The MHC and transplantation Flashcards
Normal individuals have shown to have what naturally occurring isoagglutins (in terms of blood group)?
Anti-A isoagglutins
Anti-B isoagglutins
Can transplant be performed between blood incompatible individuals?
There is a poor outcome
Using immunofluorescent staining cell membranes of which cells have been revealed to have blood group substance in their membranes?
All vascular endothelial cells and certain epithelial cells have been shown to have blood group substance in their cell membranes
What are the MHC?
Set of genes found in all vertebrate species
The MHC have an important role in what?
1) Immune function
2) Disease susceptibility
3) Reproductive success
4) Also have a role in histocompatibility, major influence on graft survival
Where are proteins encoded by the MHC expressed?
At the cell surface, 50,000-100,000 MHC molecules on the average mammalian cell
What is the function of proteins encoded by the MHC?
Function to present self and non-self antigens for inspection by T cell antigen receptors
What is the alternative name for the Human MHC?
The HLA complex
What 3 regions is the human MHC divided into and what does each code for?
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
Which class of MHC is not important in transplantation?
Class 3
Which chromosome is the human MHC found on?
Short arm of chromosome 6 (6p21.3)
How many megabases long is the MHC?
3.6Mbp
Class 1 and 2 MHC genes are roughly how many kb?
Class 1 - 3-6kb
Class 2 - 4-11kb
What are the proteins that MHC genes code for?
Human Leucocyte Antigens (HLA)
Where are Class 1 antigens found?
On all nucleated cells
Where are Class 2 antigens found?
primarily expressed on B lymphocytes but expression can be induced on T lymphocytes and other cells
What kind of proteins are HLA?
Membrane bound glycoproteins
Have a rough structure of different domains making up a discrete protein binding groove
What is the method of inheritance of HLAs?
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)
Are levels of expression of HLAs equal across all tissues, what implications does this have?
Different levels across tissues, has implications for the transplanted tissue
MHC is highly polymorphic with a large number of allelic variants at each locus, how is this allelic variation maintained?
Maintained at a population level due to survival advantage
Why is HLA polymorphism significant in fighting disease?
Significant in terms of capacity of an individual to mount an immune response to an antigenic challenge
What are the 4 main types of HLA nomenclature?
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)
Foreign HLA can be recognised in transplant tissue through direct recognition can occur, what is this process?
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
Foreign HLA can be recognised in transplant tissue through indirect recognition, what is this process?
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
How sensitive is the immune system to non self HLA?
Donor HLA can differ by only 1 amino acid and still be recognised by the recipient immune system
What is sensitisation, why is it important in transplantation?
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
What 3 events are risk factors for HLA sensitisation?
1) Pregnancy (Sensitised to HLA mismatches with partner)
2) Blood transfusion
3) Previous transplantation
What 2 methods are used to assess a recipients sensitisation to a donor?
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
What is one way that serum screening is carried out?
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
What does the cRF% tell you in terms of sensitisation in transplant?
Tells you the percentage of donors that would be inaccessible to a recipient based on the recipients pre-sensitisation
What would a cRF% of 50% tell you?
50% of donors are inaccessible to the recipient based on pre-sensitisation - reduced target for finding a match
What 3 things determine a recipients chance of finding a donor?
1) Rarity of HLA type
2) Blood group
3) Extent to which they are sensitised
How is crossmatching when a donor transplant is found carried out?
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
If positive cross matching occurs can an organ be transplanted?
As a rule no
If positive cross matching occurs and an organ is still transplanted what can this result in?
Hyperacute reaction
What happens in a hyperacute reaction?
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
Are you likely to find a perfect HLA match?
No, very unlikely that 2 non siblings will be perfectly HLA matched
What are the chances of 2 siblings being perfectly matched?
1 in 4 (as codominant expression, 1 allele from each parent)
What are the chances of 2 siblings being completely HLA mismatched?
1 in 4
What are the chances of 2 siblings being partially HLA matched?
1 in 2
What are isoagglutinins?
Antibodies produced by an individual that cause agglutination of the red blood cells of others
