Immune aspects of kidney transplant Flashcards
Do transplantations between non-identical twins show rejection?
No - share bone marrow in utero
What does HLA stand for?
Human leukocyte antigen
What does HLA do?
Responsible for the activation of the immune response
Stimulate T and B cell responses
What class of HLA are expressed on all nucleated somatic cells?
Class I HLA-B
What happens in organ rejection?
HLA recognises proteins on the transplanted organ as non-self and attacks it by mounting an immune response
What are 3 types of HLA molecules?
HLA-A, -B and -DR
What do -A, -B and -DR represent on HLA molecules?
Important alleles
Where are HLA-DR found?
On immune cells
How many alleles code for each HLA subtype (-A, -B, -DR)?
2 alleles
How do we use the HLA molecule to determine the compatibility between potential donor and recipient?
Compare the alleles that make up the HLA subtypes between the recipient and donor
For example, for the HLA-A
Donor = two alleles that code for this molecule are HLA-A1 and HLA-A1
Recipient = two alleles that code for this molecule are HLA-A1 and HLA-A2
Matching = 1
Do the same for HLA-B and HLA-DR
Complete match = 0, 0, 0
Complete mismatch= 2, 2, 2
What is the relationship between HLA and MHC?
HLA = MHC in humans
What determines the alleles that code for the HLA subtypes?
Alleles are inherited from your parents
What is the role of HLA-DR?
Binds to specialised antigen presenting cells
Stimulates activation and proliferation of T cells
Releases cytokines which stimulate the immune response
What effect does HLA mismatching have on success of transplantation?
The more different the HLA - the greater the immune response - the more immunosuppression is needed - the higher the probability of rejection of the graft
What is transplant rejection?
Process by which the immune response attacks the donor organs
What are the three types of transplant rejection?
- Hyperacute
- Acute
- Chronic
What is the timeline of hyperacute transplant rejection?
Minutes - hours
Why does hyperacute transplant rejection occur?
Pre formed antibodies are present in the body
Due to the antibodies being exposed to ANY foreign HLA in the past
Exposure to foreign HLA happens in
Pregnancy
Blood transfusion
Previous transplantation
Describe a method to test for preformed antibodies in a host
- Take serum from the recipient in which there would be preformed antibodies
- Mix serum with donor cells
- Add complement to lyse the antibodies stuck to the donor cells
- Detect whether these are preformed antibodies
What do preformed antibodies attack?
Donor HLA antigens
Blood group antigens
How do preformed antibodies lead to transplant rejection?
Preformed antigens stick to endothelial cells
Trigger complement and clot formation
Form inflammation within the vessel
Occlude the transplanted organ blood supply = ischaemia
What is the timeline of acute transplant rejection?
Days - weeks
What leads to acute transplant rejection?
Can be
Cell-mediated -> T cells, macrophages and monocytes
Antibody mediated -> bind to HLA molecules or other antigens present in the blood vessels
What leads to organ rejection in acute transplant rejection?
Triggering of the complement cascade acts as an amplification signal of inflammation and coagulation
Eventually leads to organ rejection
What is the timeline of chronic transplant rejection?
Months - years
What mechanisms leads to chronic transplant rejection?
Cellular and humoral rejection
T cell mediated response to donor cells
Complement activation
Very little can be done to slow down chronic transplant rejection
TRUE or FALSE
True
What percentage of grafts are lost due to chronic transplant rejection?
50%
What are methods by which we have managed to increase transplant donations?
Paired donation
Desensitisation crossmatch positive
Plasmapheresis
What is paired donation?
If living donors are not suitable for the recipient - check to see if they are suitable for another recipient
Non compatible donors can ve switched between the two recipients
How does desensitisation crossmatch positive work?
Remove the antibodies after observed HLA mismatch
How does plasmapheresis work?
Perform before transplantation
Removal, treatment and return of plasma from the blood circulation
Decrease the antibodies that might attack the transplanted to negligible levels
How can ABO-blood group mismatch lead to organ rejection?
If the donor and recipient are blood group mismatched then they suffer hyperacute rejection
Preformed antibodies against these antigens
What are blood group antigens?
Big antigen system expressed on the blood vessel wall
What is accommodation?
Endothelial cells lining blood vessels become down regulated to the effect of autoantibodies
What is the consequence of accommodation?
Number of antobodies increases to before plasmapheresis
But there are no adverse effects since antibodies do not instigate inflammation
What is the definition of tolerance in context to transplantation?
When the recipient becomes tolerant to the antigens presented by the donor organ
So no autoantibodies are produced against the transplanted organ
What would be the consequences of tolerance in context to transplantation?
Indefinite graft survival
No need for:
- Immunosuppression - no drug related side effects, infections or nephrotoxicity
- No chronic rejection - no need for re-transplantation
- Impact organ shortage
What was Peter Medawar’s experiment?
Cells from brown-haired mouse where injected into white-haired embryo
Skin from the brown donor animal grafted onto the white recipient
Mouse grew both white and brown hair due to tolerance
White mouse became tolerant to the antigens from the brown mouse as cells were injected into the embryo
How can injection of CD4+CD25+ regulatory T cells increase organ survival.
The regulatory cells regulate the immune response
To prevent rejection
Minimise withdrawal of immunosuppressive drugs
What is the future of reducing organ rejection?
In vitro expansion and reinfusion of autologous CD4+CD25+ REGULATORY cells in patients with increased autoimmune reactivity
