The MHC and transplantation

Question 1

Normal individuals have shown to have what naturally occurring isoagglutins (in terms of blood group)?

Answer 1

Anti-A isoagglutins

Anti-B isoagglutins

Question 2

Can transplant be performed between blood incompatible individuals?

Answer 2

There is a poor outcome

Question 3

Using immunofluorescent staining cell membranes of which cells have been revealed to have blood group substance in their membranes?

Answer 3

All vascular endothelial cells and certain epithelial cells have been shown to have blood group substance in their cell membranes

Question 4

What are the MHC?

Answer 4

Set of genes found in all vertebrate species

Question 5

The MHC have an important role in what?

Answer 5

1) Immune function
2) Disease susceptibility
3) Reproductive success
4) Also have a role in histocompatibility, major influence on graft survival

Question 6

Where are proteins encoded by the MHC expressed?

Answer 6

At the cell surface, 50,000-100,000 MHC molecules on the average mammalian cell

Question 7

What is the function of proteins encoded by the MHC?

Answer 7

Function to present self and non-self antigens for inspection by T cell antigen receptors

Question 8

What is the alternative name for the Human MHC?

Answer 8

The HLA complex

Question 9

What 3 regions is the human MHC divided into and what does each code for?

Answer 9

Class 1 region - encodes HLA-A,B,C (classical)
Class 2 region - encodes HLA-DR, DQ, DP Ag
Class 3 region - encodes HSP70, TNF, C4A, C4B, C2, BF, CYP21

Question 10

Which class of MHC is not important in transplantation?

Answer 10

Class 3

Question 11

Which chromosome is the human MHC found on?

Answer 11

Short arm of chromosome 6 (6p21.3)

Question 12

How many megabases long is the MHC?

Answer 12

3.6Mbp

Question 13

Class 1 and 2 MHC genes are roughly how many kb?

Answer 13

Class 1 - 3-6kb

Class 2 - 4-11kb

Question 14

What are the proteins that MHC genes code for?

Answer 14

Human Leucocyte Antigens (HLA)

Question 15

Where are Class 1 antigens found?

Answer 15

On all nucleated cells

Question 16

Where are Class 2 antigens found?

Answer 16

primarily expressed on B lymphocytes but expression can be induced on T lymphocytes and other cells

Question 17

What kind of proteins are HLA?

Answer 17

Membrane bound glycoproteins

Have a rough structure of different domains making up a discrete protein binding groove

Question 18

What is the method of inheritance of HLAs?

Answer 18

Mendelian inheritance,
En-bloc from each parental chromosome, each individual inherits 2 antigens at a given locus - codominant expression - all of the antigens inherited are displayed on the cell surface (HLA phenotype)

Question 19

Are levels of expression of HLAs equal across all tissues, what implications does this have?

Answer 19

Different levels across tissues, has implications for the transplanted tissue

Question 20

MHC is highly polymorphic with a large number of allelic variants at each locus, how is this allelic variation maintained?

Answer 20

Maintained at a population level due to survival advantage

Question 21

Why is HLA polymorphism significant in fighting disease?

Answer 21

Significant in terms of capacity of an individual to mount an immune response to an antigenic challenge

Question 22

What are the 4 main types of HLA nomenclature?

Answer 22

Serology - worked out from that present in patients serum
1) Serology (broad)
2) Serology (split) - higher resolution
Molecular - found through molecular techniques
3) Molecular (low)
4) Molecular (high)

Question 23

Foreign HLA can be recognised in transplant tissue through direct recognition can occur, what is this process?

Answer 23

1) WBC of donor migrate to the recipient
2) Donor WBC interacts directly with recipient T cell, presenting transplant Ag
3) Recipient T cell now recognises donor antigens
4) T cells proliferate and kill donor tissue
Only happens in transplant situation, an unusual immunological process

Question 24

Foreign HLA can be recognised in transplant tissue through indirect recognition, what is this process?

Answer 24

1) Foreign Ag presented to recipient T cells by recipient APCs
2) Recipient T cells now recognise donor antigens and proliferate
3) Donor tissue killed
This is a normal immunological process

Question 25

How sensitive is the immune system to non self HLA?

Answer 25

Donor HLA can differ by only 1 amino acid and still be recognised by the recipient immune system

Question 26

What is sensitisation, why is it important in transplantation?

Answer 26

Sensitisation - an event which elicits an HLA directed immune response
Aswell as determining donor HLA, need to determine the HLA to which the recipient has already been exposed and ‘sensitised’ and see if the recipient is already sensitised to any donor HLA

Question 27

What 3 events are risk factors for HLA sensitisation?

Answer 27

1) Pregnancy (Sensitised to HLA mismatches with partner)
2) Blood transfusion
3) Previous transplantation

Question 28

What 2 methods are used to assess a recipients sensitisation to a donor?

Answer 28

Serum screening - longitudinally whilst waiting for a transplant
Crossmatching - A safety net when get a donor organ, mix donor cells with recipient serum to check nothing has been missed on serum screening

Question 29

What is one way that serum screening is carried out?

Answer 29

Use beads coated with HLA Ag, react with the recipient serum and measure the level of activity of each bead ie the level of Ab reactivity in recipient serum for each HLA Ag

Question 30

What does the cRF% tell you in terms of sensitisation in transplant?

Answer 30

Tells you the percentage of donors that would be inaccessible to a recipient based on the recipients pre-sensitisation

Question 31

What would a cRF% of 50% tell you?

Answer 31

50% of donors are inaccessible to the recipient based on pre-sensitisation - reduced target for finding a match

Question 32

What 3 things determine a recipients chance of finding a donor?

Answer 32

1) Rarity of HLA type
2) Blood group
3) Extent to which they are sensitised

Question 33

How is crossmatching when a donor transplant is found carried out?

Answer 33

1) T lymphocyte from donor expresses HLA Ag on its surface
2) Add to the donor lymphocytes recipient serum
3) If recipient serum contains Ab to donor HLA they will bind
4) Add fluorescently labelled reporter molecules which bind to the Ab and can be detected
NB. this shouldn’t happen because of prior serum screening- this is a safety net

Question 34

If positive cross matching occurs can an organ be transplanted?

Answer 34

As a rule no

Question 35

If positive cross matching occurs and an organ is still transplanted what can this result in?

Answer 35

Hyperacute reaction

Question 36

What happens in a hyperacute reaction?

Answer 36

1) Anastamosis between donor and recipient vessel
2) Recipient blood flows in and binds to HLA on donor vascular cells
3) Get activation of clotting cascade
4) And complement activation
5) Lose endothelial integrity and damage to donor tissue

Question 37

Are you likely to find a perfect HLA match?

Answer 37

No, very unlikely that 2 non siblings will be perfectly HLA matched

Question 38

What are the chances of 2 siblings being perfectly matched?

Answer 38

1 in 4 (as codominant expression, 1 allele from each parent)

Question 39

What are the chances of 2 siblings being completely HLA mismatched?

Answer 39

1 in 4

Question 40

What are the chances of 2 siblings being partially HLA matched?

Answer 40

1 in 2

Question 41

What are isoagglutinins?

Answer 41

Antibodies produced by an individual that cause agglutination of the red blood cells of others