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Immuno 3: transplantation Flashcards

1
Q

When is transplantation used

A

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

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2
Q

Give examples of life saving transplantation, and the life supportive methods they supersede following exhaustion

A

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)

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3
Q

Give examples of life enhancing transplantation

A

Kidney – dialysis

Pancreas – in selected cases, tx better than insulin injections

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4
Q

Outline the 5-10 year mortality for kidney transplant patiets on waiting list

A

50%

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5
Q

Why does cornea fail

A

– degenerative disease, infections, trauma

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6
Q

Why does skin/composite fail

A

burns, trauma, infections, tumours

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7
Q

Why does bone marrow fail

A

tumours, hereditary diseases

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8
Q

Why do kidneys fail

A

diabetes, hypertension, glomerulonephritis, hereditary conditions

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9
Q

Why dos liver fail

A

cirrhosis (viral hepatitis, alcohol, auto-immune, hereditary conditions), acute liver failure (paracetamol)

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10
Q

Why does heart fail

A

– coronary artery or valve disease, cardiomyopathy (viral, alcohol), congenital defects

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11
Q

Why does lung fai

A

chronic obstructive pulmonary disease (COPD)/emphysema (smoking, environmental), interstitial fibrosis/interstitial lung disease (idiopathic, autoimmune, environmental), cystic fibrosis (hereditary), pulmonary hypertension

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12
Q

Why does pancreas fail

A

type I diabetes

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13
Q

What causes small bowel failure

A

mainly children (“short gut”); volvulus, gastroschisis, necrotising enteritis related to prematurity (in adults - Crohn’s, vascular disease, cancer)

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14
Q

State the types of transplantation:

Autografts 
Isogrfts 
Allografts 
Xenograft 
Prosthetic graft
A

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

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15
Q

Give example of autografts

A

Coronary artery bypass surgery

FUTURE: your own stem cells could be used to grow a ew organ to be transplanted into you

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16
Q

Xenograft examples

A 
Heart valves (pig/cow)
Skin
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17
Q

Examples of allografts

A

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

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18
Q

Types of donor for allograft

A

Deceased

Living

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19
Q

What tissues can you get from living donor

A

bone marrow, kidney, liver

from genetically related or unrelated (spouse; altruistic)

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20
Q

What is donor after brain stem death

A

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

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21
Q

What is donor after circulatory death

A

death is diagnosed and confirmed using cardio-respiratory criteria; 5 minutes observation of irreversible cardiorespiratory arrest

Longer period of warm ischaemia time

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22
Q

Overall neuroogical criteria of death

A

…..

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23
Q

What must be exluded with deceased donor

A

viral infection (HIV, HBV, HCV)

malignancy

drug abuse,
overdose or poison

disease of the transplanted organ

-USS potential donor

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24
Q

What happens after organ harvest

A

Removed organs rapidly cooled and perfused

  • absolute maximum cold ischaemia time for kidney 60h (ideally <24h)
  • much shorter for other organs
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25
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
26
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?
27
How does transplant allocation get decided
National guidelines-evidence based computer algorithm
28
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
29
Other strategies to increase transplantation
1. Deceased donation from marginal donors, DCD, elderly 2. lviing donaion transplation acoss tissue compatibility barriers, exchange programmes
30
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
31
What are the most relevant protein variations in clinical transplantation
1. ABO blood group | 2. HLA (human leukocyte antigens) coded on chromosome 6 by Major Histocompatibility complex (MHC)
32
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
33
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
34
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
35
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
36
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”
37
When can T cells 'see' antigen'
Only when an antigen is presented by HLA
38
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
39
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
40
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)
41
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
42
Which HLA chains are really polymorphonc
1-A, B, C and 2- DR
43
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
44
Why is mismatching important
Because it determines the likelihood of organ surviving
45
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)
46
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
47
What is the most common cause of graft failure
Rejection
48
How is rejection be diagnosed
histological examination of a graft biopsy | creatinine may increase in kidney transplant rejection, in liver, increased liver enzymes
49
Outline the types of rjection (timescale)
- hyperacute rejection - acute rejection - chronic rejection
50
Outline the 2 immunological basis of rejection
- T-cell mediated rejection | - antibody-mediated rejection
51
When might you want to stop immunosuppressive drugs during a rejection
If an infection is damaging transplant (immunosuppresion might make infection worse!)
52
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
53
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 ```
54
What would be seen on PAS stain in T cell mediated rejection
Infiltration of small dark nuclei (immune cells) causing the tubulitis
55
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
56
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
57
.......
.....
58
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
59
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)
60
How to prevent rejection
maximise HLA compatibility Life-long immunosuppressive drugs
61
How is rejection treated
More immunosuppressive drugs
62
What do immunosuppresive drugs targeted
Targeting T cell activation and proliferation Targeting B cell activation and proliferation, and antibody production
63
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
64
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
65
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
66
Balance rejection with what negative factors due to drugs
Infection Tumour Drug toxicity
67
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)
68
Common post transplantation malignancies
Skin cancer Post transplant lymphoproliferative disorder – Epstein Barr virus driven others

Immuno (5 decks)

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