Transplantation Flashcards
What is a transplant?
The replacement of tissues or organs that have undergone an irreversible pathological process which threatens the patient’s life or to a significant degree considerably hampers their quality of life
What can be transplanted?
- Organs including lungs, kidneys, heart, liver, pancreas and womb
- Tissues including nerve, skin, bones and corneas
What types of transplant/graft are there?
- Xenograft
- Allograft
- Isograft
- Autograft
What is a xenograft?
- From a different species
- MHC, ABO and IgM incompatible
What are unmodified xenografts guaranteed to lead to?
Immediate failure= hyperacute rejection
What is an allograft?
- Transfer between genetically non-identical members of the same species
- Most common graft
What must take place before allografting?
Careful tissue matching including ABO blood group and HLA(A,B,DR)
What is an autograft?
- Transfer of tissue between different sites within the same organism
- Example: skin graft
What is an isograft?
- From a monozygotic twin
- Same HLA match but theoretically could have different antibodies
What is histocompatibility?
Property of having the same or sufficiently similar, alleles of a set of genes on chromosome 6 (HLA)
-These genes co-dominantly expressed meaning every individual expresses each of the inherited alleles, both paternal and maternal.
What are the features of HLA class 1?
- HLA-A, B and C
- Present on all nucleated cells
- CD8/Tc cells recognise
- Present antigen peptides from within the cells (examples viruses)
What are the features of HLA class 2?
- HLA-DR,DP,DQ
- Only present on APCs
- CD4/Th cells recognise
- Present extracellular antigens such as extracellular bacteria
What are privileged sites?
Sites where there is no blood flow so no sensitisation
- No requirement for tissue matching
- No immunosuppression required
What are the advantages of living donors?
- Less rejection
- Quicker
- Last longer
- Healthier
- Easier to manage
What types of deceased donor are there?
- Brain death
- Cardiac death
What types of living donor are there?
- Related or unrelated
- Altruistic
What are the possible complications of transplants?
- Graft rejection
- Graft versus host disease
- Infection (as a result of immunosuppressive therapy or of transfer of infectious agent in graft)
- Neoplasia (lymphoma, skin tumours)
- Drug side effects
- Recurrence of original disease
- Ethical, surgical problems
What is graft rejection?
Transplanted tissue is rejected by the recipient’s immune system, which destroys the transplanted tissue
What are the causes of graft rejection?
- ABO or HLA incompatible
- Pre-formed immunity for previous transplants, transfusion or pregnancies
- Infections such as CMV or EBV and it’s postulated some environmental triggers such as pollution in lung transplant
- Failed immunosuppression, either by side effects, bad luck or non-concordance
What are the 3 phases of rejection?
- Hyperacute
- Acute
- Chronic
When does hyperacute rejection take place?
Can happen in minutes and is often characterised by an organ that won’t perfuse (pink up)
What increases the risk of hyperacute rejection?
- Previous failed transplants
- Pregnancies
- Blood transfusions
What is often the cause of hyperacute rejection?
Often incompatible ABO and/or HLA antibodies
What is the pathophysiology of hyperacute rejection?
Innate immune complement activation damages blood vessels, causing inflammation and thrombosis
When does acute rejections takes place?
Usually occurs within the first 6months and can be a mix of cell and antibody mediated
What is the pathophysiology of acute rejection?
- Cellular infiltration of graft by Tc cells, B cells, NK cells and macrophages causing endothelial inflammation and parenchymal cell damage on a comparatively slower scale
- Host T cells recognise intact allo-MHS molecules on the surface of tissues
- Unlike T and B cells, NK cell are activated by the absence of MHC molecules on the surface of target graft cells
- The recognition is mediated by various NK inhibitory receptor triggered by specific alleles of MHC class I antigens on cell surfaces
What is the commonest cause of graft failure?
Chronic rejection
When does chronic rejection occur?
> 6 months post-transplant
What is the pathophysiology of chronic rejection?
-It is mostly antibody mediated with other innate components leading to myointimal proliferation in arteries
-This leads to strangulation of blood flow over time as cytokines and antibodies cause a chronic inflammatory process that proliferates cell walls to protect themselves and due to turnover.
This in turn blocks off blood vessels more and leads to ischaemia and fibrosis
How is chronic rejection treated?
Corticosteroids
-Usually given IV in 3 pulses as 1st line
Anti-thymocyte globulin
-Given 2nd line in cell mediated rejection. Made of recombinat horse/rabbit T cell antibodies (allergies!)
Plasma exchange
-2nd/3rd line measure with immunoglobulin replacement to remove donor specific antibodies in antibody mediated rejection
How is chronic rejection prevented?
- ABO matching
- Tissue typing (Class I and II HLA)
- Prophylactic immunosuppression
- Humanised or silenced xerografts
What is graft versus host disease?
Immunologically active graft (usually bone marrow) attacks the recipient as if it was a foreign invader
What can be attacked in GVHD?
- Skin
- Gut
- Liver
- Immune cells
What is the triad of requirements for GVHD?
- Immunocompetent cells in graft (common in bone marrow)
- Defective recipient immunity (common in transplants on immunosuppression)
- HLA differences between donor and recipient (critical step which can be prevented but is a challenge
What is the treatment for GVHD?
Only treatments are immunosuppressive and cytotoxic agents
How can GVHD be prevented?
- Careful and very close tissue matching
- Deplete donor marrow of T cells in-vitro prior to grafting
What is the problem with using porcine tissues for transplant?
All humans have naturally acquired IgM class antibody directed against pig antigens and particularly against galactose residues which are present in high density on all porcine cells including endothelial cells
What can possible be done to allow porcine tissues to be used in transplantation?
- Remove the IgM antibody ex-vivo from potential pig organ recipients
- Genetically modified pigs
- Humanised transgeric pigs (chimerics)
What is the cause of hyperacute rejection?
Preformed antibody against donor HLA or ABO antigens
What is the cause of accelerated rejection?
T cells (presence of T cells pre-sensitised to donor antigens)
What is the cause of acute rejection?
T cells that are newly sensitised to donor antigens
What is the cause of chronic rejection?
Multifactorial
What is tacrolimus?
A calcineurin inhibitor
What interleukin is involved in the CD4/APC interaction in rejection?
IL-2
