39. Transplantation and Immunosuppressive Drugs

Question 1

Define a transplantation

Answer 1

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

Question 2

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

• autologous
• syngeneic
• allogenic
• xenogeneic

Answer 2

• 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

Question 3

Expand on HLA/MHC

Answer 3

• 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)

Question 4

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

Answer 4

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

Question 5

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

Answer 5

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

Question 6

What are helper T cells and cytotoxic T cells?

Answer 6

• 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

Question 7

REVISE Describe direct and indirect T-cell activation

Answer 7

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

Question 8

Live vs dead donors

Answer 8

• 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

Question 9

Types of graft rejection

Answer 9

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

Question 10

How can antibodies cause damage to transplanted tissue?

Answer 10

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)

Question 11

Expand on hyperacute rejection.

Answer 11

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

Question 12

Acute rejection

Answer 12

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

Question 13

Briefly, describe direct allorecognition of foreign MHC

Answer 13

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

Question 14

Expand on chronic rejection

Answer 14

• 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

Question 15

Chronic rejection results from indirect allorecognition of foreign MHC/HLA

Answer 15

• 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

Question 16

Expand on Haematopoietic Stem cell transfer (HSCT)

Answer 16

• 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

Question 17

Immunosuppression

Answer 17

• 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

Question 18

Intestinal microbiome

Answer 18

• 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

Question 19

What is Graft Versus Host Disease (GVHD)?

Answer 19

• 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