(13) MHC and transplantation Flashcards
Where has blood group substance been revealed by immunofluorescent staining?
In the cell membranes of all vascular endothelial cells, and certain epithelial cells
Normal individuals have naturally occuring isoagglutinins of which type?
Normal individuals have naturally occurring anti-A or anti-B isoagglutinins
How is blood group related to transplant?
Poor outcome of transplants performed between blood group incompatible individuals
Who discovered the MHC?
Peter Alfred Gorer
Describe the discovery of the MHC?
- tumour transplantation between mouse strains
- sarcoma tissue from strong’s albino A strain grew in F2 cross and backcross generations between the A strain and the resistant C57 black strain
- all susceptible animals possessed an antigen derived form their albino acceptors “antigen II”
- anti-antigen II antibody produced in C57 black mic by transfer of sarcoma tissue from the A strain
- maximal titres of anti-antigen II antibody corresponded with time of complete tumour regression
- “…genes govern the transplantability of the tumour and determine isoantigenic differences’
What was the experiment done by Peter Medawar concerning MHC?
- skin allograft rejection in burns victims
- rabbit skin graft model
gave different donor strains to incompatible recipient, measured time taken for graft to become necrotic
What were the results from Medawar’s experiment?
- recipient strain = X, donor strain = Y, graft loss = 10-14 days (1st set response)
- recipient strain = X’, donor strain = Y, graft loss = 5-7 days (2nd set response)
- recipient strain = X’, donor strain = Z, graft loss = 10-14 days (1st set response)
MHC responsible for these observations
The MHC is a set of genes found in who?
All vertebrate species
What is the role of the MHC?
- immune function
- diseases susceptibility
- reproductive success
- role in histocompatibility, major influence on graft survival
Where are the proteins encoded by the MHC expressed and what do they present?
They are expressed at the cell surface and function to present ‘self’ and ‘non-self’ antigens for inspection by T cell antigen receptors
How many MHC molecules are on the average mammalian cell?
50,000-100,000
It is the most prolific cell surface protein/antigen
Are MHC proteins polymorphic?
Highly polymorphic
Most polymorphic system in the human genome
Where is the human MHC genes found?
6p21.3
the short arm of chromosome 6
How big is the human MHC?
3.6Mbp
The MHC is divided into 3 regions. Which proteins/antigens do each of these 3 different regions encode?
class I region = HLA-A, B, C (‘classical’) antigens
class II region = HLA-DR, DQ, DP antigens
class III region = HSP70, TNF, C4A, C4B, C2, BF, CYP21
HLA-DR is encoded by what region of the MHC?
Class II region
What are the antigens encoded by MHC called?
HLA
Human leucocyte antigens
Where are class I antigens found?
On all nucleated cells
Class I HLA antigens mainly serve to present which antigens?
Endogenous antigens (result of changes in the cell eg. virus)
Where are class II antigens found?
Primarily expressed on B lymphocytes but expression can be induced on T lymphocytes and other cells
Class II HLA antigens mainly serve to present which antigens?
Exogenous antigens
What type of proteins are HLA antigens?
Membrane-bound glycoproteins
What are class I HLA-A, B, C molecules composed of?
MHC encoded 45kd heavy chain non-covalently associated with non-polymorphic B2 microglobulin
What are class II HLA-DR, DP, DQ molecules composed of?
MHC encoded 31-34kd associated A chain non-covalently associated with 26-29kd B chain
Which part of the HLA molecule presents the antigen to the T cells?
The peptide-binding groove
How are MHC inherited?
Mendelian inheritance - 1 in 4 chance of mismatch with sibling, 1 in 2 chance of partial match, 1 in 4 chance of match
En-bloc from each parental chromosome. Each individual inherits two antigens at a given locus
Codominant expression. All of the inherited antigens are displayed on the cell surface (HLA phenotype)
Describe HLA polymorphism
- MHC is highly polymorphic
- large number of allelic variants at each locus
- allelic variation maintained at population level due to survival advantage
- significant in terms of capacity of individual to mount an immune response in response to an antigenic challenge
In HLA nomenclature, what are the 3 levels of specificity?
- broad eg. HLA-A19
- split eg. HLA-A29(A19)
- allele eg. HLA-A*29:01
serology (broad)
serology (split)
molecular (low)
molecular (high)
In HLA nomenclature, what does an * mean?
- = molecular
no * = serology
What are the 3 categories of response when the immune system experiences foreign HLA in transplant tissue?
- direct recognition
- indirect recognition
- semi-direct recognition
What happens in direct recognition in response to transplant tissue (foreign HLA)?
- graft + damaged endothelium due to surgical stress
- T cell binding direct to graft
- donor DCs presenting to recipient T cells
- T cell proliferation
What happens in indirect recognition in response to transplant tissue (foreign HLA)?
- graft peptides
- movement of recipient APC
- processing of donor peptides (lymph node)
- T cells migrate to the graft (immune response)
What happens in semi-direct recognition in response to transplant tissue (foreign HLA)?
- movement of recipient APC
- donor APC
- recipient and donor APC interaction
- migration of ‘new’ APC to lymph node to present to T cells
Which type of recognition (direct, indirect, semi-direct) occurs straight away in transplantation?
Direct
Unique to transplantation
What is sensitisation and give examples of events
Any event which elicits an HLA directed immune response
- pregnancy
- blood transfusion
- transplantation
How can you determine HLA profile?
- serum screening
- cross matching (directly test recipient serum against donor cells)
cRF% is a measure of what?
Sensitisation
If you have a 0% cRF, what does this mean?
Any donor can be used
What does 50% cRF mean?
50% sensitised
lost 50% chance of finding donor
but better than 100% cRF (100% not actually possible, but have to find donor exactly matching)
What happens in hyperacute rejection?
- activate clotting cascade
- activate complement
- lost integrity of vascular endothelium
- organ engorges with blood and becomes necrotic
- DIC
