renal transplantation Flashcards
What is tissue rejection caused by?
immune responses to alloantigens on the graft which are proteins that vary from individual to individual wtihin a species and are therefore pereived as foreign by the recipient
Why is MHC matching not necessary for blood transfusion?
RBCs and platelets express small amoutns of MHC-I molecules and no MHC-II so are not usually T cell targets
What is a syngeneic graft?
graft between genetically identical animals or people
What happens when a skin graft is grafted between allogeneic individuals ?
graft intially survives but is then regected about 10-13 days after grafting–acute rejection
What is a second-set rejection?
when a second skin graft from the same donor to the same recipient results in accelerated (second-set) rejection- 6-8 days
What shows that T cells mediate rejection?
if transfer T cells from a sensitised donor to a naive recipient this results in second-set rejection- memory-type response; skin grafts into nude mice (no T clels) there is no rejection, which can be restored by adoptive transfer of normal T cells
What do studies suggest about the percentage of T cells in an individual that will respond to stimulation by cells from another, unrelatedm member of hte same species?
1-10%
Why are there so many T cells that recognise nonself MHC?
positive selction- TCRs that interact with one type of MHC are more likely to cross-react with other nonself MHC variants; germline encoded bias of TCR for MHC
Why do HLA-identical siblings still get GvHD?
differences in antigens from non-MHC proteins that also vary between individuals- proteins from the cell presented on MHC, if polymorphic proteins will be different to self— minor histocompatibility (H) antigens
Give an example of minor H antigens?
Y chromosome specific genes will incur female anti-male responses
What type of immune response does the reaction against minor H antigens resemble?
the response to viral infection- against peptides presented in MHC, but since these peptides will be expressed in lots of cells in the graft, results in loss of graft
What is direct allorecognition?
where passenger leukocytes (carried in the organ graft)- APCs traffic to secondary lymphoid tissues and activate host cells that bear the corresponding TCRs against the donor MHC and peptides they are expressing
How do passenger leukocytes travel to secondary lymphoid organs?
in the blood- lymphatic drainage of a sold organ allograft is interrupted by transplantation
what demonstrates that direct allorecognition is important in allorejection?
if the grafted tissue to deplted of APCs by treatment with antibodies, rejection occurs only after a much longer time
What is indirect allorecognition?
process by which allogeneic proteins are taken up by the recipients APCs and presented to T cells by self MHC
What is hyperacute graft reaction?
When there are preexisting alloantibodies against blood group antigens and polymorphic MHC antigens can cause rapid rejection of transplanted organs in a copmlement-dependent reaction that occurs within minutes of transplantation
what happens in hyperacute solid graft reaction?
antibodies react with antigens on the vascular endothelial cells of the graft and initiate the complement and blood clotting casacdes resulting in vessel blockage causing its rapid destruction
How can hyperacute graft reaction be avoided?
cross-matching: determining whether the recipient has antibodies that react with the WBCs of the donor
What is the problem in xenografts?
most people have antibodies that react with a cell-surface carbohydrate antigen of other mammalian species- hyperacute rejection
How has the problem of hyperacute rejection been targeted?
by developing transgenic pigs that lack the carbohydrate and that express human complement regulatory proteins
What is the current problem with transplants?
allow 1 year survival of grafts is now 90%, there has been little improvement in long term graft survival- remains about 8 years: chronic rejection
What is a major component of late failure of vascularised transplanted organs?
chronic allograft vasculopathy- especially heart and kidney allografts
What is chronic allograft vaculopathy characterised by?
concentric arteriosclerosis of graft blood vessels which leads to hypoperfusion of the graft and its eventual fibrosis and atrophy
what is thought to be the major mechanism by which chronic allograft vasculopathy occurs?
recurring, subclinical acute rejection evenst with the development of allospecific antibodies reactive to the vascular endothelium of the graft
What vascular injury do calcineurin inhibits cause?
occurs in very small arteries and causes arteriolar hyalinosis and is marked by proteinaceous deposits that narrow the vascular lumen
What is chronic rejection assocaited with in livers?
loss of bile ducts- vanishing bile duct syndrome
How are endomysial antibodies deteced?
monkey oesophagus immunofluorescence
What are other causes of chronic graft dysfunction in addition to chronic allograft vasculopathy?
ischaemia-reperfusion injury (transplanted organ has period of poor perfusion before transplantation); viral infections - immunosuppression and reuccurence of hte same disease in allograft as destroyed the original organ
What is the opposite of graft rejection?
GvHD
What is one of the major complications of allogeneic HSC transplantation?
GvHD- mature donor T cells recognise reciripient tissues as foreign causing a severe inflammatory disease in multiple tissues
How can the presence of alloreactive donor T cells be demonstrated?
mixed lymphocyte reaction when lympohcytes from a potential donor are mixed with irradiated lymphocytes from the recipients- if the donor T cells recognise alloantigens will proliferate or kill
How cna GvHD be crucial to the success of HSC tranplantation?
responsible for graft vs leukaemia effect
What demonstrates the involvement of Tregs in GvHD?
depletion of Tregs in either the recipient or HSC graft before transplantation accelerated the onset of GVHD and death ; supplementing the graft with Tregs delays or prevents GVHD; treatment with lose dose IL-2 which preferentially expands Tregs helps prevent GVHD
What is thought to contribute to fetomaternal tolerance?
outer layer of the placenta- trophoblast doesn’t express MHC-II and small numbers of MHC-I, expresses HLA-G to inihibt NK cell killing; high expression of IDO; secretion of IL-10 and TGFb; increased Tregs in pregnancy
How does the phenomenon of epitope spreading in SLE where anti-DNA antibodies are present progress to anti-histone antibodies occur?
autoreactive B cells specific for DNA pick up DNA:histone complexes (chromatin) and present histone-derived peptides on MHC molecules and recruit histone-specific autoreactive T cells, whihc help original DNA B cell but also other B cells specific for histone protein
Why do the autoimmune phenomena in APECED take time to develop and only develop in some organs?
the delayed and varied disease onset of APECED reflects the importance of peripheral tolerance which is able to slow or prevent AI attack of endocrine organs in some cases- sporaic nature reflects the intersection of the genetics of AI disease with the breakdown of natural tolerance mechanisms and environmental triggers
What demonstrated that there was immune responses involved in transplantation?
twin kidney tranplants worked, skin grafts in mice were rejected faster if repeated
What was the patient survival of kidney tranplants in the 1970s?
50% at 4 years
How was cyclosporin A discovered?
dervied from a norwegian soil sample, a drug which suppressed lymphocyte proliferation and Ab production but not cytostatic
what was the impact of cyclosporin A?
reduced acute rejection and infecitous causes of death but no difference in chronic rejection or CVS causes of death –Schweitzer
what increases the sensitivity of cytooxic cross-match?
rabbit C’ in microwells
what is seen on biopsy with acute cellular rejection?
massive infiltration of T cells, macrophages and B cells – wrong MHC
What are hte most important HLA matches?
DR>B>A
What was the result of calcineurin inhibitor free regimens?
trial halted due to high rejection rates
What are the ways of diagnosing acute cellular rejection?
biopsy; urine-lymphocytes; blood-increased TNF
What can be used to treat acute cellular rejection?
steroids; mAbs e.g anti-CD3 (alemtuzumab) ; IVIg
What is the effect of acute cellular rejection n long term graft survival?
little effect as long as early treatment and its not recurrent ( probably results in antibody production)
How is the diagnosis of antibody mediated rejection?
biopsy; sudden oliguria; macrohaematuria
What is the treatment for acute antibody mediated rejection?
plasma exchange/steroids; anti-thymocyte/lymphocyte globulin
How is a diagnosis of chronic vascular rejection diagnosed?
biopsy; creeping creatinine- relentless deterioration with eventual graft failure
What is seen in the renal artery of patietns with chronic rejection?
markdely thickened and fibrotic with interstitial fibrosis and chronic inflammation
What suggests that there are other causes of chronic allograft rejection other than antibodies?
Not all chronic allograft rejection had C4d staining on IF
What can be used to detect HLA-Ab on a large scale and improved the ability to detect de novo allo-Ab production prior to graft failure?
Luminex platform
What is seen on histology with chronic rejection?
antibody;tubular basement membrane; peritubular capillaritis; GBM double contours
What did the transcriptional signatures of rejection suggest about the nature of chronic rejection?
most late graft loss has a strong antibody mediated rejection signal (very characteristic genes are transcribed when antibody sticks to the kidney); C4d negative AbMR is possible
What is the treatment for chronic rejection?
anti-thymocyte/lymphocyte globulin; plasma exchange; steroids (rituximab etc hasnt been shown to be effective)
What are the potential treatments for chronic ab mediated rejection?
IL-6 blockage (tocilizumab); Ig-cleavage; C’ blcokers; proteasome inhibitrs
How can chronic ab mediated rejection be prevented?
only do well matched transplants - especially DR; belatacept- maybe? - soluble CTLA4 (inhibits costimulation); inhibition of EZH2 has ameliorated T cell and Ab rejection in rats (tazemetostat)
what happens when EZH2 is KO in mice?
do not form germinal centres
How could tolerance to donor organs be induced?
CTLA4-Ig plus donor specific transfusion has led to long-term acceptance of MHC mismatched cardiac allografts–Lin
