transplantation Flashcards
what are different types of transplant graft
autograft: a transplant or graft from one site of the body to another
isograft: a transplant from one genetically identical individual to another (e.g identical twin)
allograft: from one genetically different individual to another
xenograft: from one species to another
what are antigens that are considered during transplants
HLA (MHC)
ABO (blood antigens)
minor histocompatibility antigens
MICA/MICB
endothelial cell antigens
what are mechanisms of allorecognition
direct pathway: donor antigen presenting cells (APCs that come with donated organ), these then present antigens to host T cells
indirect pathway: recipient APCs are able to recognise donor antigens and present to recipient T cells
semi-direct pathway: donor and recipient APCs merge together and then present donor antigen to recipient T cells
indirect pathway is most common, and is processed as a virus/bacteria
describe genetics of MHC
mice and human MHC is very similar
the MHC is both polygenic (contains many class 1 and 2 genes), highly polymorphic, multiple variants of same gene within the population
MHC contains 4 million base pairs of DNA and more than 200 genes
MHC is co-dominantly expressed inherited as a linked set of alleles known as a haplotype
HLA-heterozygous individuals can therefore express up to 6 class 1 isoforms and 6 or 8 class 2 isoforms that present antigen to T cells (an individual may have 2 functional HLA-DRB genes)
distribution of HLA antigens in the population is not random
within particular racial groups haplotypes found with greater frequency than predicted by random distribution such that these alleles are said to be in linkage disequilibrium
important exons are the A and B from class 1 and DR from class 2, these alleles are linked ( inherited as a line), loci are close so crossover has low frequency so siblings may have HLA that is either 100%, 50% or 0% the same
what is effect of MHC mistmatches during transplantation
HLA-A does not show differences between 0,1 and 2 mismatches in the allele in transplant success
HLA-B does not show differences between 0 and 1 mismatches but 2 is lower significantly
HLA-DR shows significant differences between 0 and 1 and 2 mismatches
in transplantation HLA matches are reported by difference so a sibling with identical HLA is reported as 0-0-0
do people have HLA antibodies?
you are not born with HLA antibodies but they may develop due to: pregnancy blood transfusion prior graft (transplantation) infection vaccination
how are ABO antigens considered in transplantation
ABO antigens are present on most epithelial and endothelial cells
there are naturally occuring antibodies (born with) to non-O, non-self antigens (haemagglutins) thus immune reaction will occur if other antigens given, however these antibodies can be temporarily removed
A2 individuals express lower density of blood group A antigen and can be successful donors into patients with anti-A
rhesus factor (positive/negative; A positive/negative) is not important since it is not expressed on epithelium/endothelium
describe the process of pre transplant monitoring
pre transplant monitoring (screening)
quantitate the amount and anti-HLA specificity of pre-formed antibodies
expressed as PRA (panel reactive antibody)
%of positive donors (donors against which patients serum would react) as a representative of sample population (where you live)
%PRA is an estimate of the likelihood of having a positive XM/DSA
lower PRA is a good thing (increases chance of success), not linear though, small increase in PRA percentage leads to large decrease in chance of success
describe process of a standard CDC assay
this is done by taking a HLA-typed lymphocyte panel from donors, a fluorescent dye is added called C-FDA, the patients serum is then added followed by complement, a reaction against donor antigens causes cell lysis and the fluorescence is removed.
how is PRA calculated
luminex technique; individual solid beads have single HLA antigens on them, patients serum and secondary antibodies are added, if binding occurs a complex is formed with patients serum, the bead and secondary antibodies which is then added to a laser which detects colour profiles created from complex formation
higher values(bars) on antigen testing results mean higher chance of cross matching (lower chance of success)
what is difference between PRA and a cross match
antigen source for PRA is done from multiple antigens of a panel from the population, crossmatch occurs in a single donor
PRA is a screening test, crossmatch is a confirmatory test
the interperationg; PRA is a transplantability estimate, if the crossmatch is positive for class 1 transplantation does not occur
how is immunosupression used before transplant
just before transplant:
high dose corticosteroids; causes lysis of T cells, downregulates transcription of regions of DNA that are steroid responsive such as inflammatory mediators such as IL-1 and IL-2 and IFN-gamma
polyclonal immune globulins/monoclonal antibodies:
use of monoclonals is more common recently
polyclonal antibodies: such as thymoglobulin or ATG(created by innoculating rabbits with human thymocytes), creating anti thymocyte antibodies in the rabbits, these are used as lymphocyte depleting agents
monoclonal antibodies: IL-2 receptor CD25; anti-CD25 antibodies, causes blocking of IL-2 effects
how is immunosupression used after transplantation
maintenance (given regularly after transplant:
calcineurin inhibitors: calcineurin dephosphorylates NFATs, which normally triggers IL-2 after dephosphorylation
anti-metabolites and mTOR inhibitors are also used
how might graft rejection occur
hyperacute (right after transplantation)
acute
chronic
rejection may be cellular (T cells) or antibody mediated
rejection usually characterised by a rise in serum markers of graft function, may be accompanied by graft tenderness and in case of kidney transplant, decrease in urine output
cellular rejection occurs upon recognition of allogenic MHC molecules by recipient T cells and is mediated by T lymphocytes.
antibody mediated rejection is histological evidence of tissue injury in the setting of detectable donor-specific antibodies with evidence of current or recent antibody interaction with vascular endothelium.
examples of antibody interaction with vascular endothelium is deposition of C4d (complement split product).
what are associated risks with transplantation other than rejection
infections are common and may be subtle
increased risk of some cancers with transplantation; skin cancer+ cervical cancer so sun avoidance and increased smear tests are recommended
