Immunology 3 - Transplantation

Question 1

Recall the 3 phases of immune response to a transplanted graft

Answer 1

1. Recognition of foreign antigens
2. Activation of antigen-specific lymphocytes
3. Effector phase of grant rejection

Question 2

What are the 2 most variant protein variants in clinical transplantation?

Answer 2

ABO blood group

HLA antigens

Question 3

On which type of cell is HLA class I expressed?

Answer 3

All cells

Question 4

On which type of cell is HLA class II expressed?

Answer 4

Antigen-presenting cells

Question 5

Which part of the HLA molecule is highly variable?

Answer 5

Peptide binding groove in between the alpha subunits

Question 6

In T cell-mediated transplant reaction, how are alloreactive T cells activated?

Answer 6

1. Both donor and host APCs present foreign HLA in MHCs

2. Costimulatory signals

Question 7

Which types of HLA fall into each class?

Answer 7

HLA-A, B, C = class 1
HLA-DR, DQ, DP =class 2

Question 8

What are the actions of activated T cells in T cell-mediated transplant rejection?

Answer 8

1. Proliferation
2. Produce cytokines (especially IL2)
3. ‘Help’ CD8+ cells
4. ‘Help’ antibody production
5. Recruit phagocytic cells

Question 9

What test can be used to see if transplant rejection is occurring?

Answer 9

A biopsy - an inflammatory response will be seen

Question 10

What are the key histological features of T cell-mediated transplant rejection?

Answer 10

Lymphocytic interstitial infiltration
Ruptured tubular basement membrane
Tubulitis (inflammatory cells within the tubular epithelium)
Macrophages, recruited by the T cells

Question 11

Recall the 3 phases of antibody mediated rejection

Answer 11

1. B cells recognise foreign HLA
2. Proliferation and maturation of B cells with anti-HLA antibody production
3. Effector phase: antibodies bind to graft ENDOTHELIUM

Question 12

Recall the process of antibody-mediated rejection phase 3

Answer 12

Antibody binding to transplanted organ vessel endothelium –> complement activation to form MAC and monocyte/neutrophil recruitment via Fc receptor –> endothelial injury and inflammation (capillaritis)
Capillaritis is a cardinal feature of antibody-mediated rejection

Question 13

What are the key histological features of antibody-mediated transplant rejection?

Answer 13

1. Inflammatory cell infiltrate
2. Capillaritis
3. Immunohistochemistry shows fixation or complement fragments on endothelial cell surfaces

Question 14

Describe the effector phase of T cell-mediated transplant rejection

Answer 14

The T cells will tether, roll and arrest on the endothelial cell surface
They will then crawl through into the interstitium and start attacking the tubular epithelium

Question 15

What test is used to do HLA typing before a transplant?

Answer 15

PCR-DNA sequencing

Question 16

What at the 3 methods of screening for anti-HLA antibodies?

Answer 16

1. Cytotoxicity assays - inspects if recipient’s serum binds to the donor lymphocytes by looking for LYSIS
2. Flow cytometry - inspects if recipient’s serum binds to the donor lymphocytes by looking for BOUND FLUORESCENTLY-LABELLED ANTIBODY
3. Solid phase assays, ‘Luminex’ (uses a series of beads that contain all the possible HLA phenotypes) - fluorescently labelled immunoglobulin used to determine which HLA epitopes the antibodies bind to

Question 17

What is the most reliable HLA test nowadays?

Answer 17

Solid phase assays - uses beads that have different HLA epitopes and fluorescent colour

Question 18

Recall 2 treatments that all transplant recipients receive to prevent rejection?

Answer 18

Induction agent
Base-line immunosuppression 
Baseline immunosuppression is important to learn (has been in PPQ) = 
Mycophenalate mofetil
Tacrolimus (calcineurin inhibitor)
Prednisolone

Question 19

A pt has an episode of acute T cell-mediated rejection 2 months post-transplantation. What would be the most common drug administered?

Answer 19

Corticosteroid (prednisolone)

Question 20

Recall 3 pathologies that immunosuppresion increases risk of

Answer 20

Infection, malignancy and drug toxicity

Question 21

Recall some drugs used to manage T cell vs antibody-mediated transplant rejection

Answer 21

T cell rejection management:

• Steroids (prevent general T cell activation)
• Calcineurin inhibitors (prevent cell signalling)
• Anti-proliferative agents (mycophenalate, azothioprine)
• receptor inhibitors (eg anti-CD3)

Antibody rejection management:

• Rutiximab (anti-CD20)
• BAFF inhibitors
• proteasome inhibitors (block antibody production by plasma cells)
• complement inhibitors (block complement binding to endothelium)

Question 22

What is the main complication of HSCT?

Answer 22

GvHD

Question 23

What is the pathogenesis of GvHD in HSCT rejection?

Answer 23

1. During SCT, the host immune system is eliminated (total body irradiation and drugs)
2. Bone marrow then replaced (allogenic/autologous)
3. Allogenic SCT leads to reaction of donor lymphocytes against host tissues (related to a degree of HLA-incompatibility)
4. If there is a malignancy, the graft can help kill these cells (graft-versus-tumour)

Question 24

What are the 2 options for GvHD prophylaxis before HSCT?

Answer 24

Methotrexate

Cyclosporine

Question 25

How should GvHD following HSCT be treated?

Answer 25

Steroids

Question 26

What are the symptoms of GvHD following HSCT?

Answer 26

A bit like a slow anaphylaxis with jaundice:

• Rash
• Nausea and vomiting
• Abdominal pain
• Diarrhoea/bloody stool
• Jaundice

Question 27

What is the post-transplant risk of malignancy?

Answer 27

Viral-associated malignancies are much more common, such as:
- Kaposi sarcoma (HHV8)
- Lymphoproliferative disease (EBV)
Skin cancer is 20x more common