Transplantation immunology Flashcards
Graft
Tissue to be transplanted
Autograft
Donor is recipient
Isograft
Donor is genetically identical to recipient
Allograft
Donor is same species as recipient
Xenograft
Donor is of different species
Orthotopic graft
Donor tissue mobilised into natural anatomical location
Heterotopic graft
Donor tissue in unnatural anatomical location
Tranaplantation immunology
Events that occur after allograft or xenograft is performed
Ineligibility of tissue donation
- Active cancer
- HIV/hep C
- Ebola
- CJD
What is a domino transplant?
- CF: heart and lungs from deceased donor to CF pt, heart from CF to another recipient
- Paired donor transplant: could be 3+ pairs
Which grafts provoke immune response?
Allografts and xenografts
Which transplant will be spared of rejection?
Cornea - avascular
ABO blood groups
- Two glycolipid antigens - A and B
- Each person has 2 ABO alleles
- Lacking A or B antigens will have corresponding antibodies in serum
- These are anti-A and anti-B antibodies
- 0 blood will have no antigens - anti-A and anti-B antibodies will be present
Rh blood group
- Found in rhesus monkey
- Alleles of 3 genes code for antigen
- Can be + or -
Where are MHC I found?
Nucleated cells
Where are MHC II found?
Antigen presenting cells - dendrites, macrophages, B-cells
HLA associated with MHC I
A,B,C
HLA associated with MHC II
HLA DR, DB, DQ, DP
When will donor and recipient match?
MHC I and ii
6 antigen matches
Hyperacute rejection
- Mediated by pre-formed antibodied (ABO incompatability)
- ABO line vascular endothelium
- Binding of antibodies mediates immune response
- Graft is inflamed and organ failure occurs
- Graft must be removed
Acute rejection
- Incidence is high for 90 days
- Humoral or cell mediated
- Antibodies not pre-formed
- HLA incompatability
- T cells recognise cells as non-self
Direct recognition
- Recognising intact MHC displayed by donor APC in graft
- T cell recognises structure of intact allogeneic MHC
- Involves CD8+ and CD4+
Indirect recognition
- Donor MHC is processed and presented by recipient APC by class ii MHC molecules
- Donor MHC is handled like foreign antigen
- Involves just CD4+ cells
Acute rejection
- Cytotoxic T cells kill targets
- NK cells trigger apoptosis
- T helper cells (T1 recruit macrophages/CD8 +ve TC, type 2 recruit B cells)
- Mononuclear infiltrate occurs leading to necrosis of arterial walls
- Signs include graft failure and tenderness
- Reversible
Chronic rejection
- Low grade cell mediated immunity
- MHC
- Endovascular inflammation (mediated by T cells, alloantibodies, macrophages, cytokines)
- Smooth muscle hyperplasia - vascular congestion
- Fibrosis
- Allograft vasculopathy
- New graft required
How to reduce rejection chances
- Donor/recipient matching
- Cross matching, ABO matching and HLA matching
- Immunosuppressive therapy
Cross matching
- Test for pre-formed antibodies
- Recipient previously expose to HLAs may be antibodies already present that would increase chances of rejection
- Tested by cross matching - mixed donor blood with recipients serum
- If cross-match is negative, transplant is likely to be successful
Tissue typing
- Before graft, donor and recipient tissue typed for HLA
- HLA must be matched as closely as possible by HLA subtype and type of transplant influence importance - HLA DR very important for renal transplant
- Six antigen match is not always necessary as can use immunosuppressive drugs
Immunosuppression
- Anti-proliferative
- Glucocorticoid
- Calcineurin inhibitor
Anti-proliferative drugs
- Anti-metabolites
- Overlap with chemotherapeutics
- Alternatives include cyclophosphamide (alklyating agent) and methotrexate (dihydrofolate reductase inhibition)
- Azathioprine (pro-drug) and 6-mercaptopurine
- Interfere with purine synthesis - impair DNA/RNA replication
- Reduced cell turnover
- Azathioprine converted to 6-mercaptopurine
Glucocorticoids
- Anti-inflammatory and immunosuppressent]Inhibits phospholipase A2
- Reduced eicosanoid synthesis, cytokine synthesis, adhesion molecules
- Induces endonucleases that mediate apoptosis in white cells
- Paradoxically, neutrophils frequently raised on initiation
Calcineurin inhibitors
- Calcium dependent enzyme
- Intracellular signalling in T cells
- Inhibition produces IL-2
- IL-2 important for cell-mediated immunity
- IL-2 normally increases TH1 and 2 formation
- E.g. tacrolimus
