L23 - Transplantation & Immunosuppressive Drugs

Question 1

What is a Transplantation?

Answer 1

The Introduction of biological material like organs, tissue and cells into an organism

Question 2

What is meant by an Autologous donor/recipient relationship?

Answer 2

donations given by an individual is for their own use, like a skin graft or blood transfusion

Question 3

What is meant by an Syngenic donor/recipient relationship?

Answer 3

donation is from donor to recipient, however both individuals are genetically identical

Question 4

What is meant by an Allogeneic donor/recipient relationship?

Answer 4

Donor and recipient are the same species but genetically different

Question 5

What is meant by an Xenogeneic donor/recipient relationship?

Answer 5

donor and recipient are dofferent individuals and different species

Question 6

What does MHC have to do with transplantations?

Answer 6

Histocompatibility = tissue compatibility

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 7

How do epitopes relate to transplantations?

Answer 7

• b-cell and T-cell epitopes donor MHC
• 1000’s of HLA alleles but only 100’s epitopes
• may be reactive for recipient

Question 8

What may be recognised as foreign in a transplant?

Answer 8

The MHC moleculae and the peptide present in its binding groove

Question 9

What is Indirect Allo-recognition?

Answer 9

On recipient cell:

self HLA and non-self peptide causes T-cell activation

Question 10

What is Direct Allo-recognition?

Answer 10

On Donor cell:

Unmatched HLA and peptide causes T-cell activation

Question 11

What are the 3 types of graft rejection?

Answer 11

• Hyperacute rejection
• Acute rejection
• Chronic rejection

Question 12

Describe Hyperacute Rejection?

Answer 12

• 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 bind to endothelial cells, complement fixation, accumulation of innate immune cells, and platelet accumulation, thrombus development, organ failure.
• Antibodies to MHC can arise from pregnancy, blood transfusion or previous transplants

Question 13

How can antibodies cause damage to transplanted tissue?

Answer 13

• recognition of Fc region leading to complement activation

Question 14

Describe Acute Rejection?

Answer 14

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

T cell response develops as a result of MHC mismatch

Question 15

Describe Chronic Rejection?

Answer 15

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

Our antibodies bind to antigens on endothelial cells of transplanted organ and recruit other immune cells, which induce damage and reduce blood supply

Question 16

What is Graft versus Host disease?

Answer 16

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 17

What is Graft versus Leukaemia?

Answer 17

ismatch and donor leukocytes can be benificial - removing original leukemia

Question 18

Give examples of what Immunosuppressants for transplant can be?

Answer 18

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)

Question 19

Describe the typical immunosuppressive regimes?

Answer 19

Induction:

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.

Maintenance:

Triple drug regimen at lower doses

Rescue:

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.