Transplantation

Question 1

Most relevant proteins in transplantation

Answer 1

 ABO blood group

 HLA

Question 2

Two major forms of rejection

Answer 2

 T cell-mediated rejection

 Antibody-mediated rejection

Question 3

HLA classes

Answer 3

o HLA Class I (A, B and C) – expressed on ALL cells
 Thought to be the most immunogenic

o HLA Class II (DR, DQ, DP) – expressed on APCs (also be upregulated on other cells under stress)

Question 4

Most important HLA classes to match

Answer 4

Most important to match = DR > B > A

Question 5

Features of HLA receptors

Answer 5

 They are highly polymorphic with hundreds of alleles for each locus
 High degree of variability from the areas of protein lining the peptide-binding groove which allows us to present a wide variety of antigens in that peptide-binding groove to the cells of the immune system

Question 6

T cell mediated rejection

Answer 6

• Phase 1:
T cells require:
 Presentation of foreign HLA antigens in MHC by APCs (both DONOR and HOST APC cells are involved)
Co-stimulatory signals
Occur in the lymph nodes
Causes inflammation and graft dysfunction

Phase 2
o	Proliferation 	
o	Product cytokines (IL2 is important)
o	Provide help to CD8+ cells 	
o	Provide help for antibody production
o	Recruit phagocytic cells 

Phase 3
Migration to area
Rolling, attachment, adhesion, diapedesis

Question 7

Histological Features of T cell-mediated Rejection

Answer 7

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

Question 8

Antibody Mediated Rejection

Answer 8

o Phase 1: exposure to foreign antigen
o Phase 2: proliferation and maturation of B cells with antibody production
o Phase 3: effector phase – antibodies bind to graft endothelium (capillaries of glomerulus and around tubules)

o Antibodies bind to antigens (HLA) on the endothelium of the blood vessels in the transplanted organ
o Antibodies fix/activate complement which assembles to:
 Form MAC  endothelial cell lysis
 Recruit inflammatory cells to the microcirculation
o Antibodies can crosslink the MHC molecules, thus activating them
o The antibodies can also directly recruit mononuclear cells, NK cells and neutrophils  capillaritis

Question 9

• Action of Antibodies in Infection – the same mechanisms occur in transplant rejection:

Answer 9

o Neutralise toxins
o Opsonise (aid phagocytosis)
o Antibody-dependant cellular cytotoxicity
o Complement activation (which leads to):
 MAC lysis
 Opsonise (aid phagocytosis)
 Inflammation

Question 10

Histology of Antibiody mediated rejection

Answer 10

o	Inflammatory cell infiltrate  
o	Capillaritis (inflammatory cells in the microcirculation – a cardinal feature of antibody mediated rejection)

Question 11

Screening for anti-HLA antibodies

Answer 11

BEFORE, AT TIME (at organ assignment) and AFTER TRANSPLANT – 3 assays used:

Cytotoxicity assays:
 Inspects if recipient’s serum will kill the lymphocytes of the donor, in the presence of complement
 Positive crossmatch suggests that there is cell lysis

o Flow cytometry:
 Inspects if recipient’s serum binds to the donor’s lymphocytes
 Detection of bound AB by fluorescently labelled anti-human immunoglobulin

o Solid phase assays (uses a series of beads containing all the possible HLA epitopes):
 Recipient’s serum is mixed with beads and fluorescently labelled immunoglobulin is used to determine which HLA epitopes the antibodies bind to

Question 12

o Three signals to activate T-cells

Answer 12

 APC MHC to T-cell TCR (main signal)
 APC CD80/CD86 to T-cell CD28 (CD80/86 to CTLA4 suppresses immune reactions)
 Cytokine IL-2 to T-cell CD25 (after T-cell activation, autocrine IL-2 is released to further activate)

Question 13

Modern Transplant Immunosuppression Regimen:

Answer 13

o Induction agent: e.g. OXT3/ATG, anti-CD52, anti-CD25

o Baseline immunosuppression: calcineurin inhibitor + mycophenolate mofetil / azathioprine ± steroids

o Treatment of episodes of acute rejection:
 Cellular: steroids, OKT3, ATG
 Antibody-mediated: IVIG*, plasmapheresis, anti-C5, anti-CD20

Question 14

Pathogenesis of GvHD

Answer 14

 During SCT, the host immune system is eliminated (using total body irradiation and drugs)
 It is then replaced by own (autologous) or HLA-matched donor (allogeneic) bone marrow
 Allogeneic SCT leads to reaction of donor lymphocytes against host tissues
• Related to a degree of HLA-incompatibility
 If there is a malignancy (e.g. leukaemia), the graft can help kill these cells (graft-versus-tumour)

Question 15

GvHD symptoms and treatment

Answer 15

o	Symptoms – looks like slow-onset anaphylaxis with jaundice… 
	Rash 
	Nausea and vomiting 
	Abdominal pain 
	Diarrhoea/bloody stool
	Jaundice 

o GvHD Prophylaxis = Methotrexate/cyclosporine
o GvHD treatment = steroids

Question 16

• Post-Transplantation • Post-Transplantation Malignancy: