Different types of rejection and animal models (SGTs) Flashcards
(42 cards)
what is recognised in acute rejection?
- direct recognition of in tact donor HLA (MHC)
- male vs female H-Y antigen - minor histocompatibility antigen polymorphism
what is the effector mechanism of acute rejection?
CD4 Th1 cells, CD8 T cells
what is the pathology of acute rejection?
T cell, NK cell and macrophage infiltration into the graft
- necrosis of tissue
- fibrosis
what is the speed of acute rejection?
7-21 days, depending on the tissue
why does acute rejection occur?
donor MHC incompatibility
how can acute rejection be prevented?
immunosuppression
what is recognised in chronic graft rejection?
- Donor MHC – driven by indirect T cells recognising fragments of donor MHC presented by recipient MHC
- Minor antigen differences
- Damage during chronic rejection leads to epitope spreading = autoimmunity e.g. cardiomyosin autoantibodies in heart transplant
what are the effector mechanisms of chronic rejection?
- Lesions contain T cells and macrophages – T cell response
- Humoral responses – antibody deposition on endothelium
- Complement-fixing antibodies cause damage
- Can sometimes be just antibodies or just T cells alone
- Some antibodies mask MHC from being recognised by T cells = can protect from rejection
what is the pathology of chronic rejection?
- T cell and macrophage infiltration in the blood vessels – perivascular cuff around blood vessels: transplant vasculopathy
- Intima and media endothelial layers have underlying inflammation
- Smooth muscle cells that form the media penetrate through the intima and hyper-proliferate - concentric intimal thickening of vessels
- these cells enter vessel lumen and close it
- This impairs blood flow to the graft organ – hypoxia and collapse of graft
- gradual decrease in graft function
how fast is chronic rejection?
Accounts for most grafts that are rejected after 1 year (can be months)
- If patient stops taking immunosuppression after years – rejection can occur
why does chronic rejection occur?
Donor MHC but why later?
- Insufficient immunosuppression can lead to a response later on
- Donor DCs killed in periphery – specificity of T cells are induced by indirect recognition via recipient DCs entering the graft
how can chronic rejection be prevented?
immunosuppressives
how can alloantigen contribute to chronic rejection?
Incidence increases with acute rejection episodes
Incidence increases with inadequate immunosuppression
Incidence increases with HLA mismatch
Lesions associated with chronic rejection contain immune
cells
Correlates with the presence of antibodies to HLA
and complement deposition on endothelium
what is recognised in hyperacute rejection?
- donor MHC/HLA expressed by donor endothelium
- ABO blood-type incompatibility/mismatch
why do people naturally have antibodies against blood group antigens?
- Enzyme generates A or B or AB or lack of enzymes by default generates O
- If you have A, you naturally generate antibodies to B and vice versa, if you have O, you naturally have anti-A and anti-B
- These antibodies are generated by interactions with microbiome – specifically their glyco-structures
- Forms IgM antibodies as these are against carbohydrates
what are the effector mechanisms in hyperacute rejection?
- Mainly induced by preformed antibodies against donor MHC and ABO
- leads to complement fixation
- No T cell infiltration found in these grafts
what is the pathology of hyperacute rejection?
Complement fixation by antibody sticking to endothelium – leads to inflammation and lysis of endothelium:
- Neutrophil recruitment which cause damage
- Rapid breakdown of intima – leads to oedema – plasma from blood enters graft – causes damage
- Stimulation of endothelial cells to secrete Von Willebrand procoagulant factor
- Results in platelet adhesion and aggregation – intravascular thrombosis, lesion formation and graft loss/necrosis
- Thrombin produced – closes the vessels to the graft
how fast is hyperacute rejection?
Occurs within minutes to hours, sometimes within 48 hours of re-vascularisation
- Preformed antibody ready to bind to target within minutes, leading to complement fixation
why does hyperacute rejection occur?
Prior sensitisation:
- Recurrent/pre-existing anti-donor antibodies against HLA or ABO blood group antigens
- Patient may be sensitised to MHC antigens due to prior transplants, blood transfusions or pregnancies
- Anti-MHC generated sensitisation – tend to be IgG1,3
- In pregnancy: can get sensitised to the MHC of the father – semi-allogeneic foetus in the mother
- ABO incompatibility – transplant across blood groups can cause hyperacute
how can hyperacute rejection be prevented?
By checking for ABO compatibility – screen blood typing and only do a transplant with matched donor and recipient
- transplants are always ABO matched
Tissue typing for MHC e.g. for renal
Induction of immunosuppression provided at time of transplant e.g. plasma cell-depleting antibody, or plasmaphoresis: removal of preformed antibodies
- Memory cells are in the spleen – can undergo splenectomy to remove memory B cells
- IvIG = donor antibody cocktail to inhibit recipient preformed antibodies
- anti-CD20 B cell removal
how can MHC antibodies be tested for to prevent hyperacute rejection?
cross-match techniques between donor graft cells and recipient sera:
- Test for pre-existing donor-specific HLA antibodies using sera
- Screen recipient and donor for MHC: Take donor cells, put recipient antibody on, add complement and see if they kill the donor cells
- Cytolytic functional test of antibody
- Or use beads bound to MHC and see if antibody binds – but doesn’t shown function of antibody
if patients are MHC-mismatched, can a transplant still happen?
MHC matching doesn’t happen for heart because there are so few donors, so accept whatever you get
- sometimes there is no choice – patient may have had sensitisation in the past – but better to risk transplant rejection than not at all
when can transplants across ABO barriers occur?
Can transplant across ABO barriers in infants below age of 4 as they are immunodeficient in adaptive so won’t have preformed antibodies
- This children have poor antibody responses, so won’t recognise ABO difference
what is an example of a transplant across an ABO mismatch?
Hyperplastic left-heart syndrome - the left side of the heart fails to develop correctly in utero
- Kids born with this condition are unable to survive outside ITU
- >50% of hyperplastic left heart infants die while waiting for a heart
- Only option is a heart transplant
- need to match size and ABO
- AB antibodies not generated for first 6 months so
- ABO incompatible graft can be transplanted in neonates
- Presence of ABO incomp. graft may tolerise
- First patient – blood group O – transplanted at 23 days of age with a blood group AB heart
