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Y3 immunology and haematology > transplantation > Flashcards

transplantation Flashcards

1
Q

what is the main problem with transplantation

A

rejection

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2
Q

define rejection

A

damage done by the immune system to a transplanted organ

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3
Q

define autologous transplant

A

tissue returning to the same individual after a period outside the body, usually in a frozen state

can be for reconstructive purposes or stem cell transplant for haematological disease

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4
Q

what is syngenic transplant

A

transplant between identical twins

usually no problem w/ graft rejection

aka isograft

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5
Q

what is allogenic transplant

A

takes place between genetically non-identical members of the same species

there is always a risk of rejection

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6
Q

what is cadaveric transplantation

A

uses organs from a dead donor

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7
Q

what is xenogenic transplantation

A

takes place between different species

carries the highest risk of rejection

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8
Q

what is xenogenic transplantation

A

takes place between different species

carries the highest risk of rejection

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9
Q

what criteria must be met before solid organ transplantation

A

good evidence that the damage is irreversible

alternative treatments aren’t applicable

disease must not recur

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10
Q

how to minimise the chances of rejection in solid organ transplantation

A

donor and recipient must be ABO compatible

recipient must not have anti-donor human leukocyte antigen (HLA) antibodies

donor should be selected w/ as close as possible HLA match to the recipient

patient must take immunosuppressive treatment

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11
Q

cornea transplant

  • characteristics
  • type of donor
  • graft survival (%)
A

immunosuppression isn’t required as the cornea doesn’t become vascularised

cadaveric

> 90%

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12
Q

liver transplant

  • characteristics
  • type of donor
  • graft survival (%)
A

used for alcoholic liver disease, 1y biliary cirrhosis, viral induced cirrhosis

outcome isn’t affected by degree of HLA matching

live/cadaveric

> 60%

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13
Q

kidney transplant

  • characteristics
  • type of donor
  • graft survival (%)
A

live-related donor kidneys are often used

graft survival is optimised by HLA match

immunosuppression is required

live/cadaveric

> 80%

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14
Q

pancreas transplant

  • characteristics
  • type of donor
  • graft survival (%)
A

usually transplanted w/ kidneys in diabetic pts w/ renal failure

separated islet cells have also been infused into the vena cava

cadaveric

~50%

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15
Q

heart transplant

  • characteristics
  • type of donor
  • graft survival (%)
A

used for coronary artery disease, cardiomyopathy and some congenital heart disease

HLA matching isn’t always possible

potent immunosuppression required

cadaveric

> 80%

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16
Q

stem cell transplant

  • characteristics
  • type of donor
  • graft survival (%)
A

used in malignancy, haematologic conditions and some 1y immunodeficiency

best results achieved when there is a match of HLA-A, -B, -C and -DR

live

≤80%

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17
Q

why do stem cell transplants carry a high risk of rejection

A

recipient acting against the donor cells but also the donor cells reacting against the recipient

  • GVHD
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18
Q

what is hyperacute rejection

  • how quickly does it happen
  • how does it happen
  • how to prevent
A

within hrs of transplantation

  • preformed antibodies binding to either ABO blood group or HLA class I antigens on the graft
  • antibody binding triggers type II hypersensitivity reaction - graft is destroyed by vascular thrombosis
  • can be prevented through careful ABO and HLA cross-matching and is now rare
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19
Q

acute rejection

  • how long does it take
  • how does it happen
A

few days-wks

APC from the donor/APC from recipient present antigens from the donor to the T cells in recipient LNs

T cells migrate towards donor graft and attack it

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20
Q

what type of hypersensitivity reaction is acute rejection

A

type IV - cell mediated

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21
Q

what is the main cause of acute rejection

A

HLA incompatibility

minimising any HLA mismatch of the donor and recipient can reduce acute rejection

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22
Q

kidneys and acute rejection

A

shortage of donor kidneys leads to using a partially mismatched kidney

survival of the kidney is related to the degree of mismatching - esp at HLA-DR loci

could be antibody mediated rejection

23
Q

immunopathology of graft rejection

A

AFFERENT PHASE:
- donor MHC molecules on dendritic cells (passenger leucocytes) within the graft are recognised by the recipient’s CD4+ T cells - ALLORECOGNITION

EFFECTOR PHASE:

  • CD4+ T cells recruit effector cells responsible for the tissue damage of rejection
  • macrophages, CD8+ T cells, NK cells and B lymphocytes
  • not all parts of the graft need to be attacked for rejection to occur
24
Q

chronic rejection
- when does it happen

  • how does it occur
A

mths-yrs after transplant

element of allogeneic reaction is often mediated by T cells which can result in repeated acute rejection

chronic rejection may be cause by recurrence of pre-existing AI disease

25
Q

tolerance and transplantation

- response to transplanted tissue and pathogens

A

no response to alloantigens present on the transplanted tissue but responses to pathogens aren’t affected

26
Q

immunosuppressive drugs

  • rejection
  • tolerance
  • infection
A

prevent rejection if given at the time of transplantation; once drugs are stopped rejection still takes place

lack the specificity of true tolerance and thus prevent immune responses to infectious agents

opportunistic infections are a major limit to the use of potent immunosuppressive drugs

27
Q

2 types of tissue typing techniques

A

HLA typing - done at point of needing transplant and then placed on registry

  • donor is also HLA typed before organs are removed

HLA cross matching - B cells from donor blood (express HLA class I and II) are mixed w/ recipient serum to ensure donor hasn’t made any antibodies against donor antigens

28
Q

selection of donor and recipient in kidney transplantation

  • what are the criteria for:
  • recipient selection
  • kidney selection (living and cadaveric)
A

RECIPIENT SELECTION:

  • ABO compatible
  • -ve serum cross-match w/ donor’s T lymphocytes
  • HLA match (as near as possible, esp at D loci)

CADAVER DONOR:

  • good renal function
  • no infection
  • no malignancy/systemic disease
  • short warm ischaemia time

LIVING DONOR:

  • 2 functioning kidneys
  • no transmissible disease
  • no anomalous blood vessels
  • physiologically suitable
  • excellent health
29
Q

what is stem cell transplantation used for

A

haematopoietic stem cells are used to restore myeloid and lymphoid cells

30
Q

autologous SCT

A

marrow is removed, frozen and reinfused after potent chemotherapy has been given

autologous transplants carry minimal immunologic risk

31
Q

allogenic SCT

A

much riskier procedure than most solid organ transplants

even w/ well matched donors and in the best circumstances, mortality can be up to 20%

additional risks are due to GVHD

32
Q

when is allogenic SCT carried out

A

only carried out in:

  • haematological malignancy w/ no alt treatment options
  • cases when myeloid production is reduced or notably abnormal, such as in aplastic anaemia
  • 1y immunodeficiencies e.g. SCID
33
Q

sources of stem cells

A

bone marrow

peripheral blood

cord blood

34
Q

sources of stem cells - bone marrow

A

aspiration of a considerable amount of donor marrow under GA

35
Q

sources of stem cells - peripheral blood

A

harvested after treating the donor w/ colony stimulating factors to increase the number of circulating stem cells

36
Q

sources of stem cells - cord blood

A

contains a large number of stem cells, which can be frozen before use

immature lymphocytes are less likely to cause GVHD

small amount of cells - only enough for a child/small adult

37
Q

conditioning of recipient prior to SCT

A

high dose chemotherapy

high dose radiotherapy

destroy the recipient’s stem cells and allows the engraftment of donor cells - also removes existing immune cells and reduces potential of rejection

38
Q

what is GVHD

A

when donor T cells respond to allogeneic recipient antigens

mismatches in major and minor histocompatibility antigens

39
Q

how to prevent GVHD

A

all pts who receive SCT are given immunosuppressive drugs to prevent GVHD, even if the donor and recipient are HLA identical

40
Q

timescale for GVHD

  • mortality risk
  • organ involvement
A

acute GVHD - up to 4wks after SCT
up to 70% mortality risk when severe

involvement of skin, liver, gut and lungs is widespread

chronic GVHD occurs later and affected the skin and liver - milder disease but still dangerous

41
Q

immunosuppresive drugs - corticosteroids

A

low doses - predominantly act on APC preventing some of the early stages of graft rejection

higher doses - direct effects on T cells, used to treat episodes of rejection

42
Q

immunosuppressive drugs - T cell blockage

A

cyclosporine and tacrolimus

work by interacting w/ proteins in the intracellular T cell signalling cascade

43
Q

immunosuppressive drugs - IL-2 blockade

- 2 drugs

A

monoclonal antibodies against IL-2 receptor: basiliximab, daclizumab

rapamycin

44
Q

immunosuppressive drugs - IL-2 blockade - monoclonal antibodies against IL-2 receptor

A

basiliximab, daclizumab

completely block IL-2 and have potent immunosuppressive effects

only used to treat episodes of acute graft rejection - high risk of infection

45
Q

immunosuppressive drugs - IL-2 blockade - rapamycin

A

oral

interacts w/ signalling events downstream of IL-2 receptor

less potent and easier to take than monoclonal antibodies - used to prevent graft rejection

46
Q

immunosuppressive drugs - antiproliferatives

A

azathioprine, mycophenolate, motefil, methotrexate

all inhibit DNA production

prevent lymphocyte proliferation

not specific for T cells and can cause myelotoxicity (bone marrow suppression)

47
Q

side effects of cyclosporin

A
  1. viral, fungal and bacterial infection
  2. increased risk of certain cancers
  3. nephrotoxic
  4. diabtetes
  5. HT
  • largely due to its mode of action in inhibiting calcineurin
48
Q

side effects of rapamycin (8)

A
  1. raised lipid and cholesterol
  2. HT
  3. anaemia
  4. diabetes
  5. diarrhoea
  6. rash
  7. acne
  8. thrombocytopaenia
  9. decreased platelets and Hb
49
Q

why is xenotransplantation becoming more common

A

shortage of allografts

50
Q

problems with xenotransplantation

A

primates assemble different sugar side chains from other species

  • galactose-α1,3-galactose is present on the cells of most non-primate species
  • immune system recognises gal-α1,3-gal and all human possess antibodies against it (exposure to gut bacteria)
  • antibodies bind onto xenotransplanted organs, activate complement and trigger hyperacute rejection

complement inhibitors from other species don’t inhibit human complement - xenotransplanted organs activate complement

51
Q

steps to overcome incompatibility for xenotransplantation

A

transgenic pigs are being developed w/ reduced gal-α1,3-gal expression to prevent natural antibody binding and w/ human complement inhibitors to bypass molecular incompatibility

52
Q

why are pigs used for xenotransplantation

A

similar size to humans

easy to rear in captivity

53
Q

problems with pigs for xenotransplantation

A

acute rejection may occur - pig proteins elicit T-cell responses

even pigs reared in microbe free conditions are infected w/ endogenous retroviruses - more likely to infect recipients taking immunosuppressive drugs

Y3 immunology and haematology (20 decks)

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