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Module 3 > renal transplantation > Flashcards

renal transplantation Flashcards

1
Q

What is tissue rejection caused by?

A

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

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2
Q

Why is MHC matching not necessary for blood transfusion?

A

RBCs and platelets express small amoutns of MHC-I molecules and no MHC-II so are not usually T cell targets

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3
Q

What is a syngeneic graft?

A

graft between genetically identical animals or people

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4
Q

What happens when a skin graft is grafted between allogeneic individuals ?

A

graft intially survives but is then regected about 10-13 days after grafting–acute rejection

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5
Q

What is a second-set rejection?

A

when a second skin graft from the same donor to the same recipient results in accelerated (second-set) rejection- 6-8 days

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6
Q

What shows that T cells mediate rejection?

A

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

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7
Q

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?

A

1-10%

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8
Q

Why are there so many T cells that recognise nonself MHC?

A

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

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9
Q

Why do HLA-identical siblings still get GvHD?

A

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

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10
Q

Give an example of minor H antigens?

A

Y chromosome specific genes will incur female anti-male responses

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11
Q

What type of immune response does the reaction against minor H antigens resemble?

A

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

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12
Q

What is direct allorecognition?

A

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

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13
Q

How do passenger leukocytes travel to secondary lymphoid organs?

A

in the blood- lymphatic drainage of a sold organ allograft is interrupted by transplantation

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14
Q

what demonstrates that direct allorecognition is important in allorejection?

A

if the grafted tissue to deplted of APCs by treatment with antibodies, rejection occurs only after a much longer time

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15
Q

What is indirect allorecognition?

A

process by which allogeneic proteins are taken up by the recipients APCs and presented to T cells by self MHC

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16
Q

What is hyperacute graft reaction?

A

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

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17
Q

what happens in hyperacute solid graft reaction?

A

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

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18
Q

How can hyperacute graft reaction be avoided?

A

cross-matching: determining whether the recipient has antibodies that react with the WBCs of the donor

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19
Q

What is the problem in xenografts?

A

most people have antibodies that react with a cell-surface carbohydrate antigen of other mammalian species- hyperacute rejection

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20
Q

How has the problem of hyperacute rejection been targeted?

A

by developing transgenic pigs that lack the carbohydrate and that express human complement regulatory proteins

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21
Q

What is the current problem with transplants?

A

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

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22
Q

What is a major component of late failure of vascularised transplanted organs?

A

chronic allograft vasculopathy- especially heart and kidney allografts

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23
Q

What is chronic allograft vaculopathy characterised by?

A

concentric arteriosclerosis of graft blood vessels which leads to hypoperfusion of the graft and its eventual fibrosis and atrophy

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24
Q

what is thought to be the major mechanism by which chronic allograft vasculopathy occurs?

A

recurring, subclinical acute rejection evenst with the development of allospecific antibodies reactive to the vascular endothelium of the graft

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25
Q

What vascular injury do calcineurin inhibits cause?

A

occurs in very small arteries and causes arteriolar hyalinosis and is marked by proteinaceous deposits that narrow the vascular lumen

26
Q

What is chronic rejection assocaited with in livers?

A

loss of bile ducts- vanishing bile duct syndrome

27
Q

How are endomysial antibodies deteced?

A

monkey oesophagus immunofluorescence

28
Q

What are other causes of chronic graft dysfunction in addition to chronic allograft vasculopathy?

A

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

29
Q

What is the opposite of graft rejection?

A

GvHD

30
Q

What is one of the major complications of allogeneic HSC transplantation?

A

GvHD- mature donor T cells recognise reciripient tissues as foreign causing a severe inflammatory disease in multiple tissues

31
Q

How can the presence of alloreactive donor T cells be demonstrated?

A

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

32
Q

How cna GvHD be crucial to the success of HSC tranplantation?

A

responsible for graft vs leukaemia effect

33
Q

What demonstrates the involvement of Tregs in GvHD?

A

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

34
Q

What is thought to contribute to fetomaternal tolerance?

A

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

35
Q

How does the phenomenon of epitope spreading in SLE where anti-DNA antibodies are present progress to anti-histone antibodies occur?

A

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

36
Q

Why do the autoimmune phenomena in APECED take time to develop and only develop in some organs?

A

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

37
Q

What demonstrated that there was immune responses involved in transplantation?

A

twin kidney tranplants worked, skin grafts in mice were rejected faster if repeated

38
Q

What was the patient survival of kidney tranplants in the 1970s?

A

50% at 4 years

39
Q

How was cyclosporin A discovered?

A

dervied from a norwegian soil sample, a drug which suppressed lymphocyte proliferation and Ab production but not cytostatic

40
Q

what was the impact of cyclosporin A?

A

reduced acute rejection and infecitous causes of death but no difference in chronic rejection or CVS causes of death –Schweitzer

41
Q

what increases the sensitivity of cytooxic cross-match?

A

rabbit C’ in microwells

42
Q

what is seen on biopsy with acute cellular rejection?

A

massive infiltration of T cells, macrophages and B cells – wrong MHC

43
Q

What are hte most important HLA matches?

A

DR>B>A

44
Q

What was the result of calcineurin inhibitor free regimens?

A

trial halted due to high rejection rates

45
Q

What are the ways of diagnosing acute cellular rejection?

A

biopsy; urine-lymphocytes; blood-increased TNF

46
Q

What can be used to treat acute cellular rejection?

A

steroids; mAbs e.g anti-CD3 (alemtuzumab) ; IVIg

47
Q

What is the effect of acute cellular rejection n long term graft survival?

A

little effect as long as early treatment and its not recurrent ( probably results in antibody production)

48
Q

How is the diagnosis of antibody mediated rejection?

A

biopsy; sudden oliguria; macrohaematuria

49
Q

What is the treatment for acute antibody mediated rejection?

A

plasma exchange/steroids; anti-thymocyte/lymphocyte globulin

50
Q

How is a diagnosis of chronic vascular rejection diagnosed?

A

biopsy; creeping creatinine- relentless deterioration with eventual graft failure

51
Q

What is seen in the renal artery of patietns with chronic rejection?

A

markdely thickened and fibrotic with interstitial fibrosis and chronic inflammation

52
Q

What suggests that there are other causes of chronic allograft rejection other than antibodies?

A

Not all chronic allograft rejection had C4d staining on IF

53
Q

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?

A

Luminex platform

54
Q

What is seen on histology with chronic rejection?

A

antibody;tubular basement membrane; peritubular capillaritis; GBM double contours

55
Q

What did the transcriptional signatures of rejection suggest about the nature of chronic rejection?

A

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

56
Q

What is the treatment for chronic rejection?

A

anti-thymocyte/lymphocyte globulin; plasma exchange; steroids (rituximab etc hasnt been shown to be effective)

57
Q

What are the potential treatments for chronic ab mediated rejection?

A

IL-6 blockage (tocilizumab); Ig-cleavage; C’ blcokers; proteasome inhibitrs

58
Q

How can chronic ab mediated rejection be prevented?

A

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)

59
Q

what happens when EZH2 is KO in mice?

A

do not form germinal centres

60
Q

How could tolerance to donor organs be induced?

A

CTLA4-Ig plus donor specific transfusion has led to long-term acceptance of MHC mismatched cardiac allografts–Lin

Module 3 (33 decks)

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