L16- Transplantation

Question 1

What is an organ transplant?

Answer 1

A surgical operation in which a failing or damaged organ in the human body is removed and replaced with a functioning one.

Question 2

Where are transplanted organs obtained from?

Answer 2

1. Cadaveric- from recently dead donors (most used)
2. Living donor- either by donating one paired organ (kidneys) or a portion of an organ (liver)
3. Animal- not yet used

Question 3

What is an auto-graft?

Answer 3

Graft from one area to another on the same individual (no immune response induced) e.g bone

Question 4

What is an isograft/syngraft?

Answer 4

Transplant of cells, tissue or organ from one individual to another individual who is genetically identical to the donor e.g twins (no immune response induced)

Question 5

What is an allograft?

Answer 5

Transplant of cells/tissue/organ from one individual to another individual who is NOT genetically identical. (associated with immunological response and rejection)

Question 6

What is a xenograft?

Answer 6

Graft between a donor and a recipient from different species (e.g pigs) (associated with immunological response and rejection)

Question 7

What are the limitations of transplants?

Answer 7

1. Shortage of organs- long waiting list
2. Half life of a transplant is short (around 10 years) due to immune response so often two are needed
3. Use of immunosuppressive drugs to reduce the immune response causes a state of systemic immunodepression

Question 8

Why does the alloresponse occur?

Answer 8

Because recipient T cells are not educated to recognise the donor MHC-peptide complex and see it as foreign, inducing an immune response.

Question 9

What is the direct pathway of activating the immune response?

Answer 9

• Donor MHC on donor APC’s is directly recognised by the recipient’s T cells
• T cell receptors on recipient cells recognise the ternary structure of allo-MHC-peptide complex as a self-MHC presenting a viral peptide
• However donor APC’s in the graft die shortly after transplantation

Question 10

What is the indirect pathway of activating the immune response?

Answer 10

• The recipients APC’s migrate to the graft, take up and process allo-Ags and then display them to CD4+ and CD8+ T cells in the peripheral lymphoid organs.
• The graft gets destroyed via the activated T cells.

Question 11

What is the semi-direct pathway of activating the immune response?

Answer 11

• Recipient DC’s can acquire intact functional MHC molecules from donor cells
• The ‘acquired MHC’ is capable of stimulating antigen-specific T cells

Question 12

What happens after the immune response is activated?

Answer 12

• Activated T/B cells and antibodies migrate to the graft.
• They produce mediators such as IFN-gamma, TNF-alpha and IL-17
• This activates macrophages, NK cells, monocytes and enhances neutrophil response and inflammation.
• CD8+ T cells damage the graft
• Antibodies activate complement and ADCC

Question 13

What are the roles of antibodies?

Answer 13

• Very early graft-loss (48 hours)- hyperacute rejection
• Activate complement and clotting cascade
• Highly sensitised renal patients

Question 14

What increases the risk of rejection?

Answer 14

• Individuals who have a high exposure to ‘non-self’ human leukocyte antigens (HLA)
This results from:
• Blood transfusions
• Previous transplant
• Pregnancy- mother exposed to fathers antigens which are expressed in the cells of the body

Question 15

What is sensitisation?

Answer 15

When a persons immune system becomes hypervigilant to any invaders.

Question 16

What are the solutions to transplant rejection?

Answer 16

1. Pre-transplant cross match (live donor)
2. Desensitisation by immunoadsorption of plasma
3. Rituximab- antiCD20 drug that removes B cells

Question 17

What are the types of rejection?

Answer 17

1. Hyperacute (immediate)
2. Acute (1 day- few weeks)
3. Chronic (months to years)

Question 18

What is hyperacute rejection?

Answer 18

Mediated by previously existing Abs against donor Ags due to prior blood transfusion; pregnancy or earlier transplant

Question 19

What is acute rejection?

Answer 19

Recipient T cells recognise donor MHC on donor DC’s that have migrated from the graft to the lymph nodes.
Rejection mainly via direct pathway.

Question 20

What is chronic rejection?

Answer 20

Less well defined and can be caused by multiple factors
Can be due to:
1. Alloantigen dependent events
2. Antigen- independent factors

Question 21

What are alloantigen dependent events in chronic rejection?

Answer 21

• Ongoing episodes of acute rejection result in a continuously activated immune response
• Increased alloantibodies and CD4+ T cell responses
• Mainly via indirect recognition

Question 22

What are antigen-independent factors in chronic rejection?

Answer 22

• Injuries associated with transplantation such as ischaemia/reperfusion injury
• Activate macrophages which release inflammatory cytokines causing endothelial cell activation
• Activated EC mediate expression of chemokines, adhesion molecules and MHC on graft EC.
• Results in leukocyte recruitment, activation and infiltration into the allograft.

Question 23

What is immunological tolerance?

Answer 23

Specific unresponsiveness to an antigen that is induced by exposure of lymphocytes to that antigen
Inducing tolerance may be may be exploited to prevent graft rejection, treat autoimmune/allergic diseases

Question 24

How can tolerance be induced?

Answer 24

• By increasing number of Tregs

* By in vivo or ex vivo Treg expansion