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I&I WC1 > Transplantation immunology > Flashcards

Transplantation immunology Flashcards

1
Q

What is autografting?

A

Transfer of living cells, tissues and organs from one part of the body to another

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2
Q

What is allografting?

A

Transfer of living cells, tissues and organs from one individual to another (SAME SPECIES)

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3
Q

What is xenografting?

A

Transfer of living cells, tissues and organs from one individual to another (DIFFERENT SPECIES)

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4
Q

Why is there a need for transplantation?

A
  • Damaged organs
  • Non-functional organs
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5
Q

How do organs become damaged?

A

Disease or injury

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6
Q

Which cells are the main players in transplantation?

A

APCs and T cells

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7
Q

What are allo-antigens?

A

All antigens that differ between individuals of the same species

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8
Q

Which division can be made in the allo-antigen category?

A
  • Histocompatibility Complex antigens
  • Blood group antigens
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9
Q

Which two kinds of antigens do you have in the ‘histocompatibility Complex antigens’ category?

A
  • MHC antigens/Human Leukocyte Antigen
  • Minor histocompatibility complex antigens
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10
Q

What kind of graft rejection reaction is caused by MHC antigens? What is the main cause of graft rejection?

A
  • Fast and strong
  • Differences in HLA
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11
Q

What kind of graft rejection reaction is caused by minor histocompatibility complex antigens?

A

Slow and weak

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12
Q

What is a calcineurin inhibitor?

A

Tacrolimus

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13
Q

What is the main immunosuppressive drug?

A

Tacrolimus

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14
Q

What is a pro of tacrolimus?

A

Low level of rejection

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15
Q

What are 5 problems with tacrolimus?

A
  • Narrow therapeutic window
  • Nephrotoxicity
  • Neurotoxicity
  • Incidence of diabetes
  • A specific (infections)
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16
Q

In what way is tacrolimus better than cyclosporin?

A

Better kidney function

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17
Q

What two types of rejection are there?

A

Cellular rejection and antibody-mediated rejection

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18
Q

What mismatched cells can be recognized by CD8 cells?

A

All nucleated cells

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19
Q

What mismatched cells can be recognized by CD4 cells?

A

Antigen presenting cells and activated CD4 cells

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20
Q

How are minor allo-antigens presented?

A

They are taken up and presented by recipient HLA molecules to recipient T cells, like all other peptides

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21
Q

What are minor-allo antigens?

A

All non-MHC proteins that differ in amino acid composition between toe donor and recipient outside of MHC due to mutations or genetic polymorphisms

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22
Q

Does presentation of red blood cell antigens require T cell help?

A

No, they immediately activate B cells

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23
Q

What types of antibodies do you have if you are blood group A?

A

Anti-B

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24
Q

What type of antibodies do you have if you are blood group B?

A

Anti-A

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25
Q

What type of antibody do you have if you are blood group AB?

A

None against blood groups

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26
Q

What type of antibody do you have if you are blood group O

A

Both Anti-A and Anti-B

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27
Q

What is the most important allo-antigen recognition pathway?

A

Direct allo-recognition, of intact foreign HLA molecules on donor APCs by recipient T cells

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28
Q

What is cross-reactivity in allo-recognition?

A

When T cell receptors can recognize peptides presented by intact foreign HLA molecules, causing an immune response

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29
Q

What is peptide-independent binding?

A

When the recipient TCR recognizes the donor MHC but not the peptide

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30
Q

What is peptide-dependent binding?

A

When the recipient TCR recognizes only the peptide but not the donor MHC presenting it

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31
Q

What is foreign peptide:self MHC binding?

A

When the recipient TCR recognizes a foreign peptide on the recipient (own) MHC

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32
Q

What is indirect allo-recognition?

A

When a donor peptide is taken up by a recipient APC and presented to the recipient TCR (through self-MHC)

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33
Q

What is the semi-direct recognition pathway?

A

When an APC of the recipient presents a donor peptide on a donor HLA to a recipient TCR

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34
Q

How can donor matching be tested in the lab?

A

Mixed lymphocyte reaction with T cell activation or cytokine production as read-outs

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35
Q

What are two signs of kidney transplant rejection?

A

A rise in creatinine and descreased urine production

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36
Q

What is done after creatininine and urine tests to prove kidney rejection?

A

Biopsy and histology

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37
Q

What are measurable signs of liver rejection?

A

Rise in serum aminotransferases (ASAT, ALAT), alkaline phosphatase, bilirubin

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38
Q

How is heart rejection tested?

A

Biopsy. There is no other biochemical way.

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39
Q

What is a 4th target for organ transplant rejection?

A

Injury

40
Q

What happens when there is a blood group mismatch?

A

Blockages of capillaries, hyperacute rejection within minutes or hours. Causes severe damage by antibodies of the recipient

41
Q

What is hyperacute rejection?

A

Blood group mismatch causes severe damage to the transplant, causing organ loss within minutes or hours

42
Q

What causes the severe damage to the transplant in hyperacute rejection?

A

Immediate lysis of donor cells due to ABO or donor HLA specific antibodies

43
Q

Can there already be pre-existing anti-donor HLA antibodies?

A

Yes, due to pregnancy, blood transfusions or earlier transplantations

44
Q

What are the 2 requirements for organ transplantation?

A
  • ABO system compatibility
  • Negative cross match (except for liver)
45
Q

How does tissue injury play a role in rejection?

A

Reactive oxygen species, cellular damage, imflammatory cytokines, immune cell attraction and attachment of immune cells to inflamed endothelium

46
Q

Why can’t cardiac death donors donate?

A

Stopped circulation leads to lack of oxygen supply to the organ

47
Q

Why can’t brain dead donors donate?

A

Cytokine storm

48
Q

How can tissue injury be minimized?

A

Machine preservation

49
Q

What is the type of rejection based on?

A

The type of immune cells involved and how quickly rejection occurs

50
Q

What type of rejection can take weeks or years?

A

Humoral rejection: B cell-mediated (antibody-mediated) rejection

51
Q

How can humoral rejection be detected?

A

C4d staining in capillaries

52
Q

What is CMV seropositivity a risk factor for?

A

Antibody-mediated rejection

53
Q

How can you treat acute cellular rejection?

A

High doses of methylprednisolone, otherwise T cell depletion

54
Q

How can you treat acute antibody-mediated rejection?

A

Plasmapheresis (antibody depletion), IVIg, otherwise Rituximab (anti-CD20) therapy

55
Q

What is rituximab?

A

Anti-CD20 therapy, so B cell depletion

56
Q

What are signs of chronic kidney rejection?

A

Increase of serum creatinine, proteinuria, hypertension

57
Q

What are two reasons chronic organ rejection happens?

A
  • Low levels of immune attack against the organ
  • Chronic calcineurin inhibitor (Tacrolimus) nephrotoxicity
58
Q

What is needed for improved immunosuppressive therapy?

A

Something as effective or more effective as Chronic calcineurin inhibitors (i.e. Tacrolimus), but less nephrotoxic

59
Q

What Class I HLAs are mostly looked at in transplants?

A

A and B

60
Q

What Class II HLAs are mostly looked at in transplants?

A

DR

61
Q

Why is strict stem cell matching important?

A

Because there is a huge risk of rejection but also that the new immune system also attacks the recipient body

62
Q

What are two clinical consequences of mismatching in solid organ transplant?

A
  • Host versus graft (HvG) -> rejection
  • Graft versus host (GvH) -> GvHD
63
Q

In what setting can you get host versus graft and thus rejection?

A

Usually HLA mismatching in solid organ transplants

64
Q

In what setting can you get graft-versus-host and this graft versus host disease?

A

In hematopoetic stem cell transplation when the stem cells differentiate into immune cells that attack the recipient immune system due to HLA mismatching

65
Q

What can cause sensitization before transplantation?

A

Pregnancy, previous transplants and blood transfusion

66
Q

What is sensitization in transplantation?

A

Formation of anti-HLA antibodies such as against paternal HLA molecules during pregnancy, making it more difficult to find a suitable donor

67
Q

What happens when anti-HLA antibodies encounter a mismatched organ?

A

Hyperacute rejection

68
Q

What has reduced the incidence of hyperacute rejection?

A

Serological crossmatching

69
Q

What causes de novo antibody formation after transplantation?

A

Humoral alloimmune responses

70
Q

What can de novo antibody formation after transplantation lead to?

A

Acute humoral rejection and chronic transplant dysfunction

71
Q

What are 5 reasons to do a renal biopsy?

A
  • Provides a diagnosis (toxicity, rejection, viral, donor disease)
  • Guides treatment (changes in more than half of the cases)
  • Predicts prognoses
  • Reveals pathogenesis
  • Validates outcome (as endpoint result in clinical trials)
72
Q

What are 6 pitfalls in nephropathology?

A
  • Morphology not specific
  • Sample size
  • Sample location might not show primary lesion
  • Chronic changes can obscure origin or pathology
  • Differences in pathologist experience
    Sampling error (might miss lesion)
73
Q

Name 4 examples of clinical information that is important to know when looking at nephropathology?

A
  • Anti-donor HLA antibodies
  • Original disease
  • Drug therapy
  • Time post transplant
74
Q

What is the Banff classification?

A

Standardized grading system to grade severity and type of rejection

75
Q

What is needed for an accurate classification according to Banff?

A

A minimum of 7 glomeruli and 2 arteries, but depends on the disease

76
Q

What are the two main types of rejection in the Banff classification?

A

Antibody-mediated rejection and T-cell mediated rejection

77
Q

What are the three levels of TCMR (histologically)

A

-bTCMR (borderline)
-I Tubulo-interstitial
-II Vascular rejection

78
Q

What can be found in AMR? (cells)

A

Antibodies, monocytes, neutrophils, and NK cells

79
Q

What is needed for an AMR diagnosis?

A

Microvascular inflammation +
C4d+ and donor-specific antibodies (DSA+)

80
Q

What morphological change is found in AMR?

A

Microvascular inflammation

81
Q

What is BK nephrology?

A

Nephropathology caused by a polyomavirus, characterized histologically by enlarged nuclei (caused by viral replication in the nucleus)

81
Q

What is being done to improve diagnosis of transplant rejection?

A

microRNA profiling

82
Q

What 3 types of immunosuppression are there?

A

Induction therapy, maintenance therapy and anti-rejection therapy

83
Q

When is induction therapy given?

A

Shortly before and after the transplant surgery to fully knock out the immune system

84
Q

What type of induction therapy is given in a standard kidney transplantation?

A

Signal 3-blocking antibody (cytokines)

85
Q

What is blocked by the induction therapy used in The Netherlands?

A

Anti-CD25, which blocks the IL-2 receptor

86
Q

Why not use signal 1 antibodies?

A

A lot of side effects due to complete T cell depletion (infection susceptibility)

87
Q

What are 3 standard maintanence drugs given?

A

Tacrolimus (chronic calcineurin inhibitor), mycophenolate mofotil (MPA/MMF) and prednisolon

88
Q

What does Tacrolimus do?

A

Blocks downstream of signal 1

89
Q

How does prednisolon work?

A

It works anti-inflammatory and immuniosuppressive by inhibiting mRNA expression when interacting with corticosteroid receptor, mimicing cortisol. It inhibits T cell growth and differentiation.

90
Q

What is the standard immunosuppressive regimen in kidney transplantation in The Netherlands?

A
  • High dose immunosuppression: Induction with Anti-CD25 (basiliximab), Prednisolon, Tacrolimus and MMF
  • Taper down prednisolon for 3 months, also tacrolimus and MMF

-Tacrolimus and MMF only, no more prednisolon

91
Q

What are 3 additional immunosuppressive therapies in case of rejection?

A
  • Methylprednisolon (always, high dose intravenously)
  • Alemtuzumab (T and B depletion)
  • IVIg (little evidence that it works)
92
Q

What are 3 major adverse effects of immunosuppressive drugs?

A

Infections, malignancies and cardiovascular disease

93
Q

Which immunosuppressive drug needs to be monitored closely and why?

A

Tacrolimus due to the small therapeutic window and interactions with other drugs

94
Q

How can drugs be monitored?

A

Measuring trough levels

95
Q

Which drug affects antiviral immunity the most?

A

Prednisolon

96
Q
A

I&I WC1 (25 decks)

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