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Year 2 - MCD - Immunology > 2 - Transplantation (13.02.2020) > Flashcards

2 - Transplantation (13.02.2020) Flashcards

1
Q

Why/when are organs transplanted?

A
  • when they are failing
  • or when they have failed
  • or for reconstruction
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2
Q

Life saving vs. enhancing transplants

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)

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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3
Q

Why does a cornea fail?

A

degenerative disease
infections
trauma

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4
Q

Why does a liver fail?

A

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

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5
Q

Why does a heart fail?

A

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

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6
Q

Why does a kidney fail?

A

diabetes, hypertension, glomerulonephritis, hereditary conditions

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7
Q

Why does skin/composite fail?

A

burns, trauma, infections, tumours

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8
Q

Why does bone marrow fail?

A

tumours, hereditary diseases

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9
Q

Why does a lung fail?

A

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

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10
Q

Why does a pancreas fail?

A

T1DM

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11
Q

Why does a small bowel fail?

A

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

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12
Q

What are the types of transplantation?

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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13
Q

Autografts

A

within the same individual

e.g. skin from one place to other, growing things with stem cells and putting them back in

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14
Q

transplant within the same individual

A

autograft

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15
Q

Isograft

A

between genetically identical individuals of the same species

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16
Q

What is a transplant between genetically identical individuals of the same species called?

A

isograft

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17
Q

Allograft

A

between different individuals of the same species

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18
Q

What is a transplant between different individuals of the same species called?

A

Allograft

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19
Q

Xenograft

A

between individuals of different species

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20
Q

transplant between individuals of different species

A

Xenograft (e.g. pig/cow valves; skin)

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21
Q

Prosthetic graft

A

metal, plastic

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22
Q

What is a metal/plastic graft called?

A

Prosthetic graft

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23
Q

Allograft tissue examples

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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24
Q

What are the types of donors for allografts?

A

Deceased

Living

  • BM, Kidney, Liver
  • genetically related or unrelated (spouse; altruistic)

=> better survival with a living donor (kidney)

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25
Q

What are the 2 types of deceased donors?

A
  • DBD – donor after brain stem death

- DCD – donor after circulatory death

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26
Q

DBD

A
  • 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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27
Q

DCD

A
  • 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 -> BAD FOR THE ORGANS
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28
Q

What are the neurological criteria of death?

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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29
Q

What are exclusion criteria for donors?

A
  • viral infection (HIV, HBV, HCV)
  • malignancy
  • drug abuse, overdose or poison
  • disease of the transplanted organ
    - > USS potential donor
30
Q

What do you have to do once you remove the organs?

A
  • Removed organs rapidly cooled and perfused
    absolute maximum cold ischaemia time for kidney 60h (ideally <24h)
  • much shorter for other organs
31
Q

Transplant selection

A
  • listing (waiting list) at a transplant centre after multidisciplinary assessment
  • is the patient healthy/stable enough for a transplant? Is the patient eligible?

not the same as transplant allocation

32
Q

Transplant allocation

A
  • how organs are allocated as they become available
  • when the organ becomes available, how is it allocated to all the patients on the waiting list

not the same as transplant selection

33
Q

NHSBT

A

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
  • algorithms
34
Q

What were some strategies to increase the number of transplants?

A
  • use organs that may not have been used before (e.g. older people, DCDonors)
  • the use of elderly organs has increased, increasing the number of transplants that took place.
  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
35
Q

What is difficult about transplant allocation?

A

It has to be fair and efficient!

  • > National guidelines
  • > Evidence based computer algorithm
  • Equity – what is fair?
    • Time on waiting list
    • Super-urgent transplant - imminent death (liver, heart)
    • What else?
    • rare group/how difficult are they to match? How long will they have to wait for the next compatible donor?
  • Efficiency – what is the best use for the organ in terms of patients survival and graft survival?
36
Q

How many tiers are there for kidney transplant recipients?

A

5 tiers of patients (ABCDE) depending on

  • paediatric or adult
  • Highly sensitised or not
37
Q

What are the 7 elements that are used to decide who gets a kidney?

A
  • 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
  • Some people have to be given some extra points (e.g. if they have genes that are hard to match) because otherwise they will be waiting for an organ for way too long.
38
Q

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)
    3. also some others but rarely, the first two are the most important.
39
Q

ABO blood groups in transplantation

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
  • A and B antigens are also present on the endothelium
  • Can lead to organ rejection
  • As soon as blood starts going through the kidney becomes purple and does not function
40
Q

ABO incompatible transplantation

A
  • Remove the antibodies in the recipient (plasma exchange)
  • Good outcomes (even if the antibody comes back)
  • Kidney, heart, liver
41
Q

HLA

A
  • human leukocyte antigens
  • 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” (i.e. the cells won’t eat the sandwich by itself, it has to be presented on a plate)
  • 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)

Donor cells shed HLA molecules -> Uptake and presentation in recipient APC -> Recognised by T-cells

42
Q

What chromosome are HLA genes found on?

A

6

43
Q

Are HLA genes highly polymorphic?

A

YES!!

44
Q

Class I vs Class II MHC/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

Both have peptide binding groove

45
Q

HLA matching in transplantation

A
  • you look at the alleles that both recipient and donor have (2 alleles for each, one from mom, one from dad)
  • Look at HLA-A, HLA-B, HLA-DR (e.g. MM 1:2:0 = 3/6 mm) -> because those are the polymorphic ones
  • Number of mismatches : 0 to 6
  • Minimising HLA differences between donor and recipient improves transplant outcome!!
  • The better the match, the better the outcome
46
Q

Parent to child HLA matching

A

≥3/6 matched

47
Q

Sibling HLA matching

A

25% - 6MM
50% - 3MM
25% - 0MM

48
Q

HLA antigens in 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
49
Q

Rejection

A
  • Most common cause of graft failure
  • Diagnosis = histological examination of a graft biopsy
  • Treatment = immunosuppressive drugs
50
Q

How can rejection be classified?

A
  • T-cell mediated vs. AB mediated vs. mixed

- hyper-acute vs. acute vs chronic (when it occurs after transplantation)

51
Q

What happens in T-cell mediated rejection?

A
  • donated cell shed HLA antigens
  • APCs carry the donor antigens to local lymph nodes
  • T-cells (CD4+) are activated
  • recirculation, get to the site of the foreign HLA molecules, attach and infiltrate organs
  • start attacking the tissues (e.g. tubular epithelium in kidney)
  • T-cells also recruit other cells (CD8+ cytotoxic cells, macrophages) -> AMPLIFICATION OF INJURY
  • Inflammation and tissue damage -> rejection

-> damage to e.g. tubules (in AB mediated the damage tends to be intravascular)

52
Q

Antibody mediated Rejection

A
  • Antibody against graft HLA and AB antigen
  • Antibodies arise
    • Pre-transplantation (“sensitised”)
    • Post-transplantation (“de novo”)
53
Q

What cells would you see in T-cell mediated rejection if you typed the biopsy?

A
  • CD8+ T-cells
  • CD4+ T-cells
  • macrophages
54
Q

What patients might be sensitised?

A
  • sensitised refers to already having antibodies against foreign HLA
  • patients that had a previous transplant, patients that had many blood transfusions, women that were pregnant -> difficult to transplant because of an immediate and vigorous rejection
55
Q

How does AB mediated rejection work?

A
  • antibodies bind to the foreign (HLA or ABO) molecules
  • complement activation (via C1q -> classic complement pathway) and recruitment of inflammatory cells (which have an Fc-Receptor)
  • endothelial necrosis and coagulation
  • membrane attack, complement activation

-> intravascular damage

56
Q

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)
57
Q

Prevention of rejection

A
  • maximise HLA compatibility
  • Life-long immunosuppressive drugs

But unfortunately transplants don’t last forever, this is mainly due to immunological reactions.

58
Q

Treatment of rejection

A
  • more drugs

- e.g. steroids, azathioprine, mABs, calcineurin inhibitors

59
Q

Immunosuppressive drugs

A
  • Targeting T cell activation and proliferation
  • Targeting B cell activation and proliferation, and antibody production
  • azathioprine targets the cell cycle
  • drugs that target cd52 and deplete t-cells (mAB)
60
Q

B-cells/ ABs causing rejection - treatment

A
  • you have to remove the ABs or B-cells making them
  • Anti CD-20 (Rituximab) to deplete B-cells
  • proteasome inhibitors (bortezomib) to deplete plasma cells
  • anti-C5 to target complement activation
  • plasma exchange and IVIg dampen the AB production
61
Q

What do you have to balance with immunosuppressive therapy?

A

Rejection vs cancer+infections+drug toxicity

62
Q

Post traansplant infections

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)
63
Q

Post transplant malignancy

A
  • Skin cancer
  • Post transplant lymphoproliferative disorder – Epstein Barr virus driven
  • Kaposi’s sarcoma?
  • others
64
Q

Cellular rejection in Kidney transplant - key characteristics

A
  • inflammation in interstituum
  • ruptured tubular basement membrane
  • tubulitis (immune cells infiltrating the tubular epithelium)

Cd4+ cells also recruit cytotoxic T cells as well as macrophages.

65
Q

CD3 and CD68 stains

A

CD3: T-cell antigen (there would be a mixture of 4 and 8)
CD68: macrophages

66
Q

C4d biomarker

A
  • complement marker

- look for presence of complement in tissues

67
Q

T-cell activation

A
  • anti-t-cell activation drug
  • targeting the APC and T-cell communication
  • e.g. target co-stimulation
  • e.g. target signal 3
68
Q

How do you target AB transplant rejection?

A
  • target the antibodies
  • target the cells producing the antibodies (anti-CD20 e.g. rituximab; bortezomib is a protease inhibitor that depletes plasma cells)
  • plasma excange or IVIG will dampen the AB production
  • drugs targeting complement activation

=> give drugs based on the pathophysiology of rejection.

69
Q

Standard immunosuppressive regimen

A

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

From time of implantation - Base-line immunosuppression from the moment the transplant goes in.
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

70
Q

Orthotopic and heterotypic transplant

A

Ortho: in which the previous liver is removed and the transplant is placed at that location in the body

Hetero: e.g. the kidney is usually placed in a location different from the original kidney because the non-functioning kidneys are generally not removed.

Year 2 - MCD - Immunology (5 decks)

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