Transplantation Flashcards
what are the life saving organs and life enhancing organs?
LS- liver, heart, small bowel
LE- kidneys, pancreas, cornea
what are some reasons organs fail? give example for the kidneys, liver and heart
e. g. kidney- diabetes, hypertension, glomerulonephritis, hereditary conditions
e. g liver- cirrhosis (viral hepatitis, alcohol, auto-immune, hereditary conditions), acute liver failure (paracetamol)
e. g. heart- coronary artery or valve disease, cardiomyopathy (viral, alcohol), congenital defects
what are the 5 types of transplants that can be done?
o Autograft: within the same individual
e. g. coronary artery bypass.
e. g. use of one’s stem cells
o Isografts: between genetically identical individuals of the same species.
o Allografts (most transplants) :between different individuals of the same species.
o Xenografts:between individuals of different species
e.g. heart valves (pig/cow) and skin
o Prosthetic graft : plastic, metal.
what are the two types of donors used?
deceased and living (related or unrelated donor)
what are the 2 types of deceased donors used?
o DBD – Deceased Brain-Death (heart is beating). Confirmed with neurological criteria
o DCD – Deceased Cardiac-Death (heart not beating). Confirmed with cardio-respiratory criteria
what must be ensured to allow successful harvesting of organs from DBD donors?
Cool to minimise ischaemic damage
what must be done to ensure successful harvesting of organs from Deceased Cardiac Death donors?
Long period of warm ischaemic time therefore must be harvested quickly
Ideal for kidney transplants
what can be taken for an allograft?
Solid organs (kidney, liver, heart, lung, pancreas)
Small bowel
Free cells (bone marrow, pancreas islets)
Temporary: blood, skin (burns)
Privileged sites: cornea
Framework: bone, cartilage, tendons, nerves
Composite: hands, face, larynx
what do living donors typically donate?
bone marrow
kidney
liver
what is the exclusion criteria for deceased donors?
viral infection (HIV, HBV, HCV)
malignancy
drug abuse, overdose or poison
disease of the transplanted organ
how are organ transplantation services organised?
Transplant selection: listing (waiting list) at a transplant centre after multidisciplinary assessment
Transplant allocation: how organs are allocated as they become available
how is allocation of an organ determined?
- National guidelines
- Evidence based computer algorithm
- Equity
- Time on waiting list
- Super-urgent transplant - imminent death (liver, heart)
- Efficiency – what is the best use for the organ in terms of patients survival and graft survival?
Organs must be rapidly cooled and perfused later (transplanted):
what are the cold ischaemia times for most organs? e.g. kidney, cornea and other organs
o Max cold ischaemia time for kidneys is 60 hours (ideally <24h) – much shorter for other organs.
o Cornea is an exception at 96 hours cold ischaemia
time.
cold ischaemia time: time between the chilling of a tissue, organ, or body part after its blood supply has been reduced or cut off and the time it is warmed by having its blood supply restored.
how are kidneys allocated?
1) 5 tiers of patient – paediatric/adult, sensitised/not-sensitised.
2) 7 elements:
• Waiting time.
• HLA-matching + age.
• Donor-recipient age difference.
• Location.
• HLA-DR homozygosity.
• HLA-B homozygosity.
• ABO blood group matching.
how can transplantation activity in the country be increased?
o Increased deceased donation – from marginal donors including the elderly.
o Increased living donation
o Xenotransplantation and stem cell research opportunities
what are the most important variations among donor organs that affect transplantation opportunity?
o ABO blood group.
o HLA coded on Chr6 by the MHC.
what antibodies are present for different blood types?
A–> anti B antibody
B–> anti A antibody
O–> both anti A and B antibdoies
AB–> neither antibodies
why does ABO mismatch rejection occur?
if the donor organ is given from the wrong blood group, the pre existing anti-antigen antibodies will bind to the organ endothelium proteins and cause rejection
this is antibody mediated rejection
what do antibodies activate?
complement via classical pathway
macrophages also
how can the issue of ABO incompatibility in transplantation be addressed?
o Remove ABs in recipient plasma.
- There is often a GOOD outcome even when the antibodies come back
- Done for – kidneys, liver & heart.
what is HLA?
Human Leukocyte Antigens:
high variable cell surface proteins as part of infection and neoplasia defence
These are highly polymorphic related to their function of encountering a large plethora of antigens
what are the classes of HLA?
class 1- A,B,C expressed on all cells
class 2- DR, DQ, DP expressed on APCs
what role does HLA i.e. MHC play in foreign antigen recognition? how does this relate with donor organs?
foreign antigen is taken up by an APC which presents in on the surface via MHC (HLA molecule)
T cells can recognise this antigen now sitting in the peptide groove as it has been presented via MHC (essential for recognition)
fragments of the donor organs are taken up by APCs and also presented, able to provoke an immune response
what is the composition of class I and class II MHC molecules?
class I- alpha and beta micro globulin
class II- alpha and beta
which HLA molecules are highly polymorphic?
HLA- A and HLA- B (class I) HLA-DR (class II)
what is the result of HLA mismatch? when does it is not become tolerable?
0-6 mismatches are tolerated
the higher the number of mismatches, the greater try chance of death later on
why are related donors preferred in context of HLA?
25% chance of 0 mismatches or 6 mismatches
50% chance of 3 mismatches
children of heterozygous parents
what is the most common reason for the failure of a graft?
immune reaction causing immune graft damage and failure
this leads to rejection (the cause of graft failure)
minimising HLA mismatches between donor and recipient improves transplant outcomes
how is graft rejection diagnosed and treated?
diagnosis= histological examination
treatment= immunosuppressives
what are the different types of rejection:
- in terms of onset?
- in terms of mediator?
- hyperacute
- acute
- chronic
- T cell mediated
- antibody mediated
what happens to cause T cell mediated rejection?
donor organ sheds HLA antigens which are eventually presented on APCs which can bind to T cells via MHC
HLA antigen–> collected by APC on its MHC–> T cell activation
what is the result of lymphocyte infiltration in the interstitial area?
tubulitis:
rupture the tubular BM and causes tubulitis and local organ damage
why is it important to avoid organ becoming ischaemic in relation to T cell mediated rejection?
ischaemia makes the likelihood of rejection greater due to greater lymphocyte arrest and infiltration
what do T cell recruit in its mediation of rejection?
CTL lymphocytes :
can release granzyme B, perforin and FasL (for apoptosis)
Macrophages:
can phagocytose, release proteases, produce cytokines and oxygen/nitrogen radicals.
what occurs in antibody mediated rejection?
antibodies against graft’s HLA and AB antigens are made
when can antibodies arise in relation to the transplantation?
o Pre-transplantation – ‘sensitised’ – patient already been exposed in pregnancy, previous transplants and blood transfusions
o Post-transplantation – ‘de novo’.
what do antibodies recruit?
complement, macrophages and inflammatory cells
how does the location of antibody mediated rejection differ to that of T cell mediated?
antibody mediated occurs intravascularly while T cell mediated occurs in the interstitium
how can a graft be monitored post-transplant?
watch for deteriorating graft function
– i.e. kidneys (reduced GFR, increased creatinine)
– i.e. liver (rise in LFTs).
how is rejection prevented pre and post transplant?
o Maximise HLA compatibility.
o Give life-long immunosuppressive drugs
(this also treats rejection, drugs depend on whether there is T cell or antibody mediated rejection)
what are the two targets in preventing and treating rejection?
- APC interaction with T cell
- B cell (antibodies)
how can the APC interaction with T cells be targeted in therapy?
drug examples?
The APC affects T cell activation and proliferation by e.g. affecting downstream pathways
- Anti-CD3 ABs
- JAK3 inhibitors
- Azathioprine
- cyclosporine
(calcineurin- required for activation- inhibitor)
how can B cells be targeted in therapy?
B cell depletion so prevents their activation , proliferation and antibody production function
prevent antibody mediated rejection
what are the options to target B cell activation?
- splenectomy (maturation site of B cells)
- anti-CD20 ABs (CD20 needed for B cell development and differentiation to plasma cells)
- Bortezomib (proteasome inhibitor)
- anti-C5 (complement component 5)
- intravenous immunoglobulin plasma exchange (IVIG).
what is the general regime of drugs given?
o Pre-transplantation – Induction agent (T-cell depletion or cytokine blockade)
o From implantation
– base-line immunosuppression
o If needed – treatment of acute rejection
what can be used to provide baseline immunosuppression?
Signal transduction blockade – CNI inhibitors – e.g. Cyclosporine.
Anti-proliferative agents – Azathioprine.
Corticosteroids.
what can be used for acute rejection?
T-cell mediated rejection –-> steroids, anti-T agents.
Antibody dependant rejection–-> IVIG, plasma exchange, anti-CD20, anti-complement.
what are two risks post-transplantion?
- infections due to immunosuppressives
- malignancy
what sort of infections can arise due to immunosuppression?
- conventional infections
- opportunistic infections
e.g.
cytomegalovirus, BK virus, Pneumocytis carinii, Murcormycosis, CMV
what are the post-transplantational malignancy risks associated with treating rejection?
o Skin cancer.
o Post-transplant lymphoproliferative disorder – EBV driven.
o Other – i.e. Kaposi’s Sarcoma.
