Flashcards in 15. Introduction to transplantation immunology Deck (26)
the grafting of tissue, usually from one individual to another.
to another site on the same individual (e.g. after burns)
to a genetically identical individual (homozygos twins)
- to a genetically disparate member of the same species
- to a different species (pig o monkey to human)
(donor may be dead or alive)
- Operation: trauma & ischemia (cold and warm)
- Reperfusion of ischemic organ (reperfusion damage)
- Inflammation/would healing
- Immune response against the graft
Warm ischaemic phase vs cold ischaemic phase
warm ischaemic phase: time from interruption of circulation to the donor organ to the time when organ is flushed with hypothermic preservation solution.
cold ischaemic phase: while the organ is preserved in a hypothermic state prior to transplantation into the recipient.
Types of graft rejection
Hyperactue rejection - minutes/hours/days
Acute rejection - days-weeks, possibly later (late acute)
Chronic rejection - can be from weeks to months, years
What is the difference between a blood transfusion and a solid organ graft
Serum contains antibodies against the ABO antigens which will not be present in the recipient
All stromal cells express ABO antigens.
What about HLA-antigens?
Red blood cells do not express HLA antigens (because do not have nuclei). All nucleated cells do. (HLA is human MHC)
How do HLA antibodies cause graft injury?
By inducing phenotypic changes in the donor vasculature which activates endothelial cell (EC) which promotes recruitment of leukocytes and CD4 T cell proliferation in response to alloantigen HLA class II on EC.
Complement-activating antibodies trigger the classical pathway by binding of C1q, resulting in production of anaphylatoxins C3a and C5a, which can directly augment leukocyte recruitment and T cell alloresponses.
FcgammaR binding HLA heavy chains leads to ADCC
Lead to microvascular inflammation characteristic of antibody-mediated rejection.
FcgammaR in graft injuries
Monocytes, neutrophils, and natural killer (NK) cells also express Fc receptors (FcγRs), which can interact with the heavy chain of HLA antibodies bound to donor ECs. FcγR functions augment leukocyte recruitment and mediate phagocytosis and antibody-dependent cellular cytotoxicity.
What can prevent hyperacute rejection?
Matching donor and recipient HLA and AB0 group antigens
Use PCR - high or low resolution (2 or 4 letter code). Don't have to match all of the HLA just at the parts where they differ the most, where peptides bind in the binding groove.
How can you test for HLA antigens?
Incubation of washed donor cells with recipient serum, antibody binding detected by mouse-anti-human Ab stain of recipient cells or cytotoxicity, suitable detection system
e.g. fluorescent conjugated anti-human antibody and luminex system
Minor HLA antigens
Polymorphic self proteins that differ in amino acid sequence between individuals give rise to minor H antigen differences between donor and recipient
Donor T cells can respond to these in association with either donor or host H2 type
Mechanism behind hyperacute rejection
How do TCRs recognise antigens
The TCR recognizes peptide antigen in the ‘context’ of a special presenting molecule, the MHC complex. MHC molecules are found on most cells, however, there are different types. The most important ones are class I and class II MHC.
Whereas class-I MHC is found on all nucleated cells, class II MHC is only found on a subset.
MHC in graft rejection
Reactivity against non-self MHC is high (an estimated 10% of T-cells can recognise non-self MHC) mostly non-self MHC class II
What is the mechanism behind acute rejection?
What levels can T cell activation be blocked at?
Level of receptor/ligand interaction
Cell cycle control
Drug therapy in immunosuppression
T-cell inhibition: Cyclosporin A, Tacrolimus
(Calcineurinine inhibitor, inhibition of cytokine synthesis: IL-2, IFNg ...)
Anti-proliferative: Azathioprine, MMF (inhibits clonal expansions)
Chronic graft rejection complexity
Chronic rejection is a complex process and probably depends to a large extent on the damage done to the graft between removal from the donor and being reperfused in the recipient. Ischemic time, in particular warm ischemic time seems to be a major problem. But minor histocompatibility antigens may also contribute, and other factors, like infection or atherosclerosis. So, it is fair to say that the process is multifactorial and there is no specific therapy to stop it.
Corticosteroids block NFkB activation
And achive inhibition/reduction of
activation of APC
inhibition of cytokine synthesis (acute inflammation)
Immunosuppression can be reduced after a few months why?
‘Passenger leucocytes’ are present in the early phase, sostrong immunosuppression is required.
Donor cells provide non-self MHC
Then after a few months:
Recipient leucocytes (present all of the time). Weaker
suppression required when passenger leukocytes are gone.
Conventional view about self and non-self in transplantation
The immune system differentiates between
‘self‘ and ‘non-self‘
But, is non-self enough to trigger an immune response? Why is an embryo not rejected? Or is it?
Modern view about self and non-self in transplantation
The immune system discriminates between ‘dangerous‘ and ‘not dangerous‘
(while self and non-self are not important).
There are good arguments on both sides.