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Immuno > Immuno 3: transplantation > Flashcards

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
Q

What is transplant selection and transplant allocation

A

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

Transplant allocation: how organs are allocated as they become available

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26
Q

What is transplant allocation based on

A

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?

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27
Q

How does transplant allocation get decided

A

National guidelines-evidence based computer algorithm

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28
Q

Key elements and tiers deciding organ allocation

A

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
Q

Other strategies to increase transplantation

A
  1. Deceased donation from marginal donors, DCD, elderly
  2. lviing donaion
    transplation acoss tissue compatibility barriers, exchange programmes
30
Q

Main reason for reduced lifespan of transplanted organs, whether living or dead

A

Due to immunological differences between host and donor

Also the warm iscahemia time in deceased donors

Infection

31
Q

What are the most relevant protein variations in clinical transplantation

A
  1. ABO blood group

2. HLA (human leukocyte antigens) coded on chromosome 6 by Major Histocompatibility complex (MHC)

32
Q

Where are the A and B proteins in ABO bloof groups licated

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

33
Q

What is present in A, B, O and AB

A

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
Q

Why is ABO problematic

A

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
Q

Why is ABO group no longer really a problem (ABO-incompatible transplantation)

A

Remove the antibodies in the recipient (plasma exchange)

Good outcomes (even if the antibody comes back)

Kidney, heart, liver

36
Q

What is HLA, why is variability important

A

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
Q

When can T cells ‘see’ antigen’

A

Only when an antigen is presented by HLA

38
Q

How are donor antigens presented to T cell

A

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
Q

Class 1 vs class 2 HLA

Including the letters

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

40
Q

Characterise HLA

A

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
Q

Structure of peptide groove in class 1 and class 2

A

All composed of a chain in class 1

Half alpha and half beta in class 2

42
Q

Which HLA chains are really polymorphonc

A

1-A, B, C and 2- DR

43
Q

How are mismatches quantified

A

HLA compared for HLA-A, HLA-B and HLA-DR.

Mismatches 0-6… you look in 3 sites but this is a complication

44
Q

Why is mismatching important

A

Because it determines the likelihood of organ surviving

45
Q

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

A

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
Q

What is the clinical correlate of the HLA similarity

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

47
Q

What is the most common cause of graft failure

A

Rejection

48
Q

How is rejection be diagnosed

A

histological examination of a graft biopsy

creatinine may increase in kidney transplant rejection, in liver, increased liver enzymes

49
Q

Outline the types of rjection (timescale)

A
  • hyperacute rejection
  • acute rejection
  • chronic rejection
50
Q

Outline the 2 immunological basis of rejection

A
  • T-cell mediated rejection

- antibody-mediated rejection

51
Q

When might you want to stop immunosuppressive drugs during a rejection

A

If an infection is damaging transplant (immunosuppresion might make infection worse!)

52
Q

Outline T cell mediated rejection

A

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
Q

What happens in initial T cell graft rejection

What else can these cells recruit

A

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
Q

What would be seen on PAS stain in T cell mediated rejection

A

Infiltration of small dark nuclei (immune cells) causing the tubulitis

55
Q

Outline when the antibodies can be made in the antibody mediated graft rejection and what molecules they are made against

A

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
Q

Outline the type of immune response taking place with antibody mediated rejection and where the antibodies bind

A

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
Q

…….

A

…..

58
Q

Differentiate the type of tissue damage seen in antibody and T cell mediated

A

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
Q

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

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

How to prevent rejection

A

maximise HLA compatibility

Life-long immunosuppressive drugs

61
Q

How is rejection treated

A

More immunosuppressive drugs

62
Q

What do immunosuppresive drugs targeted

A

Targeting T cell activation and proliferation

Targeting B cell activation and proliferation, and antibody production

63
Q

Outline drugs used during a T cell mediated rejection

A

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
Q

Outline drugs used during a B cell mediated response

A

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
Q

Standard immunosuppressive regime

A

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
Q

Balance rejection with what negative factors due to drugs

A

Infection
Tumour
Drug toxicity

67
Q

Whihc infections are you susceptible to post transplant

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)
68
Q

Common post transplantation malignancies

A

Skin cancer

Post transplant lymphoproliferative disorder – Epstein Barr virus driven

others

Immuno (5 decks)

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