Transplantation immunology Flashcards
tissue involved in transplant
graft or transplant
donations
can be organs or tissue
what is rejection
describes the immune response to the graft, this is separate to graft failure
graft failure
occurs due to non-immune reasons
types of graft
based on location or based on donor
types of graft based on location
orthotopic graft
heterotopic graft
orthotopic graft
donor tissue mobilised into natural anatomical location e.g. liver
heterotopic graft
donor tissue mobilised into unnatural anatomical location - e.g. kidney, own ones not removed
types of graft based on donor
autograft
isograft
allograft
xenograft
autograft
donor is the recipient
isograft
donor is genetically identical to recipient
allograft
donor is same species as recipient
xenograft
donor is of different species to recipient
another classification of grafts
living or cadaveric
what conditions cause ineligibility for tissue donation
active cancer
HIV/ hep C
ebola virus
CJD - mad cows disease
what is the most common transplant?
kidney
deceased donors
circulatory deceased or brain deceased
viability of grafts
more viable in brain deceased donors
immunology
isografts and autografts do not provoke an immune reaction but allografts and xenografts do
decellularised transplants don’t carry antigens
avascular transplants are largely spared of rejection
avascular transplant e.g.
cornea, has little blood supply and no lymphatic drainage
decellularised transplant e.g.
biprosthetic valve
what mediates immune reactions to transplants
ABO incompatibility - crucial
HLA incompatibility - important
minor histocompatibility complexes -minor
what are the patterns of rejection?
hyperacute rejection - mins/ hours on operating table
acute reaction - weeks to months
chronic rejection - years
hyperacute rejection
mediated by pre-formed antibodies (ABO)
ABO antibodies line vascular endothelium in addition to RBCs
binding of antibodies mediates immune response to antigen on donor organ
graft becomes inflamed and organ failure
graft must be removed immediately to avoid overwhelming systemic inflammation
organ becomes thrombotic and ischaemic
can be fatal
graft will not survive
acute rejection
cell initiated - T cells humoral or cell mediated response antibodies are not pr-formed due to HLA (human MHC) incompatibility T cells recognise these cells or fragments of antigens as non-self immune response against HLA
cells involved in acute rejection
cytotoxic T cells kill targets
NKs trigger apoptosis
T helper cells recruit other cells
signs may include graft failure and tenderness
what cells due T helper cells recruit?
type 1 = macrophages and cytotoxic cells
type 2 = B cells
chronic rejection
due to long-term low grade cell mediated immunity
may be related to minor histocompatibility complexes
endovascular inflammation
smooth muscle hyperplasia - vascular congestion due to constriction
fibrosis
reduced blood flow
aka allograft vasculopathy
what causes endovascular inflammation?
mediated by T cells
alloantibodies
macrophages
cytokines
how to reduce rejection?
most important is donor/ recipient matching
immunosuppressants
donor/ recipient matching
ABO matching
HLA matching
HLA matching
ABC = MHC 1 - interact with cytotoxic cells D = MHC II = interact with T helper cells
most important HLA matching
HLAs must be matched as closely as possible, but the HLA subtype and type of transplant influence important
different aspects of the immune system are involved in rejection in different organs
HLA DR
very important for renal transplant
rejection in young children
younger than 1 they may be able to receive ABO incompatible grafts due to their immature immune systems with a similar outcome to matched ones
immunosuppressants
usually 3 agents given
what are the 3 immunosuppressant agents?
anti-proliferative
glucocorticoid
calcineurin inhibitor
to target all aspects of immune system
anti-proliferative
overlap with chemotherapeutics
usually anti-metabolites, some are cyclophosphamide and methotrexate
what anti-proliferative drugs are usually used?
azathioprine (pro drug) - converted to 6-mercaptopurine non-enzymatically in tissues
azathioprine
interferes with purine synthesis/ handling
impairs DNA/RNA replication
results in reduced cell turnover
prescribing azathioprine
can be deactivated by thipurine methyltransferase or xanthine oxidase
need to check TPMT levels before prescription as these are variable in level and so person may be unable to break down the drug
contraindication of azathiprine
allopurinol for gout inhibits the enzyme xanthine oxidase which breaks down azathioprine so the drug will accumulate and is life threatening
calcineurin
calcineurin is a calcium dependent enzyme
which is involved in intracellular signalling within T cells
calcineurin inhibitors
inhibits production of IL-2
e.g. tacrolimus
IL-2
important for enhancement of cell mediated immunity
glucocorticoids
anti-inflammatory and immunosuppressant
how do glucocorticoids work?
inhibit phospholipase A2 via lipocortin-1
reduced eicosanoid synthesis (arachidonic acid derivatives)
dampens inflammatory response
reduced cytokine secretion
reduced adhesion molecules
induces endonucleases that mediate apoptosis within white cells
neutrophils are raised
arachidonic acid derivatives
prostaglandins
thromboxanes
prostacyclins
why are neutrophils raised?
increased circulating neutrophils due to loss of adhesion molecules because they removed from cells
what can immunosuppressants not do?
prevent chronic rejection
