Immuno 3: transplantation Flashcards
When is transplantation used
Life-saving
other life-supportive methods have reached end of their use
Life enhancing
other life-supportive methods less good
or
organ not vital but improved quality of life: cornea, reconstructive surgery
Give examples of life saving transplantation, and the life supportive methods they supersede following exhaustion
these could be transplanted when the life supporting methods in brackets have reached end of use
liver
heart (LVAD – left ventricular assist device)
small bowel (TPN - total parenteral nutrition)
Give examples of life enhancing transplantation
Kidney – dialysis
Pancreas – in selected cases, tx better than insulin injections
Outline the 5-10 year mortality for kidney transplant patiets on waiting list
50%
Why does cornea fail
– degenerative disease, infections, trauma
Why does skin/composite fail
burns, trauma, infections, tumours
Why does bone marrow fail
tumours, hereditary diseases
Why do kidneys fail
diabetes, hypertension, glomerulonephritis, hereditary conditions
Why dos liver fail
cirrhosis (viral hepatitis, alcohol, auto-immune, hereditary conditions), acute liver failure (paracetamol)
Why does heart fail
– coronary artery or valve disease, cardiomyopathy (viral, alcohol), congenital defects
Why does lung fai
chronic obstructive pulmonary disease (COPD)/emphysema (smoking, environmental), interstitial fibrosis/interstitial lung disease (idiopathic, autoimmune, environmental), cystic fibrosis (hereditary), pulmonary hypertension
Why does pancreas fail
type I diabetes
What causes small bowel failure
mainly children (“short gut”); volvulus, gastroschisis, necrotising enteritis related to prematurity (in adults - Crohn’s, vascular disease, cancer)
State the types of transplantation:
Autografts Isogrfts Allografts Xenograft Prosthetic graft
Autografts
-within the same individual
Isografts
-between genetically identical individuals of the same species
Allografts
-between different individuals of the same species
Xenografts
-between individuals of different species
Prosthetic graft
-plastic, metal
Give example of autografts
Coronary artery bypass surgery
FUTURE: your own stem cells could be used to grow a ew organ to be transplanted into you
Xenograft examples
Heart valves (pig/cow) Skin
Examples of allografts
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
Types of donor for allograft
Deceased
Living
What tissues can you get from living donor
bone marrow, kidney, liver
from genetically related or unrelated (spouse; altruistic)
What is donor after brain stem death
DBD – donor after brain stem death
- majority of organ donors
- brain injury has caused death before terminal apnoea has resulted in cardiac arrest and circulatory standstill
E.g. Intracranial haemorrhage; road traffic accident
Circulation established through resuscitation
Confirm death using neurological criteria
Harvest organs and cool to minimise ischaemic damage
What is donor after circulatory death
death is diagnosed and confirmed using cardio-respiratory criteria; 5 minutes observation of irreversible cardiorespiratory arrest
Longer period of warm ischaemia time
Overall neuroogical criteria of death
…..
What must be exluded with deceased donor
viral infection (HIV, HBV, HCV)
malignancy
drug abuse,
overdose or poison
disease of the transplanted organ
-USS potential donor
What happens after organ harvest
Removed organs rapidly cooled and perfused
- absolute maximum cold ischaemia time for kidney 60h (ideally <24h)
- much shorter for other organs
What is transplant selection and transplant allocation
Transplant selection: listing (waiting list) at a transplant centre after multidisciplinary assessment
Transplant allocation: how organs are allocated as they become available
What is transplant allocation based on
Equity – what is fair?
1. Time on waiting list
2. Super-urgent transplant - imminent death (liver, heart)
What else?
Efficiency – what is the best use for the organ in terms of patients survival and graft survival?
How does transplant allocation get decided
National guidelines-evidence based computer algorithm
Key elements and tiers deciding organ allocation
5 tiers of patients depending on
- paediatric or adult
- Highly sensitised or not
7 elements…
including:
- Waiting time
- HLA match and age combined
- Donor-recipient age difference
Other strategies to increase transplantation
- Deceased donation from marginal donors, DCD, elderly
- lviing donaion
transplation acoss tissue compatibility barriers, exchange programmes
Main reason for reduced lifespan of transplanted organs, whether living or dead
Due to immunological differences between host and donor
Also the warm iscahemia time in deceased donors
Infection
What are the most relevant protein variations in clinical transplantation
- ABO blood group
2. HLA (human leukocyte antigens) coded on chromosome 6 by Major Histocompatibility complex (MHC)
Where are the A and B proteins in ABO bloof groups licated
A and B proteins with carbohydrate chains on red blood cells but also endothelial lining of blood vessels in transplanted organ
Naturally occurring anti-AB antibodies
What is present in A, B, O and AB
All have common H antigen…. made up of:
N-acetyl glucosamine
2x galactose
fucose
Then A has N-acetyl-galactososamine
B has an extra galactose
AB has both
O is just the H
Why is ABO problematic
Because if transplated organ is from B patient, and given to A,
then anti-B antibodies in the group A patient will target the B molecules on the endothelial cells in vessels of the organs
Circulating, pre-formed, recipient anti-B antibody binds to B blood group antigens on donor endothelium = antibody-mediated rejection
Why is ABO group no longer really a problem (ABO-incompatible transplantation)
Remove the antibodies in the recipient (plasma exchange)
Good outcomes (even if the antibody comes back)
Kidney, heart, liver
What is HLA, why is variability important
Cell surface proteins
Highly variable portion
Variability of HLA molecules important in defense against infections and neoplasia
Foreign proteins are presented to immune cells in the context of HLA molecules recognised by the immune cells as “self”
When can T cells ‘see’ antigen’
Only when an antigen is presented by HLA
How are donor antigens presented to T cell
Donor HLA fragment (antigen) is presented by APC of the recipient
to the CD4+ T cell of the recipient
Causes delayed type hypersensitivity reaction
Class 1 vs class 2 HLA
Including the letters
Class I (A,B,C)– expressed on all cells
Class II (DR, DQ, DP) – expressed antigen-presenting cells but also can be upregulated on other cells
Characterise HLA
Highly polymorphic – lots of alleles for each locus (for example: A1, A2, …, A341… etc.)
Each individual has most often 2 types for each HLA molecule (for example: A3 and A21)
Structure of peptide groove in class 1 and class 2
All composed of a chain in class 1
Half alpha and half beta in class 2
Which HLA chains are really polymorphonc
1-A, B, C and 2- DR
How are mismatches quantified
HLA compared for HLA-A, HLA-B and HLA-DR.
Mismatches 0-6… you look in 3 sites but this is a complication
Why is mismatching important
Because it determines the likelihood of organ surviving
What is the probability of having 0, 3 and 6 mismatches (MM) between siblings in the HLA-A, HLA-B and HLA-DR?
and what about parent to child
25% - 6MM
50% - 3MM
25% - 0MM
At least 3/6 will match in the case of parents (more if the parents happen to have some same HLA haplotype)
What is the clinical correlate of the HLA similarity
Exposure to foreign HLA molecules results in an immune reaction to the foreign epitopes
The immune reaction can cause immune graft damage and failure = rejection
What is the most common cause of graft failure
Rejection
How is rejection be diagnosed
histological examination of a graft biopsy
creatinine may increase in kidney transplant rejection, in liver, increased liver enzymes
Outline the types of rjection (timescale)
- hyperacute rejection
- acute rejection
- chronic rejection
Outline the 2 immunological basis of rejection
- T-cell mediated rejection
- antibody-mediated rejection
When might you want to stop immunosuppressive drugs during a rejection
If an infection is damaging transplant (immunosuppresion might make infection worse!)
Outline T cell mediated rejection
HLA antigens from the donor organ taken up by recipient APCs,
In lymph nodes, recipient’s APCs meet T cells
T cells recirculate in blood stream
The donor HLA antigens will be present on the surface of the endothelium, as will other chemokines, leading to T cell arrest
Travel through the vessel via diapedesis
Form lymphocytic intersistial infiltration in the INTERSTITIUM OF THE DONOR KIDNEY
Leads to tubulitis so INFLAMMATION IN THE TUBULES OF THE DONOR KIDNEY
What happens in initial T cell graft rejection
What else can these cells recruit
Th1 DTH response…
Graft infiltration by alloreactive CD4+ cells
“Cytotoxic” T cells Release of toxins to kill target Granzyme B Punch holes in target cells Perforin Apoptotic cell death Fas -Ligand
Macrophages Phagocytosis Release of proteolytic enzymes Production of cytokines Production of oxygen radicals and nitrogen radicals
What would be seen on PAS stain in T cell mediated rejection
Infiltration of small dark nuclei (immune cells) causing the tubulitis
Outline when the antibodies can be made in the antibody mediated graft rejection and what molecules they are made against
Antibody against graft HLA and AB antigen
Antibodies arise
-Pre-transplantation (“sensitised”). In the case of ABO, the antibodies are there from birth. For HLA, they may have seen the foreign antigen in the graft before and made antibodies to it e.g. if they had transfusion, pregnancy, or if they had a graft before
-Post-transplantation (“de novo”). i.e. they never seen the foreign antigen before and are now making antibodies against it
Outline the type of immune response taking place with antibody mediated rejection and where the antibodies bind
Type III, this is soluble antigen.
There is Fc binding activating complement and cellular immunity
Free antibodies can bind to donor HLA fragments or ABO molecules on the endothelial cells.
These can activate complemnet
Alternatively, antibodies bound to the endothelial cell fragments can bind Fc receptors on cells like mononuclear cells or PMNs can bind and cause endothelial cell death and graft destruction in the microcirculation
…….
…..
Differentiate the type of tissue damage seen in antibody and T cell mediated
Antibody is mostly intravascular recruitment of inflammatory cells to the microcirculation (e.g. in glomeruli)
With T cell it’s tubulitis and interstilial infiltrates
Thus need different treatments
What will be seen to show deteroration of graft function in:
kidney liver lung kidney heart
In which organs can there be subclinical rejection so what do we do instead
Deteriorating graft function
Kidney transplant: Rise in creatinine, fluid retention, hypertension
Liver transplant: Rise in LFTs, coagulopathy
Lung transplant: breathlessness, pulmonary infiltrate
Subclinical
- Kidney
- Heart (no good test for dysfunction, regular biopsies)
How to prevent rejection
maximise HLA compatibility
Life-long immunosuppressive drugs
How is rejection treated
More immunosuppressive drugs
What do immunosuppresive drugs targeted
Targeting T cell activation and proliferation
Targeting B cell activation and proliferation, and antibody production
Outline drugs used during a T cell mediated rejection
AIMED AT STOPPING T CELL ACTIVATION THROUGH INTERACTION WITH THE APC
- Calcineurin inhibitor prevents downstream TCR signalling following MHC binding
- Azathioprine used to disrupt T cell cell cycle by depleting nucleotides and causing death of the T cell. Or MMF does similarly
- Steroids have general anti-inflammatory effect
Outline drugs used during a B cell mediated response
Splenectomy
Rituximab depletes CD20+ve B cells
Bortezomib is a proteosome inhibitor Bortesomib. It has anti T cell actions but causes plasma cell apoptosis
Anti-C5 (i.e. antibodies against complement)
Or IVIG which is itravenous immunoglobulin plasma exhcange to remove antibodies or stop production of them
Standard immunosuppressive regime
Pre-transplantation: Induction agent (T-cell depletion or cytokine blockade)
From time of implantation - Base-line immunosuppression:
- Signal transduction blockade e.g. calcineurin inhibitor (CNI)
- Antiproliferative (azathioprine/MMF)
- Corticosteroids
If needed: treatment in episodes of acute rejection:
- T cell mediated: steroids and anti-T agents
- Antibody mediated: IVIG, plasma exchange, anti-CD20, anti-complemnet
Balance rejection with what negative factors due to drugs
Infection
Tumour
Drug toxicity
Whihc infections are you susceptible to post transplant
Increased risk for conventional infections
Bacterial, viral, fungal
Opportunistic infections – normally relatively harmless infectious agents give severe infections because of immune compromise
- Cytomegalovirus
- BK virus
- Pneumocytis carinii (jirovecii)
Common post transplantation malignancies
Skin cancer
Post transplant lymphoproliferative disorder – Epstein Barr virus driven
others
