T2-L6: MHC and Transplant Rejection Flashcards
What are the broad two types of HLA?
HLA1 and HLA2.
Class II are expressed mainly on antigen presenting cells. Class I are in all cells a that are nucleated - not found on red blood cells. This means that there is not sensitisation in blood tests. Class I have a different structure. It has a chain and a non-polymorphic beta-2 polyglobulin. They both have a groove with a antigen between them. They are all coded on the short arm of chromosome 6. Class I tend to pick up proteins on cytosolic proteins. Class II express external proteins.
What is the difference between HLA and MHC?
MHC is the name given to the gene. The short arm of chromosome 6. The proteins in humans are called HLA. There is a lot more polymorphisms along class I than Class II.
What is the role of MHC is evolution?
HLA are polymorphic and can combine different peptides. It is therefore likely certain types are protects. People with HLA-B53 in Africa are resistant to Malaria. The pathogens proteins may be a good fit so they generate a good immune response.
Variation may permit presentation of self peptides leading to autoimmune diseases. Ankylosing spondylitis shows an increased risk of nearly 90% for having the B27 allele.
How is HLA involved in an immune repose in transplantation? Use the example of a kidney transplant.
The APC from the donor express HLA antigens that are seen by the T cell of the receipts. The kidney cells themselves can start to express HLA and be APC.
When they migrate to regional lymph nodes. They are seen as foreign due to having different HLA molecules. It has a strong immune reaction. Looking at a generically disparate individual, the cell will look very different; the groove themselves and the peptides between them.
It is not just about signal I - TCR and MHC molecule - you also need secondary signals generated by non-polymorphic peptides: C28 and CD40L. Complement proteins. TLR receptors and other cytokines affect how this signals goes.
What happens when the donor cell in a transplant is recognised as foreign?
Once the donor cell is recognised:
- B cells to generate antibodies - CD8 - cam cause cytolysis with perforin and granzyme B - CD4 - hypersensitivity reactions
How is HLA typing used in allorecognition clinical transplantation?
We inherit HLA types.
In HLA Class I antigens A and B are important clinically. In HLA Class 2 - DR (DP and D2) are very important in transplantation. These are the most important in terms of results.
A mismatch of 1,1,1 for example would be 1 mismatch at A, 1 at B and 1 at DR. The maximum this can be is 2,2,2 (all are mismatched i.e. both alleles of antigen A) and the best it can be is 0,0,0 (no-mismatch). You cannot transplant with 2,2,2; 0,0,0 is the best option.
What do we use to HLA test? Why this done?
When typing you need to use:
- Serologically - cell based - Molecular: extraction of DNA, amplification. Detection of sequence polymorphisms (i.e. tissue type) using hybridisation to probe or sequencing This is done: - Less rejection episodes - Better graft survival - National Kidney waiting lists - allocation policy is geared to give patients that are well matched - Less sensitisation - generate less antibodies, last 10-25 years, therefore if they generate less antibodies they are likely to do better with another one later on - Establish relationships
Why do we need to detect anti-HLA antibodies? Where could they have come from?
Screened regularly. We detect them in anyone on the waiting list to prevent hyper acute rejection, to do a cross-match and avoid sensitising event. They could develop antibodies because of:
- Previous transplanting - Pregnancy - Blood transfusion - though red cells do not sensitise, blood products have sensitising white produced
How do we detect anti-HLA antibodies?
Test include complement dependent cytotoxicity test:
Serum is taken from the recipient to which cells from the donor is added. The donor cell will express many antigens inc. HLA. If the serum contains antibodies against HLA then they will stick to the cells when the cells are added. If you add complement the cells lyse. This helps to detect whether there are pre-existing antibodies. You can also do this by flow cytometry. Using florescent dye that are anti-HLA to be picked up on detection.
Can be done by beads. Screen a serums sample and adding into a mixture of beads. By picking up specificities you can detect antibodies in the serum.
What are the types of rejection?
- Acute antibody mediated rejection
- Acute cellular rejection
- Chronic antibody mediated rejection
What is acute antibody mediated rejection? When does it occur?
- Acute antibody mediated rejection - tends to happen in the first day. This happens when you take off the clamp and blood rushes into the kidney. However the reaction results as the recipients blood has antibodies. This can be catastrophic and cause the kidney to become black immediately. They may have:
- Anti-HLA antibodies
- ABO antibodies
- HLA-incompatible transplantation
- Xenograft rejection - Anti-Galapha1-3Gal - causes hyperacute rejection
This can be avoided by screening for antibodies and matching for ABO.
To avoid this before transplantation cross matching is done. Cross match involves taking serum form the recipient and cells from the donor (usually from the spleen) and seeing if there is any rejection.
What is acute cellular rejection? When does it occur?
This tends to happen in the first month. It is T cell dependent. It is directed against foreign HLA molecules. Cyclosporin and Tacrolimus are anti-T cell drugs used to combat this.
What is chronic antibody mediated rejection? When does it occur?
This occurs in the long term - around 6 months after the transplant. Any patient with anti-HLA antibodies against the donor have a much shorter graft survival than those without the antibodies. This can lead to chronic rejection. We screen for antibodies in the development of antibodies against HLA. As those developing it are developing an immune response. We can prevent this by increasing immunosuppression. This is antibody mediated.
