L10 - Transplantation Flashcards
What are the 2 important barriers against transplants?
Rejection
tissue availability (shortage)
What is the most simple transplant used in clinical practice?
blood transfusion - ABO system
What does allele A of the blood do?
modifies H into A
What does allele B of the blood do?
modifies H into B
What does Allele O of the blood do?
NON-FUNCTIONAL enzyme
What do humans produce IgM against blood of?
IgM against blood group carbohydrate YOU LACK!
What is an autograft?
graft of tissue from one site to another - SAME INDIVIDUAL
What is an allograft?
transplant from unrelated individual of same species
What is a Xenograft?
transplant using tissue of different species
What is acute rejection?
initial success
NO immunosuppression
fail after 10-14 days
What is chronic rejection?
effective immunosuppression
last months/years
degraded
What is hyperacute rejection?
Xenographs
rejected within HOURS
What molecule is a major barrier to transplantation?
MHC
Why do animals given a 2nd allograft reject it quicker than 1st?
primed rejection
memory-type response
What is acute rejection mediated by?
MHC and T cells
Are Allografts put onto nude mice, lacking T cells, rejected?
NO
What are alloantigens?
antigens that differ between members of same species
What are the most polymorphic proteins in the human pop?
MHC - diversity between donor and recip
What is polymorphism for MHC?
for single gene
e.g. allele from father and mother - codominant
LOOK AT SLIDES IF CONFUSED
What is polygeny for MHC?
for (3) different genes
COMBINED WITH 2 ALLELES FROM POLYMORPHISM = 6 DIFF MHC CLASS I
LOOK AT SLIDES
What is the other loci that contributes to graft rejection?
Minor Histocompatibility antigens
Y-chromosome encoded, any polymorphic protein
How was the other loci than MHC found?
mice with identical MHC but different strains had a longer rejection
What are the 2 main pathways for how donor MHC is recognised as an alloantigen?
DIRECT ALLORECOGNITION - APCs, T-cells,
INDIRECT ALLORECOGNITION - T-helper cells activate macrophages
What is the 3rd mechanism of allorecognition?
Semi-direct - similar to indirect
transfer of donor MHC to recipient APC
What occurs during direct allorecognition?
APC migrate out of graft into lymph nodes
engage with T-cells
TCR recognises allo-MHC/peptide
host effector T-cells attack graft
donor DC die
What is another way to get rejection of graft?
if you deplete donor DC from the graft
What occurs during indirect allorecognition?
Allogenic molecules processed by recipient DCs
presented to T cells
T-helper cells activate macrophage (presenting graft peptides)
inflammation, tissue damage - induce ALLOANTIBODIES
What signals to T-cells provide to macrophages?
IFN-y
respiratory burst
cytokine production
How do CD8 cells cause tissue damage?
attack graft directly
How do CD4 cells cause tissue damage?
help B-cells make anti-graft antibodies against graft
How do antibodies bound to the graft lead to destruction?
via complement
via ADCC
= antigen presentation
What is thymic education?
T-cells learn self from non-self
How can Allo-MHC-peptide complex bind efficiently to some TCRs?
similar net contacts between TCR and MHC-peptide
activation
What are the initial and current focuses for transplantation?
initial - MHC matching, HLA-typing
current: immunosuppressive drugs
What do immunosuppressive drugs target?
T-cell activation steps
deplete grafts of immune cells
Downside of immunosuppressive drugs?
ALL transplants will still have some degree of chronic rejection
susceptible to infection
What is the ‘future’ of transplantation?
xenotransplantation
What are immunological problems with pig xenotransplantation
Hyperacute rejection
different carb structures
a-Gal epitope added via UDP–Gal : a1,3GT
PSEUDOGENE IN HUMANS
anti-a-Gal antibodies
pig organs rapidly coated = complement-mediated destruction
Why do humans produce anti-a-Gal antibodies?
antigen carried by gut bacteria
can pigs be gen mod to minimise hyperacute rejection?
try to express human complement regulators
inactivate a1,3GT
disrupt endogenous MHC I/II expression
add genes for negative regulators of immunity
extensive immunosuppressants
What is another aspect to consider when using pig organs?
has to function correctly too
genome engineering tools - CRISPR-Cas9
What is an animal chimera?
single organisms composed of two or more different populations of genetically distinct cells
How can a diabetic mouse be treated (animal chimera)?
mouse stem cells into rat embryo
mouse pancreas inside rat
pancreatic islets transferred to mouse - also includes rat tissue = immunosuppressants required
after a while - mouse-derived vessels go through pancreas
What are issues with xenotransplantation beyond immunological rejection?
transfer infectious agents from donor
ethical considerations
What is HSC transplantation?
recipient immune system remove to allow repopulation with donor-derived HSC
recipient is allogenic to donor HSC and donor-derived immune system
What disease occurs from HSC transplantation?
graft v host disease (GVHD)
how can the allo-reaction in HSC transplantation be beneficial?
Graft v leukemia (GVL)
What is the most common allograft?
foetus is half mother, half father
50% genes have MHC from father
HEMI-ALLOGRAFT
REPEATED exposure if have more children
How is fetomaternal tolerance ahcieved?
does NOT express MHC II
very low MHC I
specialised MHC I = HLA-G : INHIBITS NK CELLS
factors suppress effector T-cells
promote inhibtory Treg
uterine tissue - chemokine limit T-cell attraction
How can fetomaternal tolerance help transplants?
understand tolerance mechanisms - apply to solid organs
