Transplantation immunology

Question 1

What is hyperacute rejection? How does this occur?

Answer 1

• occurs minutes to hours after transplant

Cell-mediated rejection:

• helper t-lymphocytes are sensitised and stimulate cytotoxic t lymphocytes, macrophages and b-lymphocytes
• these will either directly attack the transplant or form antibodies to attack it

Antibody-mediated rejection:

• pre-formed antibodies bind/attack endothelial cells
• damages the endothelium and changes the endothelium phenotype
• there is also coagulation activation (thrombus formation)
• 1hours: neutrophils in peritubular capillaries and glomeruli
• 12-24 hours: intravascular coagulation + cortical necrosis

Question 2

What is acute rejection? How does this occur?

Answer 2

• one week to 6 months after transplantation

Cell-mediated rejection:

• CD4+ active cytotoxic T lymphocytes (CD8+)
• lymphocyte infiltration, interstitial tubulitis and primarily targets peripheral lymphoid tissue
• causes endarteritis (inflammation of tunica intimacy)

Antibody-mediated (humoral) rejection:

• CD4+ activates B-lymphocytes that produce antibodies
• antibodies are against non-self molecules (ABO, MHC, MHC Class-I related chain A)
• primary targets endothelium of arteries and capillaries
• Cd4+ is deposited on the endothelium as a product of the antibody-antigen compels –> forms part of the complement activation

Question 3

Compare cellular and antibody rejection.

Answer 3

• cellular: more CD4 between cells/connecting cells

- antibody: around the blood vessels (peritubular)

Question 4

What is the criteria acute antibody mediated rejection?

Answer 4

1. evidence of acute renal injury on histology
2. evidence of antibody activity (CD4+ in peritubular capillaries)
3. circulating anti-donor specific antibodies

Question 5

What is chronic rejection? How does this occur?

Answer 5

• months to years after transplant

Chronic rejection can come from:

• pre-transplantation damage of graft
• recurrence of original disease
• rejection

Question 6

How can hyperacute rejection be prevented?

Answer 6

• ABO compatibility + presence of pre-formed antibodies

Question 7

How can acute rejection be prevented?

Answer 7

1. HLA matching
   - Human MHC = HLA
   - -> HLA presents antigen peptides to TCRs
   - MHC Class II are found on helper T cells
   - -> most common is HLADR (DR4)
   - MHC Class I is found on all nucleated cells
2. Minimising ischaemia
   - ischaemia upregulates adhesion molecules
   - increases adhesion during reperfusion
   - leads to non-specific damage and acute rejection
   - ischaemia increases levels of toxins/reactive species

Question 8

How can chronic rejection be prevented?

Answer 8

choosing the best organ

Question 9

What is immunosuppression?

Answer 9

Prevention of activation of T helper cells

Activated T cells secrete IL to cause clonal expansion

Question 10

How can corticosteroids act as immunosuppressants?

Answer 10

Prevent cytokines gene activation

Question 11

What are calcineurin inhibitors? Give examples.

Answer 11

Prevent antigen binding to allow the activation of cytokine gene activation
Examples:
- cyclosporin
- tacrolimus

Question 12

Give examples of other drugs used for immunosuppression.

Answer 12

Blocks T cell receptors:

• alemtuzumab
• OKT3

Prevent binding of IL2/anti IL-2 receptors:

• basiliximab
• daclizumab

Prevent proliferation:

• azathioprine
• mycophenolic acid (MMF, MPS)