Transplantation Flashcards
In general terms, what is the function of the immune system?
Normal immune system function
Protection from non-self - pathogens
Protection from abnormal self – e.g. tumours
What are some key players in the innate and adaptive immune system?
Innate immune system
Macrophages
Neutrophils
Complement & natural antibodies (IgM)
Adaptive immune system
Dendritic cells (antigen presentation)
T cells (helper and cytotoxic T cells)
Natural Killer (NK) cells - cytotoxic
B cells (antibody generation & memory)
What is the major histocompatibility complex (MHC)?
MHC in humans is called Histocompatibility Locus Antigen (HLA)
These molecules help the immune system to recognise ‘self’ and also to intiate immune responses.
HLA genes are very polymorphic i.e. there are many different variations possible at each gene locus
What are the two classes of HLA molecules? Where are they found?
Two broad categories
Class I - HLA-A, B and C – expressed by most somatic cells – present peptides from internally processed proteins – allows immune cells to check the health of our cells - e.g. virus proteins can be presented and recognised by T-cells for killing.
Class II – HLA-DP, -DQ and –DR - expressed on APCs – sampling their microenvironment – presenting peptides from digested material including pathogens, abnormal or foreign cells
Apart from T-Cell receptor-HLA interactions, are other signals also required for T-cell activation?
T-cell synapse – other molecules need to be present to ensure the signal is strong enough to trigger an immune response (APCs interacting with T-cell) – Co-stimulation
Are cytotoxic T-cells good killers? How do they carry out the deed?
Cytotoxic cell is a very effective killer
- Fas-Ligand, TNF-a, granzyme and perforin (punch wholes in membranes) – drives apoptosis of target cell
Outline in general terms how naive T-cells can become activated?
Dendritic cell pick up abnormal molecule – present to T-cell (antigen specific) – stimulated by IL-2 (T-cell proliferation) – leading to the clonal expansion of T-cell army – circulate body to exert function
Don’t want this to continue forever – activation induced cell death – but we are left with memory T-cells
What are 4 key principles of transplant immunology?
- Rejection of transplanted organs is directed at specific protein - antigens
- Rejection is donor specific – specific to the donor
- Rejection may be both cell or antibody mediated
- Rejection exhibits memory– 2nd similar transplant is rejected more rapidly – rapid generation of cytotoxic antibodies
What is HLA profiling?
If we transplant an organ we want to know the HLA-profile of the donor so that we can match it the best way possible with the recipient.
Longer term surivival increases with fewer mismatches.
Performed using molecular biological and serological techniques
The HLA tissue types of all patients on the Kidney Transplant waiting list is held on a central UK database and the ‘best match’ chosen when kidneys become available
Notation
* If all HLA-A, -B and –DR loci are the same the it is a 0-0-0 mismatch
* If they are all different then it is a 2-2-2 mismatch
Is HLA profiling equally important for both kidney and liver transplants?
Used to allocate kidneys but less important for other organs such as liver (less immunogenic)
What immunosuppresant treatments do we use when performing a organ transplant?
Corticosteroids – kill lymphocytes, interfere with T-cell activation/gene transcription and it is a very anti-inflammatory agent
Calcineurin inhibitors (tacrolimus) – inhibit T-cell activation – targeting intracellular pathways
Anti-proliferative agents - mycophenolate mofetil (MMF) - Inhibit clonal expansion of T cells.
Various monoclonal and polyclonal antibodies directed against:
* IL-2 receptor blockers (IL-2 stimulates clonal expansion of T cells)
* T cells (cytotoxic complement fixing Abs) – kill them
* Co-stimulatory molecules – target co-stimulatory molecules
What are some examples of transplantable organs/tissues?
- Kidney
- Pancreas (complete organ or pancreatic islets)
- Liver
- Lung
- Heart
- Small Bowel
- Cornea
- Faces, arms etc
What things do we consider when assessing a patient for a kidney transplant?
Patient assessed in specific transplant clinic
- Age is important – not as much chronological but more interested in biological age
- Cause of Kidney failure
- Kidney failure due to polycystic kidney disease can’t recur in a transplant
- Whereas Atypical Haemolytic Uraemic and Focal segmental glomerular sclerosis – always or highly likely to recur
- Comorbid disease very important – cardiovascular (IHD or PVD) and diabetes
- History of Infections are important to consider as you’ll be immunosuppressing the patient
- History of tumours - need a tumour free period – depending on the type of tumour
- Urological disease – as the kidney will be connected into the urological system
What additional investigations can be performed prior to a renal transplant?
- CARDIAC - exercise ECG, myocardial perfusion studies
- Angiography (need decent vessels for the anastomosis)
- Urodynamic studies
- Tumour markers, imaging etc
What are the two main types of donor when in comes to transplantation?
Cadaveric Transplant (commonest) e.g. subarachnoid haemorrhage
* DCD = donated after cardiac death
* DBD = donation after brain death
Living related donor Tx
* Sibling, spouse, altruistic
* Typically a kidney Tx
Note - Cadaveric transplants have worse outcomes
In a kidney transplant, where is the new kidney placed?
Kidney transplanted into the right fossa
Transplants plumbed into the pelvis into Iliac vessels and bladder – why vessel assessment is important
How is a immunological X-match carried out?
Cross match – does the patient (recipient) have any antibodies against the HLA molecules on the donors tissue
How?
1. We get the serum from recipient and donor cells from the donor
2. Add complement source which kills and green dye that enters dead cells.
3. If the antibody binds, the dye enters into the dead cells and becomes fluorescent green.
Note - Nowadays we use flowcytometry for cross-matching
What is a method used to assess the level of HLA anitbodies in a patient?
Luminex HLA antibody detection
Careful way of assess the presence and level of HLA antibodies
- Using large number of beads with many different types of HLA’s.
- Presence of corresponding antibody will bind to the HLA antigen.
- Addition of secondary antibody will result in fluorescence.
What happens in hyperacute kidney rejection?
Occurs when the Tx carries antigens to which the recipient is already sensitised – antibodies against transplant organ are already present.
Cytotoxic antibodies bind endothelial cells and induces complement activation, platelet aggregation and intravascular thrombus formation
The Tx is often destroyed ‘on the operating table’
What are factors that increase the risk of chronic rejection?
- Increased HLA mismatch (1-2-1 vs 0-0-1)
- Previous acute rejection
- Poor drug compliance (low tacrolimus levels)
- Prolonged cold ischaemia time (CIT) of kidney prior to surgery (CIT of living donor «_space;cadaveric donor)
Other factors shown on image…
Example BK Virus infection following immunosuppresion - how to treat?
Big abnormal cells – infected by BK virus
Treatment is to reduce immunosuppression
to facilitate anti-viral immunity
