Transplantation and Immunosuppressive Drugs

Question 1

What does transplantation mean

Answer 1

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

Question 2

What are the types of donor relationships

Answer 2

• Autologous and syngeinic donations
• genetically identical
• no immune reactions
• donation to and from same part of body

Question 3

What is an example of an autologous transplant

Answer 3

Skin grafts from one part to another part of the body

Question 4

What is an example of an syngeneic transplant

Answer 4

From one identical twin to another twin

Question 5

What is allogenic transplantation

Answer 5

Same species but genetically different

Question 6

What is xenogeneic transplantation

Answer 6

Transplantation between different species entirely

Question 7

What is the cause of transplantation rejection

Answer 7

• Immune responses to transplant are caused by genetic differences between the donor and the recipient
• The most important are differences between the antigens forming the major histocompatibility complex (MHC)

Question 8

What is the importance of epitopes on donor MHC

Answer 8

• 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
• Next-generation sequencing is required to assassin the difference between the HLA of the recipient and donor

Question 9

How is MHC recognised in a transplant

Answer 9

Both the MHC protein and the peptide in its binding groove may be foreign

Question 10

What is Indirect allo-recognition

Answer 10

• Where a self HLA and non-self peptide is present there is T cell activation
• Cause lysis of cell

Question 11

What is direct allo-recognition

Answer 11

• Where a unmatched HLA and peptide causes T cell activation

Question 12

How do we ensure transplant survival

Answer 12

• try to match 4/6 MHC class 2 loci
• Reduces likelihood of future transplants and problems with future transplant

Question 13

Describe the possibility of using Live vs Dead donors

Answer 13

• 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 14

What are the types of graft rejections

Answer 14

• Hyperacute rejection
• Acute rejection
• Chronic rejection

Question 15

What is hyper-acute rejection

Answer 15

• Within a few hours of transplant
• Most commonly seen for highly vascularised organs
  (e.g. kidney)
• Requires pre-existing antibodies, usually to ABO
  blood group antigens or MHC-I proteins
• (ABO antigens are expressed on endothelial cells of
  blood vessels)
• Antibodies to MHC can arise from pregnancy, blood
  transfusion or previous transplants

Question 16

How does antibodies cause damage to transplanted tissue

Answer 16

• Recognition of Fc region leading to
• Complement activation
• Antibody-dependent cellular cytotoxicity
  (Fc Receptors on NK cells)
• Phagocytosis
  (Fc Receptors on macrophages)

Question 17

How does antibodies cause damage in hyper acute rejection

Answer 17

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

Question 18

Describe acute reaction

Answer 18

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

Question 19

Describe the direct allorecognition response in acute rejection

Answer 19

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

Question 20

Describe chronic rejection

Answer 20

• 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 21

Describe the indirect allorecognition response in chronic rejection

Answer 21

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

Question 22

What is Haematopoetic stem cell transfer

Answer 22

• Previously called bone marrow transplant, now
  renamed as source is often blood
• Often autologous
• Until 1980 only HLA identical siblings could be used as donors due to the risk of rejection or graft versus host disease

Question 23

What is meant by Graft vs Host disease

Answer 23

• 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

Question 24

Describe the graft vs leukemia response

Answer 24

• Sometimes mismatch and donor leukocytes can be
  beneficial - removing original leukaemia
• Graft versus leukaemia response
• Development of GVL may prevent disease relapse

Question 25

Why is immunosuppression important

Answer 25

• essential to maintain non-autologous transplants

Question 26

What are the 3 phases of immunosuppression treatment

Answer 26

• Induction
• Maintenance
• Rescue

Question 27

What are some types of immunosuppressants used

Answer 27

• General immune inhibitors (e.g. corticosteroids)
• Cytotoxic – kill proliferating lymphocytes (e.g. mycophenolic
  acid, cyclophosphamide, methotrexate)
• Inhibit T-cell activation (cyclosporin, tacrolimus, rapamycin)

Question 28

Describe the use of cyclosporin

Answer 28

• Blocks T cell proliferation and differentiation
• improved patient and graft survival rates dramatically from 30%-50% to 80% at 1 year.
• Next generation therapies less toxic and effective at lower doses

Question 29

Describe the use of combination immunosuppressive regimes

Answer 29

• (1) Steroids – e.g. prednisolone
• (2) Cytotoxic – e.g. mycophenolate motefil
• (3) Immunosuppressive specific for T cells
  – e.g. cyclosporin A, FK506,

Question 30

Describe the Induction phase of immunosuppressive regimes

Answer 30

Antibody induction therapy:

• Lymphocyte depleting rabbit Anti-thymocyte globulins (ATG) is the most
  commonly used antibody for induction therapy, followed by basiliximab and
  alemtuzumab.

Triple drug regimen:

• a calcineurin inhibitor, an antiproliferative agent, and corticosteroid.
• Tacrolimus, mycophenolate mofetil, and prednisone is the most common regimen.

Question 31

Describe the maintenance phase of immunosuppressive regimes

Answer 31

Use of triple drug regimen at lower doses

Question 32

Describe the Rescue phase of immunosuppressive regimes

Answer 32

• T-cell mediated rejection (TCMR) is treated with ATG and steroids (eg,
  methylprednisolone 250-1000 mg per dose).
• B-cell mediated rejection (BCMR) may be treated with Intravenous
  immunoglobulin or anti-CD20 antibody and steroids.

Question 33

How do we monitor immunosuppressive therapy

Answer 33

• There is currently no immunosuppressive that will prevent
  transplant rejection whilst maintaining other immune responses
• Transplant patients more susceptible to infection and malignancy
  – Immediate risk e.g. CMV
• Immunosuppressive drug toxicity can lead to organ failure eg
  cyclosporin nephrotoxicity in kidney transplant.

Question 34

How does intestinal microbiome affect transplants and immunosuppressed patients

Answer 34

• 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