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Transplantation & Immunosuppressive Drugs Flashcards

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1
Q

What is transplantation?

A

Transplantation is the introduction of biological material (eg organs, tissue, cells) into an organism

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2
Q

How does the immune system hinder transplantation?

A

The immune system has evolved to remove anything it regards as non-self

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3
Q

What is an autologous transplantation?

A

Transplant from one part of the organism into the same organism

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4
Q

Why is an immune response against autologous transplants unlikely

A

May be inflammatory responses but no expected immune response as it is self transplant e.g. skin transplant

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5
Q

What is is a syngeneic transplant?

A

Donor material transplanted into recipient when donor and recipient are genetically identical e.g. twins

  • no immunological reaction
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6
Q

What is an allogeneic donor recipient relationship?

A

Donors and recipients are from the same species but genetically different e.g. relatives: close genetic match

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7
Q

What is a xenogeneic relationship?

A

Donor and recipient are different species

e.g. bovine

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8
Q

What is histocompatibility?

A

Histocompatibility = tissue compatibility

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9
Q

Why do immune responses occur against transplants?

A

Immune responses to transplant are caused by genetic differences between the donor and the recipient

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10
Q

What is the major cause of transplant rejection?

A

MHC incompatibility

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11
Q

Describe the diversity of HLA classes

A

3 class I HLA alleles: HLA A, B & C

3 Class II HLA alleles (dimers)

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12
Q

Which cells express the different MHC molecules?

A

All nucleated cells express MHC Class I but only immune cells express MHC II molecules

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13
Q

Describe HLA Class I expression frequency

A

Even most common (A2) HLA can be classified into dozens of subtypes - lots of variability despite same HLA

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14
Q

What epitopes are present on donor MHC molecules?

A

B-cell epitopes on donor MHC

T-cell epitopes derived from donor MHC

1000’s of HLA alleles but perhaps only 100’s of epitopes

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15
Q

What technique is used to identify donor MHC alleles?

A

Next generation sequencing required

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16
Q

What is the role of T cells in MHC Interaction?

A

T cells need to be able to recognise foreign peptides that are bound to self-MHC

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17
Q

How do APCs express MHC molecules?

A

APC will express MHC (I/II) molecules where peptides bind in their variable region grooves

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18
Q

How do T cells recognise MHC molecules?

A

TCR detects a combination of peptide and MHC complex

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19
Q

What cells do MHC I molecules activate?

A

MHC I activates TCR CD8+ cells

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20
Q

What cells do MHC II activate?

A

MHC II activates TCR CD4+ cells

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21
Q

What molecules do T cells recognise by MHC I presentation?

A

T cells recognise short peptide fragments that are presented to them by MHC) proteins (intracellular pathogens) e.g. viral infection

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22
Q

How are viral proteins processed?

A

Viral proteins processed by proteasome into peptides

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23
Q

How do MHC bind to viral peptides?

A

Peptides attract and bind MHC molecules that are then transported to cells surface

CD8 T cells can now interact

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24
Q

How are external pathogens cross presented?

A

Professional APCs (dendritic) can internalise external peptides and cross present onto MHC Class I pathway => CD8+ activation

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25
Where does MHC II loading occur?
Only on professional APCs & WBCs | - immune cells
26
Describe the process of MHC II loading
1. External antigens processed in phagolysosome into peptides 2. Peptides interact with vesicles containing MHC and CLIP 3. Vesicular complex transferred to surface 4. CD4+ T cells activated
27
What is the role of the CLIP protein in MHC II loading?
Maintains HLA shape until peptide is ready to bind
28
What molecules do MHC I bind?
Fragments of intracellular proteins
29
Which molecules do MHC II bind?
Fragments of proteins which have been taken up by endocytosis
30
What is the role of Th cells?
Helper T cells are required to produce antibody and cytotoxic T cell responses
31
What is the role of helper t cells?
Information and support for other immune cells via cytokine production
32
What is the role of cytotoxic T cells?
Highly specific killer cells
33
What is the 'foreign' proteins are detected in transplant rejection?
In transplants, both the MHC protein and the peptide in its binding groove may be foreign
34
Describe how recipient cells may induce T cell activation
Recipient Cell: No T-cell activation - Self HLA + self peptide T-cell activation - Self HLA + non self peptide
35
How may donor cells induce T cell activation?
Donor cell: No T-cell activation - Matched HLA + peptide T-cell activation - Unmatched HLA + peptide
36
How are donors matched to recipients?
``` Usually try to match 4/6 MHC class II loci, reduces likelihood of future transplants and problems with future transplants - HLA mismatch reduce survival ```
37
What is the inflammation state of transplant recipients?
Recipients will have a history of disease which will have resulted in a degree of inflammation
38
What is the caution of using deceased donors?
Organs from deceased donors are also likely to be in inflamed condition due to ischemia
39
How is transplant success affected by live / deceased donors?
Transplant success is less sensitive to MHC mismatch for live donors
40
What are the 3 types of graft rejection?
1. Hyperacute rejection 2. Acute rejection 3. Chronic rejection
41
How soon after transplant does a hyperacute rejection occur?
Within a few hours of transplant
42
When is hyperacute rejection commonly seen?
Most commonly seen for highly vascularised organs (e.g. kidney)
43
What causes a hyperacute rejection?
Pre-existing antibodies, usually to ABO blood group antigens or MHC-I proteins (ABO antigens are expressed on endothelial cells of blood vessels)
44
Where do MHC antibodies come from?
Antibodies to MHC can arise from pregnancy, blood transfusion or previous transplants
45
How do antibodies cause damage to transplanted tissues?
Recognition of Fc region leading to - 1. Complement activation 2. Antibody dependent cellular cytotoxicity (Fc Receptors on NK cells) 3. Phagocytosis (Fc Receptors on macrophages)
46
Describe how a hyperacute rejection occurs
1. Antibodies bind to endothelial cells 2. Complement fixation 3. Accumulation of innate immune cells 4. Endothelial damage, platelets accumulate, thrombi develop
47
What is acute rejection?
Inflammation results in activation of organ’s resident dendritic cells T cell response develops as a result of MHC mismatch
48
Outline how direct allorecognition of a foreign MHC occurs
1. Kidney graft dendritic cells activated 2. DC migrate to spleen and activate effector T cells 3. Effector T cells migrate to graft via blood 4. Graft destroyed by macrophages + CTLs
49
When does chronic rejection occur?
Can occur months or years after transplant
50
What are the effects of chronic rejection?
Blood vessel walls thickened, lumina narrowed – loss of blood supply Correlates with presence of antibodies to MHC-I
51
How does chronic rejection arise?
Chronic rejection results from indirect allorecognition of foreign MHC/HLA
52
Describe how indirect allorecognition occurs
1. Donor-derived cells die 2. Membrane fragments containing donor MHC are taken up by host DC 3. Donor MHC is presented into peptides presented by host MHC 4. T cell response generated to peptide derived from processed donor MHC
53
What is HSCT?
Haematopoietic Stem Cell Transfer (HSCT) Previously called bone marrow transplant, now renamed as source is often blood Often autologous
54
What are the advantages of HSCT?
HSCs can find their way to bone marrow after infusion and regenerate there They can be cryopreserved with little damage
55
What is GVHD?
Graft Vs. Host Disease When transplanted tissue is immune cells themselves, there is the risk of donor immune cells attacking the host
56
What is the best way to prevent GVHD?
Can be lethal – best approach is prevention Removing T cells from transplant or suppressing their function reduces GVHD
57
What is GVL?
Graft Vs. Leukaemia
58
Why is GVL sometimes a good thing?
Sometimes mismatch and donor leukocytes can be beneficial - removing original leukemia Development of GVL may prevent disease relapse
59
What is the significance of immunosuppression for transplants/?
Essential to maintain non-autologous transplant | Induction, maintenance and rescue phases of treatment
60
What immunosuppressors are used for transplants?
General immune inhibitors - e.g. corticosteroids Cytotoxic - kill proliferating lymphocytes - e.g. mycophenolic acid, cyclophosphamide, methotrexate Inhibit T-cell activation - cyclosporin, tacrolimus, rapamycin
61
What is a cost-effective drawback of using immunosuppressives?
Immunosuppressives may need to be maintained indefinitely
62
What is cyclosporin?
Breakthrough drug for transplant Blocks T cell proliferation and differentiation Next generation therapies less toxic and effective at lower doses

Immunology (14 decks)

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