transplantation Flashcards
graft rejection: summarise the immunological issues in transplantation and their impact on organ allocation and rejection after transplantation (including the main types of graft rejection)
most relevant protein variations in clinical transplantation
ABO blood group, HLA coded on chromosome 6 by MHC (most significant)
location of A and B proteins with carbohydrate chains in ABO blood group
on red blood cells, in endothelial lining of blood vessels in transplanted organ
what antibodies are naturally occuring concerning ABO blood group
anti-AB antibodies
group A: antibodies in plasma and antigens in red blood cell
anti-B antibodies in plasma, A antigen in red blood cell
group B: antibodies in plasma and antigens in red blood cell
anti-A antibodies in plasma, B antigen in red blood cell
group AB: antibodies in plasma and antigens in red blood cell
no antibodies in plasma, A and B antigens in red blood cell
group O: antibodies in plasma and antigens in red blood cell
anti-A and anti-B antibodies in plasma, no antigens in red blood cell
how to overcome ABO-incompatible transplantation due to antibody-mediated rejection
remove antibodies in recipient by plasma exchange (good outcomes even if antibody comes back); used in kidney, heart and liver
what are HLA
cell surface antigens with highly variable portion (polymorphic with lots of alleles for each locus; each individual has most often 2 types for each HLA molecule)
why are HLA highly variable
for defence against infections and neoplasia, as proteins presented to immune cells in context of HLA
what to T cells see with regard to peptide and HLA
peptide in context of HLA framework
describe presentation and response of donor graft antigens in mis-matched HLA transplant
recipient HLA molecule on APC, with donor HLA fragment (transplanted organ) associated with it; recognised by T cells to activate immune system
class I of HLA, and cells expressed on
A,B,C; expressed on all cells
class II of HLA, and cells expressed on
DR, DQ, DP; expressed on APC and upregulated on other cells
MHC class I molecule
a1, a2, a3, B2
MHC class II molecule
a1, a2, B1, B2
human MHC class I isotypes
HLA-: A/B/C/E/F/G
human MHC class II isotypes
HLA-:DM/DO/DP/DQ/DR
most important HLA isotypes which are associated with transplantation due to being highly polymorphic
HLA: -A,-B,-DR (6 possible mismatches between recipient and donor as 2 HLA alleles (1 from each parent) per isotype)
what does minimising HLA differences between donor and recipient achieve
improved transplant outcome
sibling to sibling % chance of mismatch
25% chance 6 mismatches, 50% chance 3 mismatches, 25% chance 0 mismatches
what does exposure to foreign HLA molecules in transplantation result in, and what can this cause
immune reaction to foreign epitopes, causing immune graft damage and failure (rejection - most common cause of graft failure)
how is rejection diagnosed
histological examination of graft biopsy
how to treat organ rejection
immunosuppresive drugs
what cells mediate hyperacute and acute rejection
T cells
what mediates chronic rejection
antibodies
T cell mediated rejection process
donated cells shed HLA antigens -> presented by APC to T cells within local lymph nodes -> T cells activate and mount immune response -> T cells recirculate through blood to reach donor organ (tether, roll, arrest, diapedesis); see interstitial inflammation (not intravascular), ruptured basement membrane and tubulitis (invasion of tubular epithelium)
T cell mediated rejection: what cells infiltrate graft first
alloreactive CD4+ cells
T cell mediated rejection: what 3 things do cytotoxic T cells do
release toxins to kill target, punch holes in target cells (perforin), cause apoptotic cell death (Fas-ligand)
T cell mediated rejection: what 4 things do macrophages, recruited by T cells, do
phagocytosis, release proteolytic enzymes, produce cytokines, produce oxygen and nitrogen radicals
antibody-mediated rejection: what do antibodies target
graft HLA and AB antigen
antibody-mediated rejection: when can antibodies arise
pre-transplantation (sensitised) or post-transplantation (de novo)
antibody-mediated rejection: what do antibodies activate
complement and macrophages (also recruit pro-inflammatory cells and cause coagulation intravascular)
2 methods of monitoring for rejection post-transplant
deteriorating graft function, subclinical (kidney, heart with regular biopsies)
what is measured for deteriorating graft function in kidney transplant
rise in creatinine, fluid retention, hypertension
what is measured for deteriorating graft function in liver transplant
rise in liver function tests, coagulopathy
what is measured for deteriorating graft function in lung transplant
breathlessness, pulmonary infiltrate
what is measured for deteriorating graft function in heart transplant
can’t, so conduct regular biopsies
