transplants Flashcards

Question

describe HLA molecules in context of graft rejection \*

Answer 1

donor graft cells shed their own HLA molecules these are taken up by APC and presented on host HLA molecules = activation of T cells towards donor HLA

Answer 2

class 1 (A B C) expressed on all cells - have a chain and B2 microglobin class 2 (DR DQ DP) expressed on APC but can also be upregulated on other cells - have a and b chain both have same peptide binding groove highly polymorphic - different alleles for doffernt types each individual likely has 2 alleles at each locus - one from each parent HLA-A B C DR are highly immunogenic - more likely to ellicit a strong immune response

Answer 3

look at the alleles for recipient and donor for HLA A B and DR see how many out of 6 mismatch more mismatches = more likely to be rejected short hand for numbe rof mismatches is MM the more MM = less well organ will last sibling to sibling - 25% MM, 50% 3MM, 25% 0MM parent to child - 3 or more/6 matched

Answer 4

exposure to foreign HLA = immune reaction to foreign epitopes = immune graft failure and damage - this is rejection

Answer 5

it is the most common cause of graft failure diagnosis is a histological examination of a graft biopsy treatment is immunosuppressive drugs rejection can be classified in 2 ways: * when it occurs after transplant - hyperacute rejection (when give A to B and organ never works), acute rejection (in weeks or months even though on immune suppression, they still mount an immune response) or chronic rejection (slow deterioration of function) * main type of immune response - T cell mediated/Ab mediated

Answer 6

donated cell shed HLA, taken up by APC in node they're presented to T cells t cell activation = immune reaction - immune cells circulate to place where the foreign HLA molecules are the T cells tether, roll and are arrested to endothelium then move by diapedesis through the endothelium they are aided through this by a number of mechanisms - explain why a graft that has had ischemia/infection are more suseptible to rejection because there are secondary signals that enhance T cell arrest and infiltration lymphocytic interstitial infiltration, ruptured tubular bm and tubulitis (immune cells attacking epi cells) are seen in biopsy

Answer 7

graft infiltration by alloreactive CD4+ T cells cytotoxic T cells - release of toxins to kill target (Granzyme B), punch holes in target cells (perforin) and apoptotic cell death (Fas-L) macrophafes - phagocytosis, release of proteolytic enzymes, production of cytokines, production of oxygen radicals and nitrogen radicals

Answer 8

PAS stain - see tubules and interstitium between them - dark cells are immune cells in interstitium and tubules - this is tubulitis can type them to see if they are CD4 or 8 or macrophages

Answer 9

ab against graft HLA and AB ag they arise pre-transplantation (when sensitised - have circulating ab against the HLA because of exposure during pregnancy, when had a lot of blood transfusions, or previous transplant) - have immediate reaction or post-transplant (de novo - after seen the foreign HLA on transplant)

Answer 10

Ig recognise the ag - fix to the surface of cells - recruit complement - activate classical complement pathway = membrane attack complex = punches holes in membrane Ig also recruit inflammatory cells that have Fc receptors on surface that recognise the Fc part of Ig - macrophage can then phagocytose or secrete enzymes = endothelial necrosis and coagulation the inflammatory cells are intravascular

Answer 11

if deteriorating graft function: * kidney transplant = rise in ctreatinine, fluid retention, hypertension, protein leakage in urine * liver transplant = rise in LFTs, coagulopathy * lung transplant = breathlessness, pulmonary infiltrate subclinical - kidney and heart (heart no good tets for rejection so have to do regular biopsies to look for it)

Answer 12

maximise HLA compatibility life-long immunosuppressive drugs - base line immunosuppression

Answer 13

more drugs targeting T cell activation and prolif or B cell activation and prolif and ab production

Answer 14

interaction between APC and TCR and the downstream pathways - the central mechanism of activation (calcineurin inhibitors) costimulation cytokines like IL-2 target cell cycle - the proliferation of cells in response to a cytokine deplete the T cells by causing apoptosis

Answer 15

deplete B cells with anti-CD20 deplete plasma cells - proteosome inhibitor plasma exchange and intravenous Ig = deplete production of plasma cells drugs that target complement activation = anti-C5

Answer 16

pre-transplant induction agent - T cell depletion or cytokine blockade from time of implantation - base line immunosuppression - signal transduction blockade - usually a CNI inhibitor, sometimes a mTOR inhibitor; anti-proliferative agents and corticosteroids if needed - to treat episodes of acute rejection - for T cell mediated steroids and anti-T cell agents, for Ab mediated - IVIG, plasma exchage, anti-CD20 and anti-complement

Answer 17

increased risk of tumours, infectioon and drug toxicity increased risk of conventional infection bacterial, fungal and especially viral opportunistic infections - CMV, BKV, pneumocytis carinii - now can control more have profilactive anti-virals increased suseptibility to any tumour and have some immunosuppressive driven malignancies especially virally driven - skin, post-transplant lymphoproliferative disorder - EBV, karposi sarcoma by HHPV8

Answer 18

owl's eye inclusions in tubular epithelial cells if not treated quickly get graft loss

Answer 19

from live donors - risk making people sick, can you get consent without coercion the definition of death - is brain death enough