Transplantation and immunosuppressive drugs Flashcards
What is autologous, syngeneic, allogeneic and xenogeneic transplantation?
In both, donors and recipients are genetically identical, do not usually generate any immunological problems.
Autologous- transplantation of biological material between one part of an organism to another part of the same organism eg skin graft
Syngeneic- transplantation of biological material between a donor to its recipient- different organisms but genetically identical eg identical twins
Allogeneic- Donors and recipients are from the same species but genetically different eg between a brother and a sister
Xenogeneic- Donor and recipient are different species eg between pigs/cows and humans eg porcine or bovine valves used in the transplantation of heart valves
What is the link between major histocompatibility antigens and transplantation tissue compatibility?
Histocompatibility = tissue compatibility
Immune responses to transplant are caused by genetic differences between the donor and the recipient
The most important are differences between the antigens forming the major histocompatibility complex (MHC)
Human transplants largely unsuccessful until identification of human MHC in 1967
In 1968 WHO nomenclature committee designated that human MHC proteins be named HLA (Human Leukocyte Antigen)
What is the importance of epitopes on donor MHC?
B-cell epitopes on donor MHC
T-cell epitopes derived from donor MHC
1000’s of HLA alleles but perhaps only 100’s of epitopes
Next generation sequencing required
What do T cells need to be able to recognise? What is their link to MHC?
T cells need to be able to recognise foreign peptides that are bound to self-MHC
T cells recognise short peptide fragments that are presented to them by major histocompatibility (MHC) proteins
CD8 cells interact with an MHC Class I and the epitope it is expressing
CD4 cells interact with an MHC Class II
What is the difference between MHC Class I and MHC Class II loading?
MHC Class I:
Protein (eg viral protein) is degraded by proteasome into peptides. These peptides are transferred by the endoplasmic reticulum to MHC Class I molecule. This MHC Class I molecule makes its way to the cell surface and can be identified by the TCR of antigen specific T cells
MHC Class II
The antigen is usually internalised by a phagolysosome. Protein is lysed into peptides which are then transferred to MHC Class II molecules, which is then presented on the surface of the cell.
As a summary, what does MHC Class I bind and what is it seen by?
MHC Class I binds fragments of intracellular proteins and it is seen by a T cell receptor on Cytotoxic T cells, with assistance from CD8.
As a summary, what does MHC Class II bind and what is it seen by?
MHC Class II binds fragments of proteins which have been taken up by endocytosis and it is seen by a T cell receptor on helper T cells, with assistance from CD4
How can T cell activation occur directly and indirectly?
In transplants, both the MHC protein and the peptide in its binding groove may be foreign
The Peptide presented by an HLA allele may be derived from an HLA molecule. Both the peptide and the HLA allele may be defined as foreign/non self
known as allo-recognition:
Recipient cell:
Self HLA + self peptide = no T-cell activation
Self HLA + non self peptide = T-cell activation
Donor cell:
Matched HLA + peptide = no T-cell activation
Unmatched HLA + peptide = T-cell activation
If no HLA matches between donor and recipient, survival is very short
What are the 3 types of graft rejection?
Hyperacute rejection
Acute rejection
Chronic rejection
What is hyperacute rejection? What occurs?
Within a few hours of transplant
Most commonly seen for highly vascularised organs (e.g. kidney)
Requires pre-existing antibodies, usually to ABO blood group antigens or MHC-I proteins
(ABO antigens are expressed on endothelial cells of blood vessels)
Antibodies to MHC can arise from pregnancy, blood transfusion or previous transplants
How it occurs:
Antibodies bind to endothelial cells
complement fixation
accumulation of innate immune cells
Endothelial damage, platelets accumulate, thrombi develop
How can antibodies cause damage to transplanted tissue?
Recognition of Fc region leading to :
1.Complement activation
2.Antibody dependent cellular cytotoxicity
(Fc Receptors on NK cells)
3.Phagocytosis
(Fc Receptors on macrophages)
What is acute rejection?
What usually occurs?
Inflammation results in activation of organ’s resident dendritic cells
T cell response develops as a result of MHC mismatch
In transplants, both the MHC protein and the peptide in its binding groove may be foreign
How it occurs:
Inflammation results in activation of organ’s resident dendritic cells
DC migrate to secondary lymphoid tissue where they encounter circulating effector T cells
Macrophages and CTL increase inflammation and destroy transplant
What is chronic rejection?
What takes place when this happens?
Can occur months or years after transplant
Blood vessel walls thickened, lumina narrowed – loss of blood supply
Correlates with presence of antibodies to MHC-I
Chronic rejection results from indirect allorecognition of foreign MHC/HLA
How it occurs?
Donor-derived cells die
Membrane fragments containing donor MHC are taken up by host DC
Donor MHC is processed into peptides which are presented by host MHC
T cell and antibody responses is generated to the peptide derived from processed donor MHC
What is haematopoietic stem cell transfer? (HSCT)
Previously called bone marrow transplant, now renamed as source is often blood
Often autologous
Until 1980 only HLA identical siblings could be used as donors due to the risk of rejection or graft versus host disease
HSCs can find their way to bone marrow after infusion and regenerate there
They can be cryopreserved with little damage
What is graft vs host disease?
When transplanted tissue is immune cells themselves, there is the risk of donor immune cells attacking the host – GVHD
Can be lethal – best approach is prevention
Removing T cells from transplant or suppressing their function reduces GVHD
