Transplant Immunology Flashcards
What are the three types of immunological rejection? [3] xx
Hyperacute: minutes to hours
Acute: one to six weeks
Chronic: months to years
(Defined on basis of time to occurrence)
What are two mechanisms that acute rejection occurs?
Acute rejection can be either via:
Acute Cellular Rejection (ACR)
- Cytotoxic T lymphocyte response
- Macrophage response
OR
Acute Antibody Mediated Response (AMR)
- B lymphocyte response making antibodies (agaisnt MHC Class 1 /2 antigens or ABO blood group antigens)
What does these histopathological slides show?
CD8 Lymphocyte infiltration: even intravascular
Antibody-mediated rejection (AMR):
What are the main antigens targets of antibodies? [3]
Where does this mainly occur? [1]
Antibody targets:
* MHC (Class I & II): HLA antigens:
* ABO antigens
* MHC class I-related chain A (MICA)
Target location: endothelium - targets arteries and capillaries (because these are the cells first meet after transplantation)
What are the histological features of antibody mediated rejection (AMR)?
(Don’t need to know that much)
- Neutrophils (or mononuclear cells) in peritubular capillaries (microvascular inflammation)
- Thrombosis
- Severe arteritis/fibrinoid necrosis of vessels
- Haemorrhage
- Infarction
- C4d deposition
Definitive diagnosis depends on detection of circulating antibodies
With regards to acute rejection of transplants, how would you detect antibody prescence?
Detect antibody presence with complement: C4d
- The antibody-antigen complex activates the compliment system
- This produces C4d molecules (which forms covalent bonds with endothelial cells)
- C4d molecules are stained easily
- This shows that acute rejection has occurred
Staining for C4d is a very good proxy for detecting antibodies
Acute antibody mediated transplatn rejecton:
there is a very good correlation between high [] levels and [] antibodies.
there is a very good correlation between high C4d levels and donor specific antibodies.
What is criteria for diagnosis of acute antibody rejection? [3]
Evidence of acute renal injury on histology (often microvascular inflammation)
Evidence of antibody activity C4d staining in peritubular capillaries
Circulating anti-donor specific antibodies
Hyperacute rejection:
Explain what hyperacute rejection is mediated by? [1]
Hyperacute: mediated by antibodies that have been preactivated:
means that immune response has occurred before the transplant has occurred
Explain three causes of preactivation that causes hyper acute rejection? [3]
Previous transplant: presence of antigen on the transplant that has already been seen on previous transplant. HLA protein common to both transplants but not seen in the recipient
Previous pregnancy: if foetal blood escapes into circulation. Paternal antigens can prime the mothers immune system
Previous blood transfuison: HLA antigen in blood, when transplant occur causes hyperacute immune response
Explain how AMR causes damage in hyperacute rejection
change from anti-coagulant to pro-coagulant state:
- antibodies bind to surface of epithelial cells: become pro-coagulant and clots form
- causes downstream infarction
- causes haem.
Summary of hyperacute rejection:
Within 1 hr you get [] infiltrate of peritubular capillaries
Within 12-24 hrs you get what effects? [2]
Within 1 hr you get neutrophils infiltrate of peritubular capillaries
Within 12-24 hrs you get intravascular coagulation and cortical necrosis
What overriding causes of chronic rejection of transplant? [2]
Failure of graft to work (not true rejection)
OR
True rejection of graft
Why may a graft fail (not true chronic rejection)? [3]
Damage before transplant
Surgical complications
Reoccurrence of orginal disease
(and then also rejection)
How can we prevent hyperacute rejection? [3]
- Use somone who is ABO compatabile (O is universal donor)
-
screen for preformed antibodies:
* Direct cross match: mix donor cells and recipient serum. Look for complement activation (positive is bad)
* Beads with bound HLA: look to see if recipient serum binds to HLA beads
What is HLA and why is it important with transplants?
HLA is responsible for presenting antigens to T cell receptor
The T cell ‘sees’ the antigen sat in the groove of the HLA protein
Therefore some HLA is exposed
The T cell can therefore recognise slightly different HLA molecules from this exposed part: can be seen as non-self and T cell acts like its a pathogen and create antibodies to the HLA
What are the most important HLAs? [3]
HLA A
HLA B
HLA DR
Each have two genes
What is aim when undergoing HLA matching for transplants?
Why can you have potentially 6 HLA mismatches? [3]
Want to find recipient / donor with as few HLA matches as possible:
The chance of graft survival increases with fewer matches
Because have HLA A, HLA B and HLA DR have two genes - have 6 possible mismatches
Why does number of HLA mismatches on first transplant impact second transplant?
If you mismatch someone with a common allele (e.g. DR4), it means that they cant have transplant from same HLA in future - which might limit their options
Explain how can you prevent acute rejection of transplants? [2]
HLA matching (make sure that not positive for match)
Minimising ischaemia-reperfusion injury:
- Ischaemia causes upregulation of adhesion molecules, which increases adhesion of leukocytes when blood is reperfused.
- More leukocytes increases chance of rejection, SO try and limit ischaemia time.
- Cold ischaemia time: 12 hrs
- Warm ishaemia time: 1 hour
How can you prevent chronic transplant rejection? [4]
Choosing best organ
Minimising surgical damage
Minimising acute rejection
Minimising drug-toxicity
How does the relationship between recipient and graft evolve over lifetime of transplant? [2]
Initially: very aggressive because the organ is covered in donor-type APC, which are then replaced with recipient APCs
Get development of active regulation from T cell which dampen down immune response
What are the two pathways of allorecognition?
Direct:
* Recipient T-cells recognise allogenic APC (donor APCs) and cause aggressive imune response to foreign HLA
Indirect:
* The allogenic APCs are replaced with auto-APCs
* Some of the peptides presented by new auto-APCS are derived from shed HLA molecules
* Causes a more gentle immune response
Explain how activation of a helper T cell / CD4 cell occurs [3]
- T helper cell receptor recognising antigen from HLA
- Co-stimulation from another molecule
Both these signals activate nucleus to make IL-2.
IL-2 binds to IL-2 receptor on different T helper cell. [3]
Causes signal at nucleus to make proliferation of T-helper cells
What are the sites of action used for immunosuppressive drugs? [3] and what drugs used?
Calcineurin inhibitors:
* Calcineurin is an enzyme that activates T-cells of the immune system.
* E.g. Cyclosporin and tacrolimus (learn !)
Anti-proliferative drugs:
* (target nucleus at end stage of T cell activation)
* e.g. Azathioprine and Mycophenolic acid
Prevent cytokine (IL-2) gene activation
* Use cortiosteroids
* e.g. Prednisolone
Standard treatment: Calcineurin inhib, steroid and anti-proliferative drugs
