Immunology 3 - Transplantation Flashcards
Recall the 3 phases of immune response to a transplanted graft
- Recognition of foreign antigens
- Activation of antigen-specific lymphocytes
- Effector phase of grant rejection
What are the 2 most variant protein variants in clinical transplantation?
ABO blood group
HLA antigens
On which type of cell is HLA class I expressed?
All cells
On which type of cell is HLA class II expressed?
Antigen-presenting cells
Which part of the HLA molecule is highly variable?
Peptide binding groove in between the alpha subunits
In T cell-mediated transplant reaction, how are alloreactive T cells activated?
- Both donor and host APCs present foreign HLA in MHCs
2. Costimulatory signals
Which types of HLA fall into each class?
HLA-A, B, C = class 1 HLA-DR, DQ, DP =class 2
What are the actions of activated T cells in T cell-mediated transplant rejection?
- Proliferation
- Produce cytokines (especially IL2)
- ‘Help’ CD8+ cells
- ‘Help’ antibody production
- Recruit phagocytic cells
What test can be used to see if transplant rejection is occurring?
A biopsy - an inflammatory response will be seen
What are the key histological features of T cell-mediated transplant rejection?
Lymphocytic interstitial infiltration
Ruptured tubular basement membrane
Tubulitis (inflammatory cells within the tubular epithelium)
Macrophages, recruited by the T cells
Recall the 3 phases of antibody mediated rejection
- B cells recognise foreign HLA
- Proliferation and maturation of B cells with anti-HLA antibody production
- Effector phase: antibodies bind to graft ENDOTHELIUM
Recall the process of antibody-mediated rejection phase 3
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
What are the key histological features of antibody-mediated transplant rejection?
- Inflammatory cell infiltrate
- Capillaritis
- Immunohistochemistry shows fixation or complement fragments on endothelial cell surfaces
Describe the effector phase of T cell-mediated transplant rejection
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
What test is used to do HLA typing before a transplant?
PCR-DNA sequencing
What at the 3 methods of screening for anti-HLA antibodies?
- Cytotoxicity assays - inspects if recipient’s serum binds to the donor lymphocytes by looking for LYSIS
- Flow cytometry - inspects if recipient’s serum binds to the donor lymphocytes by looking for BOUND FLUORESCENTLY-LABELLED ANTIBODY
- 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
What is the most reliable HLA test nowadays?
Solid phase assays - uses beads that have different HLA epitopes and fluorescent colour
Recall 2 treatments that all transplant recipients receive to prevent rejection?
Induction agent Base-line immunosuppression Baseline immunosuppression is important to learn (has been in PPQ) = Mycophenalate mofetil Tacrolimus (calcineurin inhibitor) Prednisolone (Pre-Transplant Meds = acronym)
A pt has an episode of acute T cell-mediated rejection 2 months post-transplantation. What would be the most common drug administered?
Corticosteroid (prednisolone)
Recall 3 pathologies that immunosuppresion increases risk of
Infection, malignancy and drug toxicity
Recall some drugs used to manage T cell vs antibody-mediated transplant rejection
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)
What is the main complication of HSCT?
GvHD
What is the pathogenesis of GvHD in HSCT rejection?
- During SCT, the host immune system is eliminated (total body irradiation and drugs)
- Bone marrow then replaced (allogenic/autologous)
- Allogenic SCT leads to reaction of donor lymphocytes against host tissues (related to a degree of HLA-incompatibility)
- If there is a malignancy, the graft can help kill these cells (graft-versus-tumour)
What are the 2 options for GvHD prophylaxis before HSCT?
Methotrexate
Cyclosporine
How should GvHD following HSCT be treated?
Steroids
What are the symptoms of GvHD following HSCT?
A bit like a slow anaphylaxis with jaundice:
- Rash
- Nausea and vomiting
- Abdominal pain
- Diarrhoea/bloody stool
- Jaundice
What is the post-transplant risk of malignancy?
Viral-associated malignancies are much more common, such as:
- Kaposi sarcoma (HHV8)
- Lymphoproliferative disease (EBV)
Skin cancer is 20x more common
