L15 Cell and organ transplantation

Question 1

Types of transplantation

Answer 1

Syn - with, together, same
Allo - different, other
Xeno - foreign
Autologous

Question 2

Transplantation

Answer 2

The grafting of tissue, usually from one individual to another

Question 3

Autograft (autologous)

Answer 3

To another site on the same individual (eg. after burns)

Question 4

Isograft (iso/syngeneic)

Answer 4

To a genetically identical individual (homozygous twins)

Question 5

Allograft(allogeneic)

Answer 5

To a genetically disparate member of the same species

Question 6

Xenograft (xenogeneic)

Answer 6

To a different species (pig or monkey to human)

Question 7

Features of renal transplantation(donor may be dead or alive)

Answer 7

• Operation: trauma and ischemia(cold and warm)
• Reperfusion of ischemic organ(reperfusion damage)
• Inflammation/wound healing
• Inflammation response against the graft

Question 8

What is the warm ischemic phase

Answer 8

• Time from interruption of circulation to the donor organ to the time when organ is flushed with hypothermic preservation solution

Question 9

What is the cold ischemic phase

Answer 9

• While the organ is preserved in a hypothermic state prior to transplantation into the recipient

Question 10

Types of graft rejection

Answer 10

Hyperacute rejection - mins/hrs/days

Acute rejection - days - weeks, also later(late acute)

Chronic rejection (weeks) - months, years

Question 11

Blood groups

Answer 11

Group A - has only the A antigen on red cells (and B antibody in the plasma)

Group B - has only the B antigen on red cells (and A antibody in the plasma)

Group AB - Has both A and B antigens on red cells(but neither A nor B antibody in the plasma)

Group O - Has neither A nor B antigens on red cells (but both A and B antibody are in the plasma)

Question 12

Which cells express HLA-antigens

Answer 12

• Red blood cells do not express HLA antigens

- All nucleated cells do

Question 13

How do HLA antibodies cause graft injury

Answer 13

inducing phenotypic changes in the donor vasculature:

• Causing endothelial cell (EC) activation, which promotes recruitment of leukocytes and CD4 T cell proliferation in response to alloantigen HLA class II on EC
• Complement-activating antibodies trigger the classical pathway through binding of C1q, resulting in production of the anaphylatoxins C3a and C5a, which have the potential to directly augment leukocyte recruitment and T cell alloresponses
• Monocytes, neutrophils, and natural killer (NK) cells also express Fc receptors, which can interact with the heavy chain of HLA antibodies bound to donor ECs
• FcyR functions augment leukocyte recruitment and mediate phagocytosis and antibody-dependent cellular cytotoxicity

Question 14

What causes the microvascular inflammation characteristic of antibody-mediated rejection

Answer 14

• Pleiotropic functions of HLA antibodies on the allograft ECs

Question 15

What prevents hyperacute rejection

Answer 15

• Matching donor and recipient for HLA and ABO blood group antigens

Question 16

PCR

Answer 16

High or low resolution, eg. 2 or 4-letter code or even higher resolution

• Not all parts of the HLA-molecule are important. The most important parts are those where they differ from one another. This is where peptides are bound in the binding groove

Question 17

Cross match

Answer 17

• Incubation of washed donor cells with recipient serum, antibody binding detected by mouse-anti-human Ab stain of recipient cells or cytotoxicity suitable detection system

Question 18

Effect of polymorphic self proteins

Answer 18

• Polymorphic self proteins that differ in amino acid sequence between individuals give rise to minor H antigen differences between donor and recipient

Question 19

What is the mechanism via which hyperacute rejection occurs

Answer 19

• Preformed antibodies

Question 20

What does the TCR recognise

Answer 20

• The TCR recognises peptide antigen in the ‘context’ of a special presenting molecule, the MHC complex
• MHC molecules are found on most cells, however, there are different types
• The most important ones are class I and class II MHC
• Whereas class I MHC is found on all nucleated cells, class II MHC is only found on a subset

Question 21

Mechanism via which acute rejection occurs

Answer 21

• T-cells

Question 22

Drugs involved in interfering with T-cell activation

Answer 22

Cyclosporin A, tacrolimus - T-cell inhibition (calcineurinine inhibitor, inhibition of cytokine synthesis: IL-2, IFNg…)

Azathioprine, MMF - Antiproliferative (inhibits clonal expansions)

Question 23

Chronic graft rejection (eg. kidney) - features

Answer 23

• Short ischaemic time (living [related] donor)
• Long ischaemic time (cadaveric donor)
• Immunogenicity and incidence of chronic rejection

Question 24

How do corticosteroids affect the immune system

Answer 24

Corticosteroids block NFkB activation and achieve inhibition/reduction of

• Ischaemia/reperfusion injury
• Activation of APC
• Inhibition of cytokine synthesis(acute inflammation)

Question 25

Triple drug therapy in immunosuppression

Answer 25

• Cyclosporin A, tacrolimus
• Azathiprine, MMF
• Corticosteroids (eg. methyprednisolone) - anti-inflammatory(inhibition of NFkB, cytokine synthesis and action)

Question 26

Mechanism via which chronic rejection occurs

Answer 26

• Chronic processes, including vascular changes in the graft

Question 27

Why can immunosuppression be reduced a few months after organ transplantation

Answer 27

• ‘Passenger leukocytes’ such as peptide-dominant binding and MHC-dominant binding cells are present in the early phase
• Strong immunosuppression is required, donor cells provide non-self MHC
• Recipient leukocytes(present all of the time)
• Weaker suppression required when passenger leukocytes are gone

Question 28

Ligand/receptor interactions and danger signals

Answer 28

Tissue injury - hypoxia
Cytokines - TNF, IL-1…
Microbial products - LPS, LTA, CpG DNA…

• Via TLRs and other PRRs Cytokine R, Ag-presenting cell
• Surgery provides danger signals: trauma, inflammation, ischemia/reperfusion etc
• Warm ischemic time is a significant problem