Theme 2 Lecture 11: MHC and Transplant rejection

Question 1

What is MHC?

Answer 1

• 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

Question 2

What does MHC and HLA stand for?

Answer 2

MHC - Major histocompatibility complex

HLA - Human leukocyte antigens

Question 3

What is isograft?

Answer 3

genetically identical e.g in humans this can only happen in identical twins

Question 4

What is an allograft?

Answer 4

non identical, same species

Question 5

What is a xenograft?

Answer 5

a tissue or organ transplant from a donor of a different species from the recipient

Question 6

How was HLA discovered?

Answer 6

-looked at sera of multiparous women and patients who had multiple transfusions

Question 7

Which antigen on cell surface is responsible for the reaction between leukocytes and antibodies?

Answer 7

Anti-MAC (HLA-A2)

Question 8

What are the 2 types of HLA antigens?

Answer 8

class I: more ubiquitous, expressed on all cells with a nucleus, not RCBs
class II: expressed mainly on APCs

Question 9

Which chromosome codes for HLA antigens?

Answer 9

short arm of chromosome 6

Question 10

Which class of HLA antigens present cells to effector CD8 T cells?

Answer 10

MHC Class I

Question 11

Which class of HLA antigens present cells to effector CD4 T cells?

Answer 11

MHC Class II

Question 12

Which type of cells do HLA Class I and II pick up?

Answer 12

HLA Class I tend to pick up peptides from cytosolic proteins e.g viruses
HLA Class II tend to pick up ingested, external proteins

Question 13

Give a key feature of HLA molecules?

Answer 13

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

Question 14

What is positive selection of T cells?

Answer 14

• 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

Question 15

What is negative selection of T cells?

Answer 15

• TCRs bind to MHC complexes in thymus leading to cell death
• to prevent recognising and attacking our own cells

Question 16

What is MHC restriction?

Answer 16

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

Question 17

What are people with HLA-B53 protected agaisnt?

Answer 17

cerebral malaria

Question 18

What is the immunological synapse?

Answer 18

when the recipient T cell meets the APC cell of donor - this is primary signalling by receptor and MHC molecule

Question 19

What is the direct pathway?

Answer 19

recipient T cell directly recognises donor APCs

Question 20

What is indirect pathway?

Answer 20

method by which APCs are usually presented

Question 21

Once the cells from the recipient have recognised the APC, what types of response can they generate?

Answer 21

1. can generate B cells that generate anti donor antibodies
2. can generate cytotoxic CD8 cells which cause cytolysis of class I HLA antigens
   - CD4 cells can set up hypersensitivity reactions

Question 22

What is HLA typing?

Answer 22

genetic test used to identify certain individual variations in a person’s immune system.

Question 23

Why do we do HLA typing?

Answer 23

• 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

Question 24

What is tissue typing?

Answer 24

“test sample” of skin graft before organ transplantation

Question 25

Explain the renal transplant pathway

Answer 25

1. medically fit for listing 2. HLA typing 3. details on waiting list / regular serum screening for antibodies 4. organ offer 5. real or virtual crossmatch 6. renal transplant 7. post op monitoring

Question 26

Why do we need to check patient dosen't have antibodies before transplant?

Answer 26

prevents hyperacute rejection

Question 27

What is the complement dependent cytotoxicity test (CDC)?

Answer 27

- 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

Question 28

What is flow cytometry?

Answer 28

- 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)

Question 29

What are the 3 types of rejection?

Answer 29

1. acute antibody mediated rejection - most severe, occurs in first day, will only occur if recipient has pre-formed antibodies 2. acute cellular rejection - occurs in first week 3. chronic antibody mediated rejection - occurs in 6 months

Question 30

What is HAR?

Answer 30

- hyperacute rejection | - if patient has pre formed antibodies

Question 31

Why would we perform pre transplant cross match?

Answer 31

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

Question 32

What is acute cellular rejection?

Answer 32

- t cell dependant - t cell immunosuppression directed against foreign HLA molecules - effect of HLA mismatch - typically 7-10 days after transplant

Question 33

what is the long term effect of anti-HLA antibodies?

Answer 33

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