Transplantation Flashcards
What is the definition of a transplant and graft?
Transplant - an organ, tissue or group of cells are removed from one person and transplanted into another
Graft - piece of tissue that is transplanted
What are the types of grafts?
Autograft - grafted back on original donor
Isograft - between syngeneic individual (like identical twins)
Allograft - between allogenic individuals like human to human
Xenograft - between xenogeneic individuals like pig to human
What is the risk of rejection/ GCHD in graft types?
Autograft and isograft - no risk
Allograft - risk of GCHD/ rejection
What is the most common allograft?
Blood transfusion
Mismatching can cause haemolysis, intravascular coagulation, chills and nausea
What donor antigens can trigger rejection?
Major histocompatibility antigens (MHC) like HLA in humans
Others - Minor histocompatibility antigens and ABO blood group
How are HLA alleles defined?
By their gene sequence
Class II - provoke CD4 T-cell responses
Class I - gene products are targets for alloreactive CD8 T-cells
Describe variation in HLA
Evolutionary value - need for T-cells to recognise their own individual specificities provides defence against microbial molecular mimicry
Class I and II MHC genes are most polymorphic
Describe the inheritance of HLA
Each child inherits one HLA haplotype from each parent - 4 different combinations are possible in the offspring
25% chance of having HLA identical or zero haplotype matched sibling donor
What are key players in donor antigen presentation/ recognition?
Antigen presenting cells - present antigen on MHC molecules
Recipient T-cells - 10% of all T-cells react with alloantigens
Describe the direct pathway of donor antigen presentation
Large number of recipient alloreactive T-cells recognise allo-MHC on the surface of donor cells
Donor APC and TCR on recipient T cell
Describe the indirect pathway of donor antigen presentation
Smaller number of recipient T-cells recognise peptides derived from allo-MHC presented by self MHC molecules on recipients own antigen presenting cells
Processing donor antigen on APC
What reaction does a graft rejection cause?
Immunological reaction
Shows specificity
Mediated by lymphocytes and antibodies specific for the graft
Recognition - activation - effector
What are the immune responses to an allograft?
Solid organ transplant
Mismatch of MHC and miH
Dialogue between innate and adaptive immunity
What are the types of graft rejection?
Hyper-acute - rejection in minutes
Acute - rejection within several days
Chronic - rejection within months to years
Describe the pathogenesis of hyper-acute rejection
Circulating antibodies specific for antigens on graft endothelial cells
Antibodies present before transplant - most are anti-HLA
Bind to vascular endothelium activating complement and clotting cascade
What is the pathogenesis of acute rejection?
Graft infiltration with cytotoxic T-cells
Release of effector molecules granzyme ad perforin via exocytosis lead to cell death
Type IV delayed type hypersensitivity
Parenchymal cell damage, interstitial inflammation and endothelialitis
What are the risk factors of acute rejection?
Degree of HLA mismatching is important
Describe the pathogenesis of chronic rejection
Mechanisms not fully understood
Can involve lymphocytes, phagocytes, antibody and complement
Chronic CTH, reaction in vessel wall, intimal smooth muscle cell proliferation and vessel occlusion
How can HLA alleles be identified?
Serology and sequencing or typing
Can identify HLA antibodies cross-matching - important in hyper-acute rejection
What is the definition of cross-matching?
A technique used to investigate whether the recipient has previously reacted to HLA molecules that will be presented on donor organ after transplantation
At risk - pregnancy, previous transplants and blood transfusions
What are types of cross-matching techniques?
Complement based
Flow cytometry based
Single antigen bead - beads coated with single HLA molecules
What is used for the final cross-match?
Indirect immunofluorescence
What can be given to limit immunological rejection as organ shortage?
Immunosuppressants
Combination are used to control the rejection response
Over suppression can result in infections, drug side effects and other diseases like cancer
How does ciclosporin work?
Calcineurin inhibitors block IL-2 transcription and inhibit proliferation
Can cause tremor, hypertension, gum hypertrophy and hirsutism
What are the sources of haematopoietic stem cells?
Bone marrow, peripheral blood and umbilical cord
Describe conditioning
Makes space for incoming stem cells
Pre-transplant phase - stem cell collection, processing and storage from donor and patient
Transplant phase - stem cell infusion
Patient undergoes conditioning regime - high dose chemo and possible radiation
What is GVHD?
Graft vs host disease
T-cells in the transplant attack the host tissues
Allograft can give acute/ chronic
What are the clinical features of GVHD?
Early acute and advanced acute GVHD of the skin
Early acute and advanced acute GVHD of the intestine
What is the treatment of GVHD treatment?
High dose steroids
Immunosuppressants
Faecal microbial transplant
Ruxolitinib
Describe CMV disease
Cytomegalovirus
Most commonly affects the lung, GI tract, eye, liver or CNS
CMV pneumonia is most serious complication with 50% mortality
Describe post transplant lymphoproliferative disease (PTLD)
Immunosuppression driven lymphoma
EBV
Management is reduction in immunosuppression and Rituximab
What play a role in chronic rejection?
T lymphocytes
