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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
tolerance and transplantation | - response to transplanted tissue and pathogens
no response to alloantigens present on the transplanted tissue but responses to pathogens aren't affected
26
immunosuppressive drugs - rejection - tolerance - infection
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
2 types of tissue typing techniques
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
selection of donor and recipient in kidney transplantation - what are the criteria for: - recipient selection - kidney selection (living and cadaveric)
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
what is stem cell transplantation used for
haematopoietic stem cells are used to restore myeloid and lymphoid cells
30
autologous SCT
marrow is removed, frozen and reinfused after potent chemotherapy has been given autologous transplants carry minimal immunologic risk
31
allogenic SCT
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
when is allogenic SCT carried out
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
sources of stem cells
bone marrow peripheral blood cord blood
34
sources of stem cells - bone marrow
aspiration of a considerable amount of donor marrow under GA
35
sources of stem cells - peripheral blood
harvested after treating the donor w/ colony stimulating factors to increase the number of circulating stem cells
36
sources of stem cells - cord blood
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
conditioning of recipient prior to SCT
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
what is GVHD
when donor T cells respond to allogeneic recipient antigens mismatches in major and minor histocompatibility antigens
39
how to prevent GVHD
all pts who receive SCT are given immunosuppressive drugs to prevent GVHD, even if the donor and recipient are HLA identical
40
timescale for GVHD - mortality risk - organ involvement
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
immunosuppresive drugs - corticosteroids
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
immunosuppressive drugs - T cell blockage
cyclosporine and tacrolimus work by interacting w/ proteins in the intracellular T cell signalling cascade
43
immunosuppressive drugs - IL-2 blockade | - 2 drugs
monoclonal antibodies against IL-2 receptor: basiliximab, daclizumab rapamycin
44
immunosuppressive drugs - IL-2 blockade - monoclonal antibodies against IL-2 receptor
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
immunosuppressive drugs - IL-2 blockade - rapamycin
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
immunosuppressive drugs - antiproliferatives
azathioprine, mycophenolate, motefil, methotrexate all inhibit DNA production prevent lymphocyte proliferation not specific for T cells and can cause myelotoxicity (bone marrow suppression)
47
side effects of cyclosporin
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
side effects of rapamycin (8)
1. raised lipid and cholesterol 2. HT 3. anaemia 4. diabetes 4. diarrhoea 5. rash 6. acne 7. thrombocytopaenia 8. decreased platelets and Hb
49
why is xenotransplantation becoming more common
shortage of allografts
50
problems with xenotransplantation
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
steps to overcome incompatibility for xenotransplantation
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
why are pigs used for xenotransplantation
similar size to humans easy to rear in captivity
53
problems with pigs for xenotransplantation
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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