Theme 2 Lecture 11: MHC and Transplant rejection Flashcards
What is MHC?
- The genetic complex that creates the proteins that result in the expression of antigens
- MHC is the DNA that generates HLA proteins in humans
- human MHC = HLA
What does MHC and HLA stand for?
MHC - Major histocompatibility complex
HLA - Human leukocyte antigens
What is isograft?
genetically identical e.g in humans this can only happen in identical twins
What is an allograft?
non identical, same species
What is a xenograft?
a tissue or organ transplant from a donor of a different species from the recipient
How was HLA discovered?
-looked at sera of multiparous women and patients who had multiple transfusions
Which antigen on cell surface is responsible for the reaction between leukocytes and antibodies?
Anti-MAC (HLA-A2)
What are the 2 types of HLA antigens?
class I: more ubiquitous, expressed on all cells with a nucleus, not RCBs class II: expressed mainly on APCs
Which chromosome codes for HLA antigens?
short arm of chromosome 6
Which class of HLA antigens present cells to effector CD8 T cells?
MHC Class I
Which class of HLA antigens present cells to effector CD4 T cells?
MHC Class II
Which type of cells do HLA Class I and II pick up?
HLA Class I tend to pick up peptides from cytosolic proteins e.g viruses
HLA Class II tend to pick up ingested, external proteins
Give a key feature of HLA molecules?
they are highly polymorphic - lots of variability so each molecule can bind to very different peptides
There is much more polymorphism in class I HLA than class II
What is positive selection of T cells?
- cells in the thymus present peptides on their own MHC Class I and II molecules, allowing immature T cells to bind
- If a T cells TCR binds to MHC complexes on thymic cells, it will be positively selected
- if not, apoptosis will occur
What is negative selection of T cells?
- TCRs bind to MHC complexes in thymus leading to cell death
- to prevent recognising and attacking our own cells
What is MHC restriction?
A T cell can interact with a self MHC molecule and a foreign peptide bound to it, but will only respond to the antigen when it is bound to a particular MHC molecule
What are people with HLA-B53 protected agaisnt?
cerebral malaria
What is the immunological synapse?
when the recipient T cell meets the APC cell of donor - this is primary signalling by receptor and MHC molecule
What is the direct pathway?
recipient T cell directly recognises donor APCs
What is indirect pathway?
method by which APCs are usually presented
Once the cells from the recipient have recognised the APC, what types of response can they generate?
- can generate B cells that generate anti donor antibodies
- can generate cytotoxic CD8 cells which cause cytolysis of class I HLA antigens
- CD4 cells can set up hypersensitivity reactions
What is HLA typing?
genetic test used to identify certain individual variations in a person’s immune system.
Why do we do HLA typing?
- less rejection episodes if donor tissue is well-matched to recipient
- better graft survival
- less sensitisation - will develop less antibodies so they can have another transplant in the future
What is tissue typing?
“test sample” of skin graft before organ transplantation
Explain the renal transplant pathway
- medically fit for listing
- HLA typing
- details on waiting list / regular serum screening for antibodies
- organ offer
- real or virtual crossmatch
- renal transplant
- post op monitoring
Why do we need to check patient dosen’t have antibodies before transplant?
prevents hyperacute rejection
What is the complement dependent cytotoxicity test (CDC)?
- test for antibodies
- detects complement fixing IgG/ IgM HLA and non-HLAs
- developed in 1970s
- you take serum from the recipient and add in cells from donor
- cells from donor will express HLA on surface
- if recipient has antibodies against HLA antibodies then they will stick to the cells when the serum is added
What is flow cytometry?
- take donor serum and add to cells - use flourescent dye to show if antibodies are adherent after washing
- this technique is more sensitive than CDC
- it is now more common to use beads (luminex screening)
What are the 3 types of rejection?
- acute antibody mediated rejection - most severe, occurs in first day, will only occur if recipient has pre-formed antibodies
- acute cellular rejection - occurs in first week
- chronic antibody mediated rejection - occurs in 6 months
What is HAR?
- hyperacute rejection
- if patient has pre formed antibodies
Why would we perform pre transplant cross match?
involves taking cells from recipient and cells from the spleen of the donor to see if there is any reactivity - if there is reactivity we do not go ahead due to the chance of rejection
What is acute cellular rejection?
- t cell dependant
- t cell immunosuppression directed against foreign HLA molecules
- effect of HLA mismatch
- typically 7-10 days after transplant
what is the long term effect of anti-HLA antibodies?
developing antibodies against the HLA molecules of your donor will cause the graft survival time to decrease so you will develop chronic antibody mediated rejection
