Transplantation and Immunosuppressive Drugs Flashcards

(56 cards)

1
Q

What is the definition of transplantation?

A

➝ The introduction of biological material (organs, tissues, cells) into an organism

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2
Q

What is an autologous transplant?

A

➝ transplantation of tissue from one part of the organism to another part of the same organism

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3
Q

What is an example of an autologous transplant?

A

➝ Skin graft

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4
Q

What is a syngeneic transplant?

A

➝ donor material transplanted into the recipient when the donor and recipient are genetically identical

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5
Q

What is an allogenic transplant?

A

➝ Donors and recipients are from the same species but genetically different

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6
Q

What is a xenogenic transplant?

A

➝ donor and recipient are different species

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7
Q

What are immune responses to transplant caused by?

A

➝ genetic differences between the donor and recipient

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8
Q

What are human MHC proteins called?

A

➝ human leukocyte antigen

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9
Q

On what chromosome is HLA found?

A

➝ chromosome 6

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10
Q

How many MHC Class I alleles are there?

A

➝ 3

➝ A, B, C

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11
Q

How many MHC Class II alleles are there and what structures do they form?

A

➝ 3

➝ heterodimers of two proteins

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12
Q

Which cells in the body express both MHC class I and II?

A

➝ White blood cells

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13
Q

What are the MHC Class II alleles?

A
➝ DRA
➝ DRB
➝ DPA
➝ DPB
➝ DQA
➝ DQB
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14
Q

What is needed to define epitopes on HLA?

A

➝ next generation sequencing

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15
Q

What do T cells recognise?

A

➝ short peptide fragments that are presented to them by MHC proteins

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16
Q

What can professional APCs do with external proteins?

A

➝ internalise them and cross present them on the MHC class I pathway

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17
Q

What does MHC class II bind?

A

➝ Fragments of proteins which have been taken up by endocytosis

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18
Q

What does MHC Class I bind?

A

➝ Fragments of intracellular proteins

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19
Q

What is the function of CLIP?

A

➝ Maintains the shape of the HLA until the peptides are ready to bind

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20
Q

Describe indirect allo-recognition?

A

➝ The recipient cell has self HLA on its cell if the cell expresses the self peptide as normal cells do there is no immune response
➝ the TCR will be quiescent
➝ When self HLA presents a peptide (eg influenza peptide) an immune response will occur against the influenza
➝ if the recipient has a transplantation and the self HLA can present a peptide from the donor HLA molecule there is indirect allo-recognition

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21
Q

What is indirect allo-recognition?

A

➝ TCR of recipient detecting non-self peptide on self HLA

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22
Q

Describe direct allo-recognition?

A

➝ A recipient has transplanted tissue which contain donor immune cells
➝ If they have been perfectly matched the donor HLA is the same as the recipient HLA and there is no reaction
➝ when there is an unmatched donor there is direct allo-recognition
➝ the TCR from the recipients T cells will detect the MHC
➝ even if the peptide isn’t recognised as foreign (because it is from a conserved region) the unmatched HLA activates the T cells

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23
Q

What is direct allo-recognition?

A

➝ TCR of the recipient reacting to donor HLA molecules

24
Q

How many MHC loci are usually matched?

A

➝ 4/6 MHC class II loci

25
Why are live donors better than dead donors?
➝ Recipients will have a history of disease which results in a degree of inflammation ➝ organs from deceased donors are likely to be inflamed due to ischemia
26
What are the three types of graft rejection?
➝ Hyperacute rejection ➝ Acute rejection ➝ Chronic rejection
27
When does hyperacute rejection occur?
➝ within a few hours of transplant
28
What organs does hyperacute rejection usually occur with?
➝ highly vascularised organs
29
How does hyperacute rejection occur and what is needed?
➝ requires pre-existing antibodies usually to ABO blood group antigens or MHC I proteins ➝ ABO antigens are expressed on endothelial cells of blood vessels
30
What are the three ways antibodies to MHC can arise?
➝ Pregnancy ➝blood transfusion ➝ previous transplant
31
What does recognition of the Fc region lead to?
➝ Complement activation ➝ antibody dependent cellular cytotoxicity (Fc receptors on NK cells) ➝ Phagocytosis (Fc receptors on macrophages)
32
How do thrombi develop in hyperacute rejction?
➝ Antibodies bind to endothelial cells ➝ Complement fixation ➝ Accumulation of innate immune cells ➝ Endothelial damage, platelets accumulate, thrombi develop
33
What causes acute rejection?
➝ T cell response develops as a result of MHC mismatch
34
Describe how transplants are destroyed by acute rejection?
➝ Dendritic cells migrate to secondary lymphoid tissue where they encounter circulating effector T cells ➝ Macrophages and CTL increase inflammation and destroy the transplant
35
When does chronic rejection occur?
➝ months or years after the transplant
36
What does chronic rejection result from?
➝ Indirect allorecognition of foreign MHC/HLA
37
Describe how chronic rejection occurs?
➝ Blood vessel walls thickened, lumina narrowed and loss of blood supply ➝ correlates with the presence of antibodies to MHC-I ➝ Donor derived cells die ➝ membrane fragments containing donor MHC are taken up by host dendritic cells ➝ donor MHC is presented into peptides which are presented by host MHC ➝ T cell response is generated to the peptide derived from the processed donor MHC
38
What is a HSCT?
➝ haematopoietic stem cell transfer
39
What is graft vs host disease?
➝ if the transplanted tissue is immune cells there is the risk of donor immune cells attacking the host
40
What reduces graft vs host disease?
➝ Removing T cells from the transplant or suppressing their function
41
What is graft vs leukaemia?
➝ Sometimes mismatch and donor leukocytes can be beneficial which removes the original leukemia
42
What is essential to maintaining a non-autologous transplant?
➝ Immunosuppression
43
What are the three categories of immunosuppressant?
➝ General immune inhibitors ➝ Cytotoxic (kill proliferating lymphocytes) ➝ inhibit T cell activation
44
What is an example of general immune inhibitors?
➝ Corticosteroids
45
What are three examples of cytotoxic drugs used in immunosuppression?
➝ Mycophenolic acid ➝ cyclophosphamide ➝ methotrexate
46
What are three examples of drugs that inhibit T cell activation?
➝ Cyclosporin ➝ tacrolimus ➝ rapamycin
47
How does cyclosporin work?
➝ inhibits IL-12 production
48
How does mycophenolic acid work?
➝ Blocks lymphocyte proliferation through inhibition of DNA synthesis in T and B cells
49
How does rapamycin work?
➝ Blocks lymphocyte proliferation by inhibiting IL-2 signalling
50
How does anti IL-2 receptor antibody work?
➝ Inhibits T cell proliferation by blocking IL-2 binding
51
How does anti CD3 monoclonal antibody work?
➝ depletes T cells by targeting them for destruction
52
What is an example of a combination immunosuppressive regime?
1) steroids - prednisolone 2) cytotoxic 3) immunosuppressive specific
53
What is an immediate risk for transplant patients?
➝ more susceptible to infection and malignancy such as CMV
54
What can immunosuppressive drug toxicity lead to?
➝ organ failure | ➝ e.g cyclosporin nephrotoxicity
55
What is the microbiome involved in?
➝ regulating adaptive immune responses
56
How can anti-cancer immune responses be improved?
➝ FMT (fecal matter transplant)