Transplantation Flashcards
What are the two barriers of transplantation
Rejection, tissue availability
What is the simplest medical transplant
Blood transfusion
How many genes is the ABO system encoded by, what enzyme does it encode
- ABO system is determined by single gen encoding a glycosylation enzyme that modified cell surface antigens
Humans produce what Ig against blood group carbohydrates you lack
IgM, due to cross-reactivity with bacterial antigens
Define an autograph/autologous graft
Graft from one anatomical site to another of the same individual
Example of an autograph
skin graft
Allograft definition
Transplant from unrelated individual of the same species
Example of allograft
Kidney transplant
Define xenograft
Transplant using tissue from different species
Two types of rejection of allografts
Allografts are initially successful (without immunosuppression), but fail after 10-14 days = acute rejection
With effective immunosuppression, allografts can last month’s/years, but degrade overtime = chronic rejection
Type of rejection of xenografts
Hyperacute rejection
What family of molecules is a major barrier to transplantation
MHC
What revealed a set of linked genes determined a major component of compatibility, MHC
Genetic crosses- mouse model
What primed cell response is against grafts (think of the mouse models with allografts)
Primed T cell response
Allografts put on what type of mice are not rejected and why?
Allografts put onto nude mice (which lack T cells) are not rejected!
MHC are the most what molecules in the human popualtion
MHC are most polymorphic molecules in human population.
MHC is p_______, p______ and the alleles are co-______
MHC is polygenic, polymorphic and alleles are co-dominant.
Up to the 90s there was large effort to improve ____ matching for solid organ transplantation
Up to 90s, big effort to improve MHC matching for solid organ transplantation. Perfect matching isn’t sufficient.
How is donor MHC recognised as an alloantigen: (£)
Direct allorecognition
Indirect allorecognition
Semi-direct (similar to indirect)
How does tissue damage occur in organ transplants
Immune pathways are interconnected.
CD8 cells from direct recognition attack the graft directly,
CD4 cells from indirect recognition help B cells to make anti-graft antibodies against graft
Antibodies bound to graft lead to destruction via complement and via ADCC (macrophage and NK cells) and aid further antigen presentation
CD4 T cells from indirect recognition help macrophage to become activated and damage tissue etc
Local inflammation during surgery will also attract any cells that have been primed to go back to the graft.
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Why are large numbers of T cell eractive to all-MHC
- T cells are positively and negatively selected during development for those whose TCR can bind to self-MHC, but which do not react with self-peptide
- Thymic education, T cells learn self from non-self
- T cells that bind very strongly to MHC are eliminated, autoimmunity.
- However transplanted tissue presents new molecules to cells post-thymic education.
Allo-reactivity requires what complex forming
allo-MHC-peptide
What was the biggest improvement in transplantation
Immunosuppressive drugs which target T cells activation
What antibody leads to rapid hyperacture rejection in xenotransplantation in pigs to humans. Why?
Anti-alpha-Gral antibodies. Pig organs have alpha-Gal epitopes, in humans its an pseudogene
5 ways pigs can be genetically modified to minimise hyperacute rejection
Engineer transgenic pigs to express human complement regulators
Inactivate alpha-1,3GT gene in pig germline
Disrupt endogenous MHC class I and class II expression
Add genes for negative regulators of immunity, clotting and inflammation
Extesntive immunosuppresive drugs
Animal chimaeras
Inject host pluripotent stem cells into animal blastocyte lacking the organ development of the needed organ, the animal then grows the organ to its relative size.
HSC stands for
Haematopioetic stem cell
HSC transplantation steps
Recipient endogenous HSC is destroyed
Donor HSC is infused
In HSC transplants, what is rejection known as
Graft versus host disease (GVHD)
The allo-reaction in HSC trasnplantation can be beneficial in what
beneficial in graft versus leukaemia (GVL) effects.
What is the most common allograft
A fetus, hemi-allograft
How does the mother not reject the fetus in terms of limiting allo-MHC reaction
The foteal-maternal interface (trphoblast) doesn’t express MHC II, low MHC , specialised MHC I class called HLA-G which inhibits NK cells
The placenta is rich in factors that suppress
Suppress effector T cells and promote inhibitory Tregs
Uterine maternal tissue has mechanisms to limit T cell attraction via what
chemokines
