicker
• Last longer
• Healthier
• Easier to manage

Question 15

What types of deceased donor are there?

Answer 15

• Brain death

- Cardiac death

Question 16

What types of living donor are there?

Answer 16

• Related or unrelated

- Altruistic

Question 17

What are the possible complications of transplants?

Answer 17

• Graft rejection
• Graft versus host disease
• Infection (as a result of immunosuppressive therapy or of transfer of infectious agent in graft)
• Neoplasia (lymphoma, skin tumours)
• Drug side effects
• Recurrence of original disease
• Ethical, surgical problems

Question 18

What is graft rejection?

Answer 18

Transplanted tissue is rejected by the recipient’s immune system, which destroys the transplanted tissue

Question 19

What are the causes of graft rejection?

Answer 19

• ABO or HLA incompatible
• Pre-formed immunity for previous transplants, transfusion or pregnancies
• Infections such as CMV or EBV and it’s postulated some environmental triggers such as pollution in lung transplant
• Failed immunosuppression, either by side effects, bad luck or non-concordance

Question 20

What are the 3 phases of rejection?

Answer 20

• Hyperacute
• Acute
• Chronic

Question 21

When does hyperacute rejection take place?

Answer 21

Can happen in minutes and is often characterised by an organ that won’t perfuse (pink up)

Question 22

What increases the risk of hyperacute rejection?

Answer 22

• Previous failed transplants
• Pregnancies
• Blood transfusions

Question 23

What is often the cause of hyperacute rejection?

Answer 23

Often incompatible ABO and/or HLA antibodies

Question 24

What is the pathophysiology of hyperacute rejection?

Answer 24

Innate immune complement activation damages blood vessels, causing inflammation and thrombosis

Question 25

When does acute rejections takes place?

Answer 25

Usually occurs within the first 6months and can be a mix of cell and antibody mediated

Question 26

What is the pathophysiology of acute rejection?

Answer 26

- Cellular infiltration of graft by Tc cells, B cells, NK cells and macrophages causing endothelial inflammation and parenchymal cell damage on a comparatively slower scale - Host T cells recognise intact allo-MHS molecules on the surface of tissues - Unlike T and B cells, NK cell are activated by the absence of MHC molecules on the surface of target graft cells - The recognition is mediated by various NK inhibitory receptor triggered by specific alleles of MHC class I antigens on cell surfaces

Question 27

What is the commonest cause of graft failure?

Answer 27

Chronic rejection

Question 28

When does chronic rejection occur?

Answer 28

>6 months post-transplant

Question 29

What is the pathophysiology of chronic rejection?

Answer 29

-It is mostly antibody mediated with other innate components leading to myointimal proliferation in arteries -This leads to strangulation of blood flow over time as cytokines and antibodies cause a chronic inflammatory process that proliferates cell walls to protect themselves and due to turnover. This in turn blocks off blood vessels more and leads to ischaemia and fibrosis

Question 30

How is chronic rejection treated?

Answer 30

Corticosteroids -Usually given IV in 3 pulses as 1st line Anti-thymocyte globulin -Given 2nd line in cell mediated rejection. Made of recombinat horse/rabbit T cell antibodies (allergies!) Plasma exchange -2nd/3rd line measure with immunoglobulin replacement to remove donor specific antibodies in antibody mediated rejection

Question 31

How is chronic rejection prevented?

Answer 31

- ABO matching - Tissue typing (Class I and II HLA) - Prophylactic immunosuppression - Humanised or silenced xerografts

Question 32

What is graft versus host disease?

Answer 32

Immunologically active graft (usually bone marrow) attacks the recipient as if it was a foreign invader

Question 33

What can be attacked in GVHD?

Answer 33

- Skin - Gut - Liver - Immune cells

Question 34

What is the triad of requirements for GVHD?

Answer 34

- Immunocompetent cells in graft (common in bone marrow) - Defective recipient immunity (common in transplants on immunosuppression) - HLA differences between donor and recipient (critical step which can be prevented but is a challenge

Question 35

What is the treatment for GVHD?

Answer 35

Only treatments are immunosuppressive and cytotoxic agents

Question 36

How can GVHD be prevented?

Answer 36

- Careful and very close tissue matching | - Deplete donor marrow of T cells in-vitro prior to grafting

Question 37

What is the problem with using porcine tissues for transplant?

Answer 37

All humans have naturally acquired IgM class antibody directed against pig antigens and particularly against galactose residues which are present in high density on all porcine cells including endothelial cells

Question 38

What can possible be done to allow porcine tissues to be used in transplantation?

Answer 38

- Remove the IgM antibody ex-vivo from potential pig organ recipients - Genetically modified pigs - Humanised transgeric pigs (chimerics)

Question 39

What is the cause of hyperacute rejection?

Answer 39

Preformed antibody against donor HLA or ABO antigens

Question 40

What is the cause of accelerated rejection?

Answer 40

T cells (presence of T cells pre-sensitised to donor antigens)

Question 41

What is the cause of acute rejection?

Answer 41

T cells that are newly sensitised to donor antigens

Question 42

What is the cause of chronic rejection?

Answer 42

Multifactorial

Question 43

What is tacrolimus?

Answer 43

A calcineurin inhibitor

Question 44

What interleukin is involved in the CD4/APC interaction in rejection?

Answer 44

IL-2