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Health 31 > Transplantation > Flashcards

Transplantation Flashcards

1
Q

L1 Transplatation & Tolerance
LO
immunology behind transplant rejection
different types of rejection
difficulty with preventing rejection
the promise of transplant tolerance

A
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2
Q

what is the most transplanted organ globally?

A

kidney

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3
Q

What are the 3 different types of transplant?

A
  • autograft
  • isograft
  • allograft
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4
Q

What is an autograft /autologous transplant?

A

patient’s own tissue
skin graft eg major burns, wounds

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5
Q

What is an isograft transplant?

A

donor and recipient are identical twins
(rarer)

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6
Q

What is an allograft transplant?

A

genetically non-identical recipient of same species
(most common type)

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7
Q

Which antigens in man are the most polymorphic in biology?

A

MHC (HLA in man)

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8
Q

What is the main molecular target of rejection?

A

HLA which determines the major histocompatibility complex

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9
Q

How many genetic combinations are possible with the HLA gene?
pic p544

A
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10
Q

What does HLA incompatibility initiate and drive?

A

rejection

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11
Q

allografts can be subject to immune mediated rejection. what does the immune system see on those allografts?

A

differences on MHC

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12
Q

MHC is fundamental to the activation of what cells?

A

t cells

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13
Q

minor antigens (MiHC) can also stimulate rejection, give an example of this?

A

HY male antigen stimulates a response in female recipients seen if you use boy girl twins

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14
Q

how many combinations of MHC class II are there?

A

> 2 billion

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15
Q

what cells are most important for rejection?

A

T cells

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16
Q

naive T cells primed by what 2 types of DC (dendritic cells)?

A

donor
recipient

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17
Q

do cells or antibodies reject transplants?

A

cells

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18
Q

what effect does depletion of t cells have on allograft rejection?

A

rejection would not occur

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19
Q

name 3 innate immune cells that would be involved in the rejection process that are found in the blood?

A

NK, macrophage and neutrophils

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20
Q

outline the chain of events that lead to acute rejection?

A
  • ischaemia/ reperfusion injury
  • innate immune attack of transplants
  • dendritic cell trafficking for initiating adaptive immunity
  • t cell response to transplant via pathways of recognition
  • t cell subsets and mechanisms -> graft rejection
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21
Q

what is meant by ischaemia?

A

blood supply to new organ lost

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22
Q

ischaemia/ reperfusion injury results in hypoxia, when this is detected by oxygen sensing receptors on stromal cells what is produced as a result?

A

free radicals

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23
Q

name 2 pro inflammatory cytokines that are release when necrosis occurs?
(ischaemia/ reperfusion injury + surgical trauma)

A

TNFa and IL1 (/6)

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24
Q

give 3 things that are upregulated to drive the rejection process. inflammatory cytokines?

A

MHC, chemokine and cytokine expression
(due to TNFa and IL1)

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25
Q

in ischaemia and reperfusion injury endothelial cells become activated and are the first point of contact between donor organ and recipient blood. What happens to these cells when they are activated?

A

increased permeability (vasodilate, easier for cells to pass barrier -> tissue)

upregulation of adhesion molecules = more sticky

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26
Q

MHC, chemokine, cytokine expression upregulated and endothelial cells activated leading to..?

A

graft ‘flagged’ as an inflammatory target

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27
Q

although we add buffer and put the transplants in ice, they are not…

A

quiescent.
still have reactive bits of tissue

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28
Q

what happens during ischaemia/reperfusion injury that leads to an innate response?

A

formation of ROS, MHC upregulation, TNF and IL upregulation.

increased permeability.

flagging

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29
Q

What is reperfusion injury?

A

tissue damage caused when blood supply returns to the tissue after a period of ischemia or lack of oxygen

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30
Q

how do the innate cells contibute to rejection

A

although they dont cause rejection themselves they exacerbate inflammation by production of cytokines and chemokines which recruit DC/Tcells.

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31
Q

what are the properties of an immature DC?

A

sample environment. low MHC, cytokines, costimulatory molecules, inflammatory chemokine receptors, poor t cell stimulators

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32
Q

what are the properties of a mature DC?

A

opposite to immature and express lymphoid chemokine receptors

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33
Q

what stimulates dc maturation? 3

A

TLR,
inflamm cytokines,
costimulatory molecules (CD40)

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34
Q

where are TLR

A

immune cells, endothelial and stromal cells

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35
Q

how do neutrophils cause graft damage

A

ROS, proteolytic enzymes

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36
Q

how do NK cause graft damage

A

perforin granzyme, FAS-FAS-L

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37
Q

how do macrophages cause graft damage

A

ROS, proteolytic enzymes

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38
Q

role of chemoattractants: CXCL9 and 10?

A

recruiting T-cells and NK cells to sites of infection/ inflammation and enhancing their cytotoxic activity against infected or abnormal cells.

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39
Q

role of chemoattractant: CCL3-5?

A

recruitment of monocytes, macrophages, and T-cells to sites of inflammation or injury.

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40
Q

what cell secretes tnfa, IL-1b, IL-12. IL-18? ()

A

macrophages produce TNF-alpha and IL-18,
DC produce IL-12, and
macrophages and dendritic cells produce IL-1beta.

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41
Q

once transplant done with donor tissue, then may get activation of innate immune cells due to what?

A

inflammation

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42
Q

what do activated T cells, and D cells facilitate further? after innate response?

A

further immune cell recruitment

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43
Q

DC have 2 origins, name them

A

donor tissue
in recipient

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44
Q

mature or immature DC :

highly pinocytic, low levels of MHC, costimulatory molecules, cytokine secretion, poor stimulators of t cell response

A

immature

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45
Q

dendritic cell trafficking occurs for initiating the adaptive immune system. what 2 states do they exist in?

A

mature and immature

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46
Q

to get immature DC to sites of inflammation they express inflammtory chemokine receptors, once they sample the environement they get exposed to the stimulation. Give 3 thingsthat can facilitate this?

A

TLR, costimulatory molecules and inflammatory cytokines

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47
Q

once immature DC cells mature what characterstics do they have?

A

poorly pinocytic, high levels of MHC, costimulatory molecules and cytokine secretion, express lymphoid chemokine receptors

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48
Q

are mature or immature DCs potent stimulators of the t cell response?

A

mature

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49
Q

full process of DC trafficking for adaptive immunity

A
  1. innate response
  2. DAMPs
  3. donor cells mature w/ alloantigen
  4. migrate to lymphoid
  5. stimulation of immune cells

6.immature cells back into graft

  1. they acquire alloantigen
  2. they go back to the resident lymphoid tissue
50
Q

where do mature DC cells migrate to, to stimulate an immune response?

A

recipient lymphoid tissue

51
Q

recipient DC cells traffick into the donor graft and require antigens, mostly MHC, and are subjected to inflammation and DAMPS. what happens to them as a result of this?

A

mature, upregulate lymphoid receptors and exit the graft and make their way to recipient lymphoid tissue

52
Q

what are the 3 different pathways that t cells can become activated to alloantigens?

A

direct, indirect and semi direct

53
Q

what is the direct pathway of alloantigen recognition

(predominant pathway of stimulating T cells)

A

donor MHC presented by donor DC recognised by T cell

54
Q

what is the indirect pathway of alloantigen recognition

A

donor MHC acquired by recipient APC/ DC

55
Q

what is the semidirect pathway of alloantigen recognition

A

recipient APC presenting intact donor MHC plus donor peptide

56
Q

which t cell alloantigen recognition pathway recognises:
intact donor MHC + peptide complexes presented by donor APC?

A

direct

57
Q

which t cell alloantigen recognition pathway involves a recipient APC presenting donor MHC?

A

indirect

58
Q

what does precursor frequency (or T cells) tell you?

A

% of T cells able to recognise alloantigen in these diff pathwyas and be stimulated by recognition of MHC

59
Q

how does the semi direct pathway happen - 4 steps?

A
  1. donor graft releases exosomes
  2. these are picked up by recipient DC
  3. binds to cell surface
  4. presentation of intact MHC complex
60
Q

acute rejection in transplantation is predominantly mediated by Th1?

A

true

61
Q

what is meant by cross dressed DC in terms of semi direct pathway of T cell alloantigen recognition?

A

exosomes released from donor graft containing intact donor MHC I and II peptides which are presented by the recipient lymphoid tissue

62
Q

in transplantation what do Th1 cells predominantly mediate?

A

cytotoxicity (IL-2 too)

delayed type hypersensitivity (IRN-y too)

63
Q

what role do TH2 cells play in transplant rejection?

A

humoral antibodies and eosinophils

64
Q

what role do th17 cells play in transplant rejection?

A

enhance neutrophil response

65
Q

is the overriding immune response mediated by th1, th2, th17 or treg cells?

A

th1

66
Q

what cell are
th1, th2, th17 or treg cells derived from?

A

naive CD4 T cell

67
Q

what must be given to prevent chronic rejection

A

immunosuppressants
in 7-14 days

68
Q

chronic rejection happens within first year of transplant.
diffuse concentric intimal thickening of vessels leads to what?

A

rgadual dec in graft function

69
Q

when does chronic rejection occur?

A

months- years after transplant

70
Q

why does lumen of blood vessel get smaller in chronic rejection?

A

intimal hyperplasia
-> smooth muscle cells migrate due to inflammation from adventitia into lumen… gets smaller

… then organ starved of O2 blood

71
Q

what increases chronic rejection? 3
(contribution of alloantigen to chronic rejection)

A

acute rejection,
inadequate immunosuppression,
HLA mismatch

72
Q

do lesions associated with chronic rejection contain immune cells or not?

A

yes

73
Q

antibodies to HLA and complement deposition on endothelium may be present in chronic rejection T/F?

A

true

74
Q

what nonimmunogenic factors contribute to chronic rejection?

A

older donor, hypertension, chronic effects of cyclosporin/tacrolimus, ischaemic injury

75
Q

what is hyperacute rejection?

A

rejection in mins to hours due to a preformed antibody which recognises HLA of donor

76
Q

what are the 3 types of rejection?

A

acute: 7-14 days, typ in first yr

chronic: gradual, over 1 year

hyper acute: minutes-hours

77
Q

hyperacute rejection is not mediated by T cells, but instead: antibody, why?

A

T cells: take time

78
Q

process of hyperacute rejection
(thrombolytic cascade)

A
  1. antibody
  2. complement activation

neutrophil accumulation and activation

  1. endothelial cell damage
  2. platelet adhesion and fibrin
  3. thrombosis
  4. no blood flow
  5. necrosis
79
Q

primary target of hyperacute rejection?

A

HLA expressed on endothelial cells

80
Q

what are some causes of hyperacute rejection

A

due to pre-formed abs

req prior sensitisation due to:
- previous blood transfusion/transplant/pregnancy
(increased antibodies)

81
Q

if someone has blood type A, which antibodies will they have?
which antigen?

A

anti-b

A antigen (the one on surface)

82
Q

if someone has blood type B, which antibodies will they have?
which antigen?

A

anti-A

B antigen (on surface)

83
Q

if someone has blood type AB, which antibodies will they have and what blood can they accept?

A

none, universal acceptors: A and B antigens

84
Q

if someone has blood type O, which antibodies do they have and to what blood groups can they donate?

A

anti a and b,
no antigens - universal donors

85
Q

when to screen blood group in process of transplant, to stop hyperacute rejection?

A

Before

86
Q

why is blood type important in transplantation?

A

AB sugars are present on the endothelium

87
Q

how can you identify if someone might have a hyperacute rejection?

A

assays to determine whether recipient has particular antibodies

88
Q

what is the cytotoxic assay (cytotoxic cross-match)?

A

lytic anti-donor abs detected by culturing recipient serum with donor cells.

89
Q

how can you prevent hyperacute rejection?

A

remove abs:
- plasmapheresis,
- B cell removal by rituximab,
- splenectomy
- IVIg

90
Q

ADAs can be detected by what?2

A

luminex or flow cytometry

90
Q

ADAs can be detected by what?2

A

luminex or flow cytometry

91
Q

T/F:
current immunosuppression is not specific for transplanted organ?

A

true

92
Q

why doesnt B cell removal by rituximab deplete plasma cells?

A

only stops new ones being formed because plasma cells do not have CD20

93
Q

what is a xenogenic transplant

A

from a different species

94
Q

why are current immunosuppressive agents not specific for transplanted organ?

A

dont distinguish between protective responses against pathogens and destructive responses against grafts

95
Q

alloreactive T cells are simply a subset of what cell pool?

A

normal T cells

96
Q

current immunosuppression not specific thus leads to immune complications such as… 2

A

increased risk of
- infection
- malignancy

97
Q

What are the 3 non-immune complications of immunosuppression?

A

nephrotoxic
HTN
hyperlipidaemia

98
Q

immunosuppressives: expensive and unpleasant.
taken for how long in these px?

A

for life

99
Q

What is the problem with current immunosuppression?

A

It is not specific for the transplanted organ

100
Q

What are alloreactive T cells?

A

T cells that react against non-self MHC molecules

101
Q

What is transplant tolerance?

A

Targeting only T cells that react against the transplanted organ, allowing for allograft acceptance without continuous immunosuppression

102
Q

What is the pathway to tolerance in adults?

A

Regulatory T cells suppress effector T cells, leading to tolerance induction

103
Q

are there more or less of: regulatory, and effector moleculaes in rejection?

A

less effector
more regulatory

104
Q

how does proportion of effector and regulatory cells change in tolerance?

A

less effector T cells

more regulatory T cells

105
Q

What are the two signals required for T cell activation?

A

Signal 1: MHC-peptide binding
(int of TCR w MHC + peptide)
Signal 2: costimulation

106
Q

What happens when T cells receive only Signal 1?

A

No response or rejection

107
Q

What happens when T cells receive both Signal 1 and Signal 2?

A

Optimal activation or rejection

108
Q

What happens when T cells receive neither Signal 1 nor Signal 2?

A

No response or rejection

109
Q

What happens when T cells receive Signal 1 but not Signal 2?

A

Incorrect activation leading to tolerance

110
Q

What is the result of blocking costimulation?

A

Tolerance, as demonstrated in a skin graft experiment

111
Q

alloantigen-reactive Treg needed to facilitate tolerance T/F?

A

true

112
Q

transplantation= successful therapy for end stage organ failure due to what

A

immunosuppressive drugs

113
Q

what is a xenogenic transplant

A

from a different species eg pig

114
Q

what initiates and drives rejection?

A

HLA incompatibility

also minor antigens (MiHC) eg H-Y male antigen stim response in female recipients

115
Q

what specifically rejects transplant?

A

cells not antibodies

116
Q

What are the physiological ligands for TLRs in transplantation?

A

Damage associated molecular patterns (DAMPs).

117
Q

what are the pre formed antibodies to pig directed against?

A

Galactose α1-3 galactose (α Gal) epitopes

118
Q

What is the purpose of generating α Gal knockout pigs?

A

To prevent xenogeneic responses

119
Q

What is the purpose of generating transgenic pigs that express molecules that inhibit the formation of the MAC complex and/or coagulation?

A

To prevent xenogeneic responses

120
Q

What are the 3 potential outcomes of T cell activation?

A

Inactivation (anergy),
activation induced cell death,
conversion to Treg

121
Q

What are the current issues with immunosuppressive drugs?

A

Serious side effects causing significant mortality and morbidity

Health 31 (16 decks)

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