CSIM 1.29 Transplantation Flashcards
What mechanisms exist to prevent pathogens mutating to evade presentation by MHC?
MHC has two properties:
• Polygeny (many MHC genes)
• Polymorphism (many forms)
Describe MHC polygeny. Name the genes and what chains they code for.
MHC genes are co-dominant, and have different ranges of peptide binding specificities so that mutations in antigen cannot evade presentation. Cells have one of each gene:
MHC class I genes FOR α CHAIN:
• HLA-A (x2)
• HLA-B (x2)
• HLA-C (x2)
MHC class II genes FOR α AND β CHAINS:
• HLA-DR (x2)
• HLA-DQ (x2)
• HLA-DP (x2)
IMG 73
NB: Each gene has two pairs so each MHC class has 6 copies
Describe MHC polymorphism
There are multiple variants of each gene within a population. MHC genes are the most polymorphic genes in the human genome. Every person has a different ‘allele’ combination for each gene for MHC molecules.
This variation occurs in the peptide binding groove
e.g:
• HLA-A1 & HLA-A303
Describe what is meant by ‘MHC restriction’.
A TCR will only recognise an antigen if it is bound to the same MHC class, gene and polymorphism (e.g. HLA-A1) that it was bound to when the T cell was activated.
This is because the T cell is specific for the combination of MHC+antigen (IMG 74)
What is an ‘MHC alloreactive response’?
When a donor and recipient of a transplanted tissue have different MHC, an immune response can mound against the non-self MHC I molecules
This is instigated by the inflammation resulting from the invasiveness of the surgery
What proportion of T cells are activated by foreign tissue MHC molecules and why?
Up to 10%, because unprecedented binding occurs due to the foreign MHC (IMG 75):
Peptide-dependent binding
• Affinity between peptide and TCR is strong enough to overcome lack of specificity for foreign MHC
Peptide-independent binding
• MHC is similar enough to host MHC for TCR to bind to it without
• The affinity between the TCR and nonself MHC is strong enough to overcome the lack of specificity
In which two ways can donor antigen be presented to recipient T cells in order to reject a graft?
Direct Allorecognition
• Donor APCs from transplanted organ migrate to recipient regional lymph node
• Recipient T cells are activated by this APC through peptide-dependent or peptide-independent binding
• Activated T cell migrates to graft and attacks it
Indirect Allorecognition (IMG 76)
• Recipient APC processes and presents peptides from inflammed or dead cells from the transplanted organ
• T cell activated, migrates to graft and attacks it
Describe the differences in rejection pattern seen between direct and indirect allorecognition
Direct Allorecognition
• Up to 10% of the recipients T cells activated
• Mainly CD8 cells involved
• Results in direct cytotoxic attack of tissue
• Acute rejection over 10-14 days
Indirect Allorecognition
• Few T cells activated - oligoclonal
• Mainly antibody response
• Causes slow tissue injury and fibrosis
• Arteriosclerosis occurs from this fibrosis,causing ischaemia
• Chronic rejection over months
What can cause hyperacute rejection?
Recipient carries PRE-EXISTING antibodies/immune memory against blood group antigens or non-self MHC present in donated organ
What happens in hyperacute rejections?
The pre-existing antibodies immediately begin reacting with the antigen on the organ endothelium
• Complement and coagulation cascades are initiated
• Organ vessels are blocked
• Organ death follows
Rejection occurs in hours
How long does acute rejection take?
10-14 days
What is graft versus host disease (aGvHD)?
Following bone marrow transplantation
• Donor cells perceive the recipient as foreign and try to reject the recipient
What is the name given to the set of criteria for aGvHD to occur? What are these criteria?
Billingham criteria:
• Graft must contain immunologically competent cells
• Host must possess important transplant alloantigens lacking in the donor graft
• The host must be incapable of mounting an effective immunologic reaction against the graft
Describe the three stages of aGvHD pathogenesis
Phase 1
• Tissue injury occurs
• Inflammatory cytokines are released
• MHC and adhesion molecules on host cells upregulated
Phase 2
• Donor T cells are activated by upregulated APC
• Th1 cell differentiation, releasing IL-2 and IFNƔ
• These cytokines expand T-cytotoxic cells and NK cells
Phase 3
• T-cytotoxic and NK cells attack the host’s cells
Why do corneal transplants not require immunosuppression?
Corneas are ‘immune-privelaged sites’
