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Immunology > Transplantation & Immunosuppressive Drugs > Flashcards

Transplantation & Immunosuppressive Drugs Flashcards

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
Q

Where does MHC II loading occur?

A

Only on professional APCs & WBCs

- immune cells

26
Q

Describe the process of MHC II loading

A
  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
Q

What is the role of the CLIP protein in MHC II loading?

A

Maintains HLA shape until peptide is ready to bind

28
Q

What molecules do MHC I bind?

A

Fragments of intracellular proteins

29
Q

Which molecules do MHC II bind?

A

Fragments of proteins which have been taken up by endocytosis

30
Q

What is the role of Th cells?

A

Helper T cells are required to produce antibody and cytotoxic T cell responses

31
Q

What is the role of helper t cells?

A

Information and support for other immune cells via cytokine production

32
Q

What is the role of cytotoxic T cells?

A

Highly specific killer cells

33
Q

What is the ‘foreign’ proteins are detected in transplant rejection?

A

In transplants, both the MHC protein and the peptide in its binding groove may be foreign

34
Q

Describe how recipient cells may induce T cell activation

A

Recipient Cell:

No T-cell activation
- Self HLA + self peptide

T-cell activation
- Self HLA + non self peptide

35
Q

How may donor cells induce T cell activation?

A

Donor cell:

No T-cell activation
- Matched HLA + peptide

T-cell activation
- Unmatched HLA + peptide

36
Q

How are donors matched to recipients?

A 
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
Q

What is the inflammation state of transplant recipients?

A

Recipients will have a history of disease which will have resulted in a degree of inflammation

38
Q

What is the caution of using deceased donors?

A

Organs from deceased donors are also likely to be in inflamed condition due to ischemia

39
Q

How is transplant success affected by live / deceased donors?

A

Transplant success is less sensitive to MHC mismatch for live donors

40
Q

What are the 3 types of graft rejection?

A
  1. Hyperacute rejection
  2. Acute rejection
  3. Chronic rejection
41
Q

How soon after transplant does a hyperacute rejection occur?

A

Within a few hours of transplant

42
Q

When is hyperacute rejection commonly seen?

A

Most commonly seen for highly vascularised organs (e.g. kidney)

43
Q

What causes a hyperacute rejection?

A

Pre-existing antibodies, usually to ABO blood group antigens or MHC-I proteins

(ABO antigens are expressed on endothelial cells of blood vessels)

44
Q

Where do MHC antibodies come from?

A

Antibodies to MHC can arise from pregnancy, blood transfusion or previous transplants

45
Q

How do antibodies cause damage to transplanted tissues?

A

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
Q

Describe how a hyperacute rejection occurs

A
  1. Antibodies bind to endothelial cells
  2. Complement fixation
  3. Accumulation of innate immune cells
  4. Endothelial damage, platelets accumulate, thrombi develop
47
Q

What is acute rejection?

A

Inflammation results in activation of organ’s resident dendritic cells

T cell response develops as a result of MHC mismatch

48
Q

Outline how direct allorecognition of a foreign MHC occurs

A
  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
Q

When does chronic rejection occur?

A

Can occur months or years after transplant

50
Q

What are the effects of chronic rejection?

A

Blood vessel walls thickened, lumina narrowed – loss of blood supply
Correlates with presence of antibodies to MHC-I

51
Q

How does chronic rejection arise?

A

Chronic rejection results from indirect allorecognition of foreign MHC/HLA

52
Q

Describe how indirect allorecognition occurs

A
  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
Q

What is HSCT?

A

Haematopoietic Stem Cell Transfer (HSCT)

Previously called bone marrow transplant, now renamed as source is often blood
Often autologous

54
Q

What are the advantages of HSCT?

A

HSCs can find their way to bone marrow after infusion and regenerate there

They can be cryopreserved with little damage

55
Q

What is GVHD?

A

Graft Vs. Host Disease

When transplanted tissue is immune cells themselves, there is the risk of donor immune cells attacking the host

56
Q

What is the best way to prevent GVHD?

A

Can be lethal – best approach is prevention

Removing T cells from transplant or suppressing their function reduces GVHD

57
Q

What is GVL?

A

Graft Vs. Leukaemia

58
Q

Why is GVL sometimes a good thing?

A

Sometimes mismatch and donor leukocytes can be beneficial - removing original leukemia

Development of GVL may prevent disease relapse

59
Q

What is the significance of immunosuppression for transplants/?

A

Essential to maintain non-autologous transplant

Induction, maintenance and rescue phases of treatment

60
Q

What immunosuppressors are used for transplants?

A

General immune inhibitors
- e.g. corticosteroids

Cytotoxic

  • kill proliferating lymphocytes
  • e.g. mycophenolic acid, cyclophosphamide, methotrexate

Inhibit T-cell activation
- cyclosporin, tacrolimus, rapamycin

61
Q

What is a cost-effective drawback of using immunosuppressives?

A

Immunosuppressives may need to be maintained indefinitely

62
Q

What is cyclosporin?

A

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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