L15 Cell and organ transplantation Flashcards
Types of transplantation
Syn - with, together, same
Allo - different, other
Xeno - foreign
Autologous
Transplantation
The grafting of tissue, usually from one individual to another
Autograft (autologous)
To another site on the same individual (eg. after burns)
Isograft (iso/syngeneic)
To a genetically identical individual (homozygous twins)
Allograft(allogeneic)
To a genetically disparate member of the same species
Xenograft (xenogeneic)
To a different species (pig or monkey to human)
Features of renal transplantation(donor may be dead or alive)
- Operation: trauma and ischemia(cold and warm)
- Reperfusion of ischemic organ(reperfusion damage)
- Inflammation/wound healing
- Inflammation response against the graft
What is the warm ischemic phase
- Time from interruption of circulation to the donor organ to the time when organ is flushed with hypothermic preservation solution
What is the cold ischemic phase
- While the organ is preserved in a hypothermic state prior to transplantation into the recipient
Types of graft rejection
Hyperacute rejection - mins/hrs/days
Acute rejection - days - weeks, also later(late acute)
Chronic rejection (weeks) - months, years
Blood groups
Group A - has only the A antigen on red cells (and B antibody in the plasma)
Group B - has only the B antigen on red cells (and A antibody in the plasma)
Group AB - Has both A and B antigens on red cells(but neither A nor B antibody in the plasma)
Group O - Has neither A nor B antigens on red cells (but both A and B antibody are in the plasma)
Which cells express HLA-antigens
- Red blood cells do not express HLA antigens
- All nucleated cells do
How do HLA antibodies cause graft injury
inducing phenotypic changes in the donor vasculature:
- Causing endothelial cell (EC) activation, 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 through binding of C1q, resulting in production of the anaphylatoxins C3a and C5a, which have the potential to directly augment leukocyte recruitment and T cell alloresponses
- Monocytes, neutrophils, and natural killer (NK) cells also express Fc receptors, which can interact with the heavy chain of HLA antibodies bound to donor ECs
- FcyR functions augment leukocyte recruitment and mediate phagocytosis and antibody-dependent cellular cytotoxicity
What causes the microvascular inflammation characteristic of antibody-mediated rejection
- Pleiotropic functions of HLA antibodies on the allograft ECs
What prevents hyperacute rejection
- Matching donor and recipient for HLA and ABO blood group antigens
PCR
High or low resolution, eg. 2 or 4-letter code or even higher resolution
- Not all parts of the HLA-molecule are important. The most important parts are those where they differ from one another. This is where peptides are bound in the binding groove
Cross match
- 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
Effect of polymorphic self proteins
- Polymorphic self proteins that differ in amino acid sequence between individuals give rise to minor H antigen differences between donor and recipient
What is the mechanism via which hyperacute rejection occurs
- Preformed antibodies
What does the TCR recognise
- The TCR recognises 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
Mechanism via which acute rejection occurs
- T-cells
Drugs involved in interfering with T-cell activation
Cyclosporin A, tacrolimus - T-cell inhibition (calcineurinine inhibitor, inhibition of cytokine synthesis: IL-2, IFNg…)
Azathioprine, MMF - Antiproliferative (inhibits clonal expansions)
Chronic graft rejection (eg. kidney) - features
- Short ischaemic time (living [related] donor)
- Long ischaemic time (cadaveric donor)
- Immunogenicity and incidence of chronic rejection
How do corticosteroids affect the immune system
Corticosteroids block NFkB activation and achieve inhibition/reduction of
- Ischaemia/reperfusion injury
- Activation of APC
- Inhibition of cytokine synthesis(acute inflammation)
Triple drug therapy in immunosuppression
- Cyclosporin A, tacrolimus
- Azathiprine, MMF
- Corticosteroids (eg. methyprednisolone) - anti-inflammatory(inhibition of NFkB, cytokine synthesis and action)
Mechanism via which chronic rejection occurs
- Chronic processes, including vascular changes in the graft
Why can immunosuppression be reduced a few months after organ transplantation
- ‘Passenger leukocytes’ such as peptide-dominant binding and MHC-dominant binding cells are present in the early phase
- Strong immunosuppression is required, donor cells provide non-self MHC
- Recipient leukocytes(present all of the time)
- Weaker suppression required when passenger leukocytes are gone
Ligand/receptor interactions and danger signals
Tissue injury - hypoxia
Cytokines - TNF, IL-1…
Microbial products - LPS, LTA, CpG DNA…
- Via TLRs and other PRRs Cytokine R, Ag-presenting cell
- Surgery provides danger signals: trauma, inflammation, ischemia/reperfusion etc
- Warm ischemic time is a significant problem
