39. Transplantation and Immunosuppressive Drugs Flashcards Preview

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Flashcards in 39. Transplantation and Immunosuppressive Drugs Deck (19)
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1
Q

Define a transplantation

A

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

2
Q

What is the difference between the following donor/recipient relationships?

  • autologous
  • syngeneic
  • allogenic
  • xenogeneic
A
  • Autologous – tissues from one part of the organism to another part of the same organism
  • Syngeneic – donor and recipient are genetically identical ~ no immune response
  • Allogeneic - same species but genetically different
  • Xenogeneic - different species
3
Q

Expand on HLA/MHC

A
  • Class 2 HLA are heterodimers of 2 proteins
  • Class 1 is one with the molecule called B2M (beta 2-macroglobulin)
  • Almost all nucleated cells (and APC) express HLA (MHC) class I ~ ACTIVATE TCR AND CD8+ T CELLS
  • Only immune cells and WBCs express both HLA class 1 and 2
  • APC express MHC class 2 and with peptides, it will activate CD4 T CELLS (with the correct TCR)
4
Q

What is MHC class I seen by and what does it bind?

A
  • Seen by T cell receptor on Cytotoxic T cells, with assistance from CD8
  • Binds fragments of intracellular proteins
5
Q

What is MHC class II seen by and what does it bind?

A
  • Seen by T cell receptor on helper T cells, with assistance from CD4
  • Binds fragments of proteins which have been taken up by endocytosis
6
Q

What are helper T cells and cytotoxic T cells?

A
  • Helper T cells – information and support for other immune cells via cytokine production
    ~ Helper T cells are required to produce antibody and cytotoxic T cell responses
  • Cytotoxic T cells – highly specific killer cells
7
Q

REVISE Describe direct and indirect T-cell activation

A

DIRECT of self HLA

  • Matched HLA + peptide = no T-cell activation
  • Unmatched HLA + peptide = T-cell activation

INDIRECT ALLO-RECOGNITION of self HLA and non-self peptide ~ recipient has transplant HLA

  • Self HLA + self peptide = no T-cell activation
  • Self HLA + non self peptide = T-cell activation
8
Q

Live vs dead donors

A
  • Recipients will have a history of disease which will have resulted in a degree of inflammation
  • Organs from deceased donors are also likely to be in inflamed condition due to ischemia
  • Transplant success is less sensitive to MHC mismatch for live donors
9
Q

Types of graft rejection

A

1) Hyperacute rejection
2) Acute rejection
3) Chronic rejection

10
Q

How can antibodies cause damage to transplanted tissue?

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)

11
Q

Expand on hyperacute rejection.

A

Within a few hours of transplant. Usually seen for highly vascularised organs. Requires pre-existing antibodies. Antibodies to MHC can arise from pregnancy, blood transfusion or previous transplants

Antibodies bind to endothelial cells -> complement fixation -> accumulation of innate immune cells -> Endothelial damage, platelets accumulate, thrombi develop

12
Q

Acute rejection

A
  • Inflammation results in activation of organ’s resident dendritic cells
  • T cell response develops as a result of MHC mismatch
13
Q

Briefly, describe direct allorecognition of foreign MHC

A

1) Inflammation results in activation of organ’s resident dendritic cells
2) DC migrate to secondary lymphoid tissue where they encounter circulating effector T cells
3) Macrophages and CTL increase inflammation and destroy transplant

14
Q

Expand on chronic rejection

A
  • Can occur months or years after transplant
  • Blood vessel walls thickened, lumina narrowed – loss of blood supply
  • Correlates with presence of antibodies to MHC-I
15
Q

Chronic rejection results from indirect allorecognition of foreign MHC/HLA

A
  • Donor-derived cells die
  • Membrane fragments containing donor MHC are taken up by host DC
  • Donor MHC is presented into peptides which are presented by host MHC
  • T cell response is generated to the peptide derived from processed donor MHC
16
Q

Expand on Haematopoietic Stem cell transfer (HSCT)

A
  • Previously called bone marrow transplant, now renamed as source is often blood
  • Often autologous
  • HSCs can find their way to bone marrow after infusion and regenerate there
  • They can be cryopreserved with little damage
17
Q

Immunosuppression

A

• Essential to maintain non-autologous transplant
• Induction, maintenance and rescue phases of treatment
• Immunosuppressants for transplant can be:
- General immune inhibitors (e.g. corticosteroids)
- Cytotoxic – kill proliferating lymphocytes (e.g. mycophenolic acid, cyclophosphamide, methotrexate)
- Inhibit T-cell activation (cyclosporin, tacrolimus, rapamycin)
•Immunosuppressives may need to be maintained indefinitely

18
Q

Intestinal microbiome

A
  • The microbiome, particularly of the intestine, is involved in regulating adaptive immune responses
  • Immunosuppressed patients (e.g. cancer patients) can take FMT – faecal material transplant – in order to promote effective anti-cancer immune responses
  • May be implicated in transplantation outcomes
19
Q

What is Graft Versus Host Disease (GVHD)?

A
  • When transplanted tissue is immune cells themselves, there is the risk of donor immune cells attacking the host – GVHD
  • Can be lethal – best approach is prevention
  • Removing T cells from transplant or suppressing their function reduces GVHD
  • But sometimes mismatch and donor leukocytes can be benificial - removing original leukemia
  • Graft versus leukemia response
  • Development of GVL may prevent disease relapse

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