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Immunology year 2 > Organ transplantation > Flashcards

Organ transplantation Flashcards

1
Q

Ultimately, why are organs transplanted

A

Organs are transplanted when they are failing or have failed, or for reconstruction

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2
Q

What is meant by a life saving transplant

A

Life-saving
other life-supportive methods have reached end of their use
liver
heart (LVAD – left ventricular assist device)
small bowel (TPN - total parenteral nutrition)

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3
Q

What is meant by a life enhancing transplant

A

Life-enhancing
other life-supportive methods less good
Kidney – dialysis
Pancreas – in selected cases, tx better than insulin injections
organ not vital but improved quality of life: cornea, reconstructive surgery

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4
Q

Essentially, what is the difference between a life saving and a life enhancing transplant

A

Life-saving – other life-supportive methods are not fully developed or other life-supportive methods have reached the end of their possible use
Life-enhancing – other life-supportive methods are less good e.g. Kidneys and dialysis – the organ is not vital but it improves the quality of life

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5
Q

What does the data show regarding kidney, heart and liver transplantation

A

Those receiving a transplant (from either a living or deceased donor have a better survival rate than those on the waiting list.
Living donor organs > deceased donor organs

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6
Q

Summarise the different reasons why organs may fail

A

Cornea – degenerative disease, infections, trauma
Skin/composite – burns, trauma, infections, tumours
Bone marrow – tumours, hereditary diseases

Kidney – diabetes, hypertension, glomerulonephritis, hereditary conditions
Liver – cirrhosis (viral hepatitis, alcohol, auto-immune, hereditary conditions), acute liver failure (paracetamol)
Heart – coronary artery or valve disease, cardiomyopathy (viral, alcohol), congenital defects

Lungs – chronic obstructive pulmonary disease (COPD)/emphysema (smoking, environmental), interstitial fibrosis/interstitial lung disease (idiopathic, autoimmune, environmental), cystic fibrosis (hereditary), pulmonary hypertension
Pancreas – type I diabetes
Small bowel – mainly children (“short gut”); volvulus, gastroschisis, necrotising enteritis related to prematurity (in adults - Crohn’s, vascular disease, cancer)

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7
Q

Describe the different types of transplantation

A 
Autografts
within the same individual (CABG)
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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8
Q

Give some other examples of autografts

A

e.g. Vascular transplants/stem cells

Stem cells to make own organ e.g

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9
Q

Give some examples of xenografts

A 
Heart valves (pig/cow)
Skin
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10
Q

Give some 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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11
Q

Describe the statistics regarding organ transplants in the U.K

A

 Total organ transplant numbers have increased (just pancreas and intestinal have fallen) with majority kidneys.
o ~50,000 people have a functional transplant in the UK as of march 2018

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12
Q

What are the two different types of donor for allografts

A

Deceased donor

Living donor
bone marrow, kidney, liver
genetically related or unrelated (spouse; altruistic)

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13
Q

What are the different types of deceased donor

A

Donor after brain death – brain dead but heart-beating

Donor after cardiac death – non-heart beating donors

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14
Q

Describe donors 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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15
Q

Describe death after circulatory death

A

DCD – donor after circulatory death
death is diagnosed and confirmed using cardio-respiratory criteria; 5 minutes observation of irreversible cardiorespiratory arrest
Controlled: generally patients with catastrophic brain injuries who while not fulfilling the neurological criteria for death have injuries of such severity as to justify withdrawal of life-sustaining cardiorespiratory treatments on the grounds of best interests
[Uncontrolled: no or unsuccessful resuscitation]
Longer period of warm ischaemia time

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16
Q

Describe the neurological criteria of death for DBD

A 
irremediable structural brain damage of KNOWN cause 
apnoeic coma NOT due to
cardiovascular instability
depressant drugs
metabolic or endocrine disturbance
hypothermia
neuromuscular blockers

demonstrate absence of brain stem reflexes
Pupillary reflex absent (light)
Corneal reflex absent (touch)
Ocular vestibular reflex (no eye movements with cold caloric test)
Motor response cranial nerves (to orbital pressure)
Cough and gag reflex
Lastly - Apnoea test: no respiratory movements on disconnection from ventilator (with PaCO2 >50 mmHg)

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17
Q

What must be excluded with deceased donors

A 
Exclude:
viral infection (HIV, HBV, HCV)
malignancy
drug abuse, overdose or poison
disease of the transplanted organ
USS potential donor
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18
Q

What must be done to removed organs

A

Removed organs rapidly cooled and perfused
absolute maximum cold ischaemia time for kidney 60h (ideally <24h)
much shorter for other organs
o Cornea is an exception at 96 hours’ cold ischaemia time.

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19
Q

Summarise the organisation of transplantation services

A

Transplant selection: listing (waiting list) at a transplant centre after multidisciplinary assessment

Transplant allocation: how organs are allocated as they become available

NHSBT (NHS Blood and Transplant)
Provision of a reliable, efficient supply of blood, organs and associated services to the NHS
Establishes rules for organ allocation and monitors allocation

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20
Q

Describe transplant selection

A

 Transplant selection – for access to the waiting list:
o Referral for assessment  MDT assess eligibility  NHS transplant list AND inspect contraindications (too early to be placed on list, co-morbidities, patient wishes).
o Transplant numbers have been dropping and available organs rising but there is still a disconnect.

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21
Q

What is the nationwide assessment for organ allocation based on

A

National guidelines
Evidence based computer algorithm

Equity – what is fair?
Time on waiting list
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?

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22
Q

What are the different tiers and elements for the waiting list

A

5 tiers of patients depending on
paediatric or adult
Highly sensitised or not

7 elements
Waiting time
HLA match and age combined
Donor-recipient age difference
Location of patient relative to donor
HLA-DR homozygosity
HLA-B homozygosity
Blood group match
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23
Q

How many people die on the waiting list

A

6000 people died in circumstances making them eligible for donation

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24
Q

Describe the different strategies to increase transplant activity to match supply with demand

A
  1. deceased donation
    Marginal donors – DCD, elderly, co-morbidities
  2. living donation
    transplantation across tissue compatibility barriers
    Exchange programmes: organ swaps for better tissue matching
  3. The future?
    Xenotransplantation
    Stem cell research
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25
Q

Describe the different assessments of kidney transplants

A

DBD kidney transplant patients are assessed nationally.
DCD kidney transplant patients are assessed locally.

This is so the kidneys can be implanted with less warn ischaemia.

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26
Q

What is the half life for a transplanted adult kidney

A

Living donor- 12 years

Deceased- 10 years

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27
Q

Summarise the management of transplant organisation

A

 50% of potential donors after brain death donate organs – mainly due to declined consent by the family.
 This is aiming to be raised by:
o UK Gov. Dept. of Health initiatives.
o Public engagement.
o Improved quality of organ retrieval and transplantation.
o Donor transplant co-ordinators – critical care nurses and carry out family interviews to gain consent.

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28
Q

Summarise the immunology of transplantation

A

The immune system recognises someone else’s organ as foreign
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)

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29
Q

Summarise the ABO blood group

A

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

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30
Q

Describe the structure of the different ABO antigens

A

o O+ = 1x fructose, 1x n-acetyl-glucosamine, 2x galactose.
o A+ = 1x fructose, 1x n-acetyl-glucosamine, 2x galactose, 1x n-acetyl-galactosamine.
o B+ = 1x fructose, 1x n-acetyl-glucosamine, 3x galactose.

31
Q

Describe ABO incompatibility

A

Heart transplant from blood group B donor –

i.e. cells express blood group B

Patient: blood group A
Red cells express A
Patient serum contains naturally occurring anti-B antibodies

Circulating, pre-formed, recipient anti-B antibody binds to B blood group antigens on donor endothelium = antibody-mediated rejection

Complement cascade, thrombi formation in organ- organ will go purple after a few minutes of donating

32
Q

Describe how we can overcome ABO incompatible transfusions

A 
Remove the antibodies in the recipient (plasma exchange)
Good outcomes (even if the antibody comes back)
Kidney, heart, liver
33
Q

Summarise HLA

A

Discovered after first failed attempts at human transplantation
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

34
Q

Describe how T cells recognise foreign antigens

A

APC ingests foreign peptides and presents them in the context of HLA (MHC) which the T cell recognises.
T cell recognises foreign peptide in the context of host MHC.
Donor graft cell can ‘shed off’ its own HLA molecules, which can be recognised as foreign by the recipient’s APC cells and presented to CD4+ T cells to activate them- leading to an immune response against the donor graft cell

35
Q

Describe the key features of HLA

A 
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

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)

36
Q

Describe the structure of MHC 1

A

Peptide binding groove between a2 and a1
a3 (membrane spanning)
b2-macroglobulin

37
Q

Describe the structure of MHC 2

A

Peptide binding groove between b1 and a1

b2 and a2 membrane spanning domains

38
Q

Which HLA types are highly polymorphic

A

A
B
C
DR

39
Q

Which HLA do we match for in transplantation

A 
A
B
DR
These are immunogenic- so relevant
BUT also- highly polymorphic

Number of mismatches : 0 to 6
Expressed as a ratio of A:B:DR
E.g 2:1:0 - 3 mismatches

Fewer mismatches between donor and recipient HLAs associated with Better outcomes in kidney transplants

40
Q

Describe the benefits of related living donation

A

Parent to child:
≥3/6 matched

Sibling to sibling:
25% - 6MM
50% - 3MM
25% - 0MM

41
Q

Describe the importance of HLA antigens for transplantation

A

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

42
Q

Summarise rejection

A

Most common cause of graft failure
Diagnosis = histological examination of a graft biopsy
Treatment = immunosuppressive drugs

43
Q

Describe the different classifications of rejection

A

 Rejection can be T-cell mediated or anti-body mediated.

 Rejection can be hyper-acute, acute or chronic.

44
Q

Describe hyper acute rejection

A

Hyperacute rejection takes place within hours of transplantation and is caused by preformed antibodies binding to either ABO blood group or HLA class I antigens on the graft (Fig. 34.1A). The recipient may have formed anti-HLA class I antibodies after exposure to allogeneic lymphocytes during pregnancy, blood transfusion, or a previous transplant. Antibody binding triggers a type II hypersensitivity reaction, and the graft is destroyed by vascular thrombosis. Hyperacute rejection can be prevented through careful ABO and HLA cross-matching and is now quite rare.

45
Q

Describe acute rejection

A

Acute rejection is a type IV (cell-mediated) delayed hypersensitivity reaction and therefore takes place within days, and sometimes weeks, of transplantation. Acute rejection takes several days to develop because donor dendritic cells must first stimulate an allogeneic response in a local lymph node for responding T cells to proliferate and migrate into the donor kidney.
Acute rejection takes place if there is HLA incompatibility. Recipient T cells can respond to donor peptides presented by recipient major histocompatibility complex (MHC) or to donor MHC molecules (see Fig. 34.1). Although attempting to minimize any HLA mismatch of the donor and recipient can reduce acute rejection, the shortage of donor kidneys often means that a partially mismatched kidney is used. The survival of the kidney is related to the degree of mismatching, especially at the HLA-DR loci

46
Q

Describe the minor histocompatibility complex

A

Alternatively, the recipient may respond to minor histocompatibility antigens presented by donor or recipient cells (see Box 34.1). Minor antigens are proteins that have different amino acid sequences in the donor and recipient; they are encoded by genes situated outside the HLA. Minor histocompatibility antigen mismatches are not detected by standard tissue-typing techniques. The term minor antigens may be misleading in terms of importance; even when an HLA-matched, living related donor is found, these antigens can cause graft rejection in up to one-third of transplants.

47
Q

When are acute rejections more likely to take place

A

Acute rejection is more likely to develop if the donated kidney has been damaged. For example, if the kidney is not immediately placed on ice, it will be damaged by hypoxia. The damage-associated molecular patterns (DAMPs) induced by hypoxia are detected by pattern recognition molecules, which in turn stimulate the production of danger signals

48
Q

Describe chronic rejection

A

Chronic rejection takes place months or years after transplant. An element of allogeneic reaction is often mediated by T cells in chronic rejection, which can result in repeated acute rejection. In some cases, chronic rejection may be caused by recurrence of preexisting autoimmune disease. In other cases, no direct evidence of damage caused by the adaptive immune system is apparent.

49
Q

Describe the mechanism of T-Cell mediated rejection

A

Host and donor APC present donor HLA and migrate to lymphoid organs
APC meet T cells in secondary lymphoid organs
Naive and central T cells recirculate between secondary lymphoid organs
Traffic controlled by S1P receptors and chemokine receptors
Effector T cells attack graft

50
Q

Describe the tissue damage caused by T-cell mediated rejection

A

T cells pass through endothelium via diapedesis
This leads to lymphocytic interstitial infiltration
can then rupture the basement membrane and invade tubular cells- leading to tubilitis

Ischaemia or damage to the organ during transplant process can precipitate to diapedesis

51
Q

Which cells infiltrate the graft

A

Graft infiltration by alloreactive CD4+ cells

52
Q

Describe the roles of cytotoxic T cells in T-cell mediated rejection

A 
“Cytotoxic” T cells
Release of toxins to kill target
Granzyme B
Punch holes in target cells
Perforin
Apoptotic cell death
Fas -Ligand
53
Q

Describe the role of macrophages in T-cell mediated rejection

A 
Macrophages
Phagocytosis
Release of proteolytic enzymes
Production of cytokines
Production of oxygen radicals and nitrogen radicals
54
Q

Describe how we can histologically stain for T-cell mediated rejection

A

PAS stain
CD3

Will show T cell infiltration and tubulitis

55
Q

Summarise antibody-mediated rejection

A

Antibody against graft HLA and AB antigen
Antibodies arise
Pre-transplantation (“sensitised”)
Post-transplantation (“de novo”)

56
Q

Describe normal antibody function.

A

Fab region binds to antigen (HLA antigen expressed on graft)
Can activate classic complement pathway- leading to formation of MAC
FcyR on macrophages can then bind to Fc region of bound antibody and phagocytose the cell

57
Q

What is another key difference between antibody-mediated rejection and T-cell mediated rejection

A

Ab- intravascular process- glomerulitis, per tubular capillaritis
T cell- interstitial process

58
Q

How else can you diagnose antibody-mediated rejection

A

Complement fragment
C4d

Stain for this using immunohistochemistry- will see it stacked on the endothelial cells

59
Q

Summarise post transplant monitoring for rejection

A

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
Q

Summarise the prevention and treatment of rejection

A 
Prevention of rejection
maximise HLA compatibility
Life-long immunosuppressive drugs
Treatment of rejection
more drugs…
61
Q

What are the key aims of immunosuppressive drugs

A

Targeting T cell activation and proliferation

Targeting B cell activation and proliferation, and antibody production

62
Q

Describe how we can interfere with antigen presentation to the T cell (signal 1)

A 
Anti-cd3 mAb
Calcineurin inhibitor (signalling pathway upon activation)- cyclosporine or tacrolimus
63
Q

Describe how we can interfere with co-stimulation (signal 2)

A

CTLA-4-Ig

64
Q

Describe how we can interfere with cytokine signalling (signal 3)

A

Anti-CD25 mAb
mTOR inhibitors (sirolimus, everolimus)- signalling pathway
proliferation- azathiproin, MMF

65
Q

Describe how we can cause T cell depletion

A

Anti- CD52 mAb

66
Q

Describe the roles of the different immunosuppressive drugs

A

 Immunosuppressive drugs:
o Target T-cell activation and proliferation.
 Anti-CD3 ABs, JAK3 inhibitors, Azathioprine, cyclosporine.
o Target B-cell activation, proliferation and antibody production.
 Splenectomy, anti-CD20 ABs (rituximab) , Bortezomib (proteasome inhibitor), anti-C5, intravenous immunoglobulin plasma exchange (IVIG).

67
Q

Outline the standard immunosuppressant regimen

A

Pre-transplantation - Induction agent (T-cell depletion or cytokine blockade)

From time of implantation - Base-line immunosuppression
Signal transduction blockade, usually a CNI inhibitor: Tacrolimus or Cyclosporin; sometimes mTOR inhibitor (Rapamycin)
Antiproliferative agent: MMF or Azathioprine
Corticosteroids

If needed - Treatment of episodes of acute rejection
T-cell mediated: steroids, anti-T cell agents
Antibody-mediated: IVIG, plasma exchange, anti-CD20, anti-complement

68
Q

Describe the risks of immunosuppression

A

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)
Kaposi's sarcoma

Drug toxicity is also important

Balance determines success of transplant

69
Q

What should be given to transplant patients on immunosuppression

A

Prophylactic anti-viral therapy (acyclovir for CMV)

Pneumositsis infections prevented by giving septrin post-transplantation - prevent pneumonia

70
Q

What can be seen on CMV infection

A

Owls eyes inclusion sin tubular epithelial cells- can cause graft loss
Mucormycosis- fungal

71
Q

Summarise post transplant malignancy

A

Skin cancer
Post transplant lymphoproliferative disorder – Epstein Barr virus driven- viral driven- kaposi’s sarcoma
others

72
Q

What is important to remember about transplantation

A

Transplantation is life-saving/life-enhancing
Not without risks – surgery, immunosuppressive burden (infections, malignancy, drug toxicity)
Issues related to supply/demand, ethics, biology limit its use

73
Q

Summarise the complications of transplantation

A

Surgical problems (blood vessels, ureter anastomosis)
Poor quality organ – established fibrosis; poor blood supply
Rejection
Recurrence of original disease causing kidney failure (for ex. Glomerulonephritis)
Infection
Conventional micro-organisms – increased incidence
Opportunistic infections
CMV
Pneumocystis
BK virus
Drug side effects – cardiovascular morbidity and mortality
Malignancy
UV-induced skin cancer
post-transplant lymphoproliferative disease (PTLD; mostly B cell, EBV-driven)
conventional malignancies are marginally increased

74
Q

Summarise the key features of each type of rejection

A

• Hyperacute rejection
o Caused by pre-existing antibodies to donor AB or HLA
o Historical sensitisation e.g. through previous transplant, transfusion or pregnancy
o Antibody binds to graft endothelium in minutes and destroys the graft in hours
o Autoantibodies can be identified and removed by plasma exchange
• Acute rejection: weeks-years after transplant
• Chronic rejection: often associated with non-compliance to immunosuppressant drugs
o Months-years post transplant

Immunology year 2 (5 decks)

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