Solid-organ allo-transplantation Flashcards
What does syngeneic transplantation mean?
The donor and the recipient are genetically identical (i.e.twins)
What does allogenic transplant mean?
The recipient and the donor are from the same species, but aren’t genetically identical
What does a xenogenic transplant mean?
The donor and the recipient are from different species (e.g. a pig)
What organs can living donors donate?
Haematopoietic stem cells
Kidney
Liver lobe
Lung lobe
Is it better to receive a kidney from a living or dead donor?
A living donor (95% 5 year patient survival rate, compared to an 89% 5 year survival rate from a dead donor)
Name three things the NHS blood and transplant directorate consider when deciding who to give organs to.
Clinical need
Waiting time
Compatibility
What donor are the blood groups A, B, AB and O compatible with?
A is compatible with A and O
B is compatible with B and O
AB is compatible with A, B, AB and O
O is only compatible with O
What is the major histocompatibility complex?
A group of genes, found on the short arm of chromosome 6, that contain our human leukocyte antigen (HLA) genes
What are the names of out HLA genes?
HLA-A HLA-B HLA-C HLA-DR HLA-DQ HLA-DP
Which HLA genes are class I?
HLA- A,B and C
Where is the polymorphism located on class I HLA genes?
Exons 2 and 3 (affecting the alpha-1 and 2 protein domain)
What is the function of an HLA class I protein?
Presents peptides from inside an affected cell (e.g. Viral infection), and so are located on all cells
Which HLA genes are class II?
HLA-DQ, DP and DR
Where is the polymorphism located on a class II?
Exon 2 on both the alpha and beta chain (affecting the alpha1 and beta1 protein domain)
What is the function of a HLA class II protein?
Presents antigens from outside the cell to the T-lymphocytes. So only certain APCs have them.
How are antigenic peptides that have been broken down within a cell transported to the HLA I protein?
Via the transporter associated with antigen processing (TAP) heterodimer from the cytoplasm to the ER membrane. Because that is where the HLA class I protein is located.
Which accessory molecule helps associate HLA class I with TAP on the luminal side of the ER membrane?
Tapasin
What transports the HLA class I and peptide complex to the plasma membrane, and what does it do when it gets there?
The Golgi transports it to the membrane, where it present the antigen to a killer T-cell
In the ER, what three chains come together to make an inactive HLA class II molecule?
The alpha chain, beta chain and invariable chain.
What is the function of the variable chain?
Stabilises the class II molecule and prevent peptides form binding to the peptide groove while the molecule is still in the ER
Where and when does peptide (antigen) binding occur on a HLA class II molecule?
It occurs in the MIIC vesicle after the molecule has left the ER and the variant chain has stopped binding to it
When does the class II protein get transported to the cell surface, and what cell does it present too there?
It is transported once an optimum peptide has bound to the peptide binding groove, and it the present to helper T-cells
Where does the class I and II molecules get the antigenic peptide that they are supposed to bind to?
Class I = inside the cell during a viral infection
Class II = outside of the cell during a bacterial infection
What HLA molecules can an antigen presenting cell present?
All of them, potentially all at once. And they can each be binding a different peptide
Why does each person have so much diversity in regards to their histocompatibility complex?
We need the different classes because they have structural differences that affect peptide binding.
This increases the chance that a person will have an HLA molecule that will allow initiation of an immune response against a certain pathogen
Why does a population have so much diversity between people?
Increases the chance of species survival when all exposed to the same pathogen
What’s the problem which HLA polymorphism is transplantation?
In HLA incompatible people, the cells of the host may try to attack and kill the cells of the donor, because the proteins they are presenting are too different from their own and are seen as pathogenic
How many circulating T-cells can be allorecative before it becomes a problem?
10%
What is alloreactivity?
T-cells responding vigorously to non-self HLA molecules.
Can someone be given an organ they aren’t a perfect HLA match for?
Yes- but they have to be some form of a match, and the mismatched part can be overcome with immunosupression
Which organs do they perform HLA matching on and which HLAs do they match?
Kidneys - match HLA-A, DR and B, but low resolution
Liver - HLA matching not performed
Cardiothoracic- HLA matching is important, but isn’t done due to logistics
When would a transplant be avoided in kidney and cardiothoracic?
When donor specific antibodies are found
What is the problem with donor specific antibodies?
Antibodies against certain non-self HLA can be formed already in certain people, and they can never receive an organ from some with that HLA
When can people form donor specific antibodies?
Pregnancy
Blood transfusion
Previous transplant
Viral infection
What is HLA sensitisation?
The status of the recipient must be determined prior to transplantation, and any donor specific antibodies must be identified.
What is hyperacute rejection?
Occurs when patient has performed donor specific antibodies.
Occurs minutes /hours after the blood vessels are sown together
What pathophysiology occurs in hyperacute rejection?
- The alloantibidy from the recipient binds to the donor endothelial cell, causing endothelial damage and release of inflammatory cytokines
- complement is activated and the recipients neutrophils are recruited causing endothelial damage along with lytic enzymes
- platelet aggregation and activation occurs, creating a thrombus and blocking the blood vessels
- ischemia and graft death occurs
What is acute rejection?
Immune mediated
Can be treated with immunosupression
What is chronic allograft nephropathy?
Indolent but progressive form of immunological injury to the graft
Slowly compromises organ function and then leads to acute rejection
What is an autologous transplant?
When the donor and the recipient are the same person
What is the pathophysiology of chronic allograft nephropathy?
Graft arteriosclerosis leads to fibrosis
Name the immunological factors that can lead to chronic allograft nephropathy.
Two things lead to the acute rejection incident that is a major risk factor for chronic allograft nephropathy:
- Poor HLA matching and presence of HLA alloantibodies
- sub-optimal innumosupression and/or non-compliance of the patient
Name the non-immunological factors that lead to chronic allograft nephropathy.
Older donor Poor graft quality Cause of death (e.g. Ischemia or injury to the organ) Hypertension Hyperlipidaemia Toxic effects of immunosupression
What is the prioritisation assigned to patients on the waiting list for an organ?
1) paediatric patients- HLA match, highly sensitised
2) paediatric patients - HLA match
3) adult patients - HLA match, highly sensitised
4) adult patients - HLA match
5) all other patients
Priority for transplantation of based on what criteria?
Time on waiting list HLA match Age Age difference Location HLA homozygosity Blood group match
Four test done before every transplantation
HLA type patient
HLA type donor
Patient screening every three months for preformed HLA alloantibodies
Cross match donor and patient just before transplant to assure no negative reactions
