Transplantation Flashcards
Who is the father of transplantation?
Peter Medawar
Why does transplant rejection occur?
Consequence of a robust immune system that was never designed for transplantation
Rejects all that is non-self
When was the first transplant carried out?
1954
Peter Brent Birgham Hospital
Between two identical twins
Recipient lived another 10 years and donor until he was 70
Why is the number of donations from dead donors always larger than from live donors?
You can take two kidneys from dead donors
What are the two types of donors of organ transplants?
Deceased (cadaveric)
Live
What are the two types of deceased donors?
Donation after brain death
Donation after circulatory death
Why is the quality of organs after brain death better than after circulatory death?
During brain death, the heart is still beating so the perfusion of the organ continues
How many hours after circulatory death must one wait before retrieving organs from the donor?
3 hours
People involved in live donor transplants
Relative, spouse friend
Paired exchange
Altruistic
What is an autograft?
Transplants or grafts from one site of the body to another in the same individual
What is an isograft?
Transplant from one genetically identical individual to another
What is a xenograft?
Transplant from one species to another
What is self-tolerance?
Normal immune homeostasis
Characterised by tolerance to antigens expressed in the individual’s own cells
When does self-tolerance develop?
In the thymus during childhood
Examples of transplantation antigens
HLA
ABO
Minor histocompatibility antigens
MICA/MICB
Endothelial cell antigens
What is an alloimmune response?
Induction of adaptive immune response to an allograft
Which arm of the immune response primarily causes rejection?
Adaptive immune response
What is allorecognition?
The process through which APCs recognise the foreign antigen present on allografts
What is the normal pathway by which APCs present foreign antigens to T cells?
Indirect pathway
Which pathways do APCs act through following transplantation?
Indirect pathway
Direct pathway
Semi-direct pathway
Describe the indirect pathway
Recipient APCs present non-self antigens to CD4+ T cells
Descibe the direct pathway
Donor APCs present non-self antigens to recipient CD8+ and CD4+ T cells
Describe the semi-direct pathway
Recipient APCs fuse with donor MHC
Recipient APCs use donor MHCs to present the foreign antigens to CD4+ and CD8+ T cells
What are ABO antibodies?
Naturally occurring preformed antibodies to non-O, non-self antigens
Why is the rhesus factor not important in transplantation?
Rhesus is not express in the epithelium
So it won’t be expressed on the organ
What is special about A2 individuals?
Blood group A2 individuals (20%) express lower densities of blood group A antigen
Can be successful donor in patients with anti-A
Which chromosome code for the MHC proteins in mice?
Chromosome 17
Which chromosome code for the HLA proteins in humans?
Chromosome 6
Features of MHC
Polygenic
Polymorphic
Codominantly expressed
Inherited from parents as a linked set of alleles = haplotypes
How many base pairs code for MHC
4 million
How many genes code for MHC
More than 200 genes
What is the MHC expression profile of HLA-heterozygous individuals?
Express up to 6 class I isoforms
Express six or eight class II isoforms
HLA genes
A B and C for class I
DR DQ DP for class II
How is the HLA used to determine suitability for transplantation?
Use HLA mismatch in HLA A, B and DR
All matches in the codominantly expressed genes = 0 (mismatches)
1 match in the codominantly expressed genes = 1
No matches in the codominantly expressed genes = 2
Which HLA mismatch profile is linked to highest transplant survival?
0,0,0
All HLA genes have the same influence in transplant survival
TRUE or FALSE
FALSE
DR genes have greater influence in gene survival compared to A
What is pre transplant sensitisation?
Determines the % of viable donors which the patient’s serum reacts to
How can antibodies against donor HLA develop?
Pregnancy
Transfusion
Prior graft
Infection
Vaccination
How does vaccination increase the possibility of anti-HLA developing?
The vaccination agent might share epitopes that the organ is also expressing
How is pre transplant sensitisation determined?
Using a panel of reactive antibody
Measures the amount of anti-HLA preformed antibodies
How were PRAs carried out originally?
T cell CDC assays
Describe the process behind T cell CDC assays
Add serum and complement with antigen you are testing
If there was a reaction, a stain would show up
The number of individuals the serum reacted against the total number of individuals tested was calculated
Using this percentage, the probability of a negative preliminary crossmatch was determined
What percentage of individuals is a complement with a PRA <10% suitable for?
98% of individuals would not react negatively
What percentage of individuals is a complement with a PRA >80% suitable for?
5% of individuals would not react negatively
Individual will have to wait a long time
How is PRA calculated now?
Solid phase testing
Flow cytometry and luminex
What does solid phase testing determine?
Calculates the likelihood of transplantation
Determines the number of existing alloantibodies in the individual and correlates it with the frequency of relevant HLA alleles in the population
Describe how solid phase testing is carried out
Patient serum is added to the luminex machine
The machine contains beads with specific antigens, so the matching antibodies in the patients’ serum will bind and form a complex
A fluorescently labelled antibody will bind to this complex
The combination of dyes will form a special colour
The dye is then used to determine the number of antibodies specific to antigens
What is the difference between a PRA and a crossmatch test?
PRA looks at pre-transplantation on a population basis
The crossmatch test in done at the time of the transplant and looks at the reaction between the serum and the donor specifically
What is a positive crossmatch associated with?
Immediate graft failure
What is induction therapy?
The short term use of immunosuppressants
Drugs taken during induction therapy
Corticosteroids
Polyclonal immune globulins/ monoclonol antibodies
What is maintenance?
Drugs given on a long-term since there is always a potential for an immune response
What drugs are taken during maintenance?
Calcineurin inhibitors
mTOR inhibitors
Anti-metabolites
What arms of the immune system are targeted through immunosuppression?
Anti-CD25 - IL-2 receptor required for cell proliferation
Anti-metabolites - block enzymes involved in nucleotide synthesis (cell cycle)
When can rejection occur?
Any time after transplantation
What are the characteristics of transplant rejection?
Rise in serum markers of graft function
What are the the three types of transplant rejection?
Hyperacute
Acute
Chronic
When does hyperacute rejection occur?
On the table
The kidneys turn blue
High levels of antibodies
When does acute rejection occur?
Not time-dependent
Measures how active the immune system is
Determined by the cellular arm of the immune system or B cells and their antibodies
Characteristics of chronic rejection
High creatine
Low urine output
One reason why hyperacute rejection occurs
Recipient has pre-existing antigens
Which two mechanisms of rejection exist?
Cellular rejection
Antibody-mediated rejection
Which cells mediate cellular rejection?
T lymphocytes
How is cellular rejection defined?
A decline in clinical function of the allograft
Characteristics of cellular rejection
Well-defined histological changes on allograft biopsy
Which cells mediate antibody-mediated rejection?
B cells
How is antibody-mediated rejection defined?
Histological evidence of tissue injury in the setting of detectable donor-specific antibodies
Characteristics of antibody-mediated rejection
Current or recent antibody interaction with the vascular endothelium
Deposition of complement split product c4d => antibody has bound to the endothelium and complement has deposited
The presence of microvascular inflammation or accumulation of CD3 => accumulation of lymphocytes
What increases the chance of rejection?
Pre-formed antibodies present specific to HLA I
Why are infections common in transplant recipients?
Due to immunosuppression
What are the types of infection that arises in transplant recipients?
Viral
Fungal
Opportunistic
Others
What is a way to reduce the chances of infection in transplant recipients?
Infection prophylaxis
What are medical complications of transplantation?
Cancer
Infection
What additional precautions must transplant recipients make to prevent complications?
Avoidance of sun exposure and smoking
Annual cervical smear test
What is graft versus host disease?
Occurs following transplant of immunologically competent T cells or T cell precursors into the immunocomprimised recipients
T cells recognise the non-self antigens of the recipient and start attacking healthy tissue
What are the two types of graft versus host disease?
Acute < 100 days post-transplant
Chronic > 100 days post-transplant
What is the incidence of graft vs host disease?
1-2% incidence
What is transplant tolerance?
A well-functioning graft lacking histological signs of rejection, in the absence of any immunosuppressive drugs, in an immunocompetent host
What are proposed strategies to achieve central and peripheral transplant tolerance?
Bone marrow transplantation
Cellular therapy
What are the barriers of xenotransplantation?
Immunological
Ethical
