L18 - Immunology of Transplantation Flashcards
Transplantation
Involves the artificial transfer of tissue, cells or organs, from one anatomical site to another to replace lost or failing function
Does rejection follow general immune trends?
Yes, it’s an Immunological Phenomena Showing Specificity and Memory - second wave is accelerated compared to the first set rejection
Transplantation: what ongoing challenges are there?
Managing Organ Rejection:
* Long-term global immune suppression
* Chronic rejection
Organ Supply
* Demand heavily outweighs supply
Types of grafts
Described based on the relationship between donor and recipient
- Autograft - self-graft
- Isograft - from a genetically identical donor
- Allograft - from a donor not genetically identical
- Xenograft - from an animal donor
Autografts and isografts are syngenic/isogenic
Histocompatibility
No immune response (fully tolerant) - Syngeneic grafts
Graft accepted
Histoincompatible
Immune response (against antigenic differences) - Allogeneic/Xenogeneic grafts
Graft rejected
Histocompatible antigens
Major histocompatibility antigens - stronger immune response than minor ones
What is it that is recognised by the immune system to trigger graft rejection?
Gene loci responsible for the most vigorous graft rejection are located in the Major Histocompatibility Complex (MHC)
Gene loci responsible for less vigorous allograft rejection encode minor histocompatibility antigens
Minor HC antigens explain why fully matched MHC grafts may still result in rejection
Major histocompatability antigens
- Strongest response
- Highly polymorphic class I and II MHC molecules
- T cell cross-reactivity
Minor histocompatability antigens
- Weaker response
- Allelic difference in a non-MHC encoded gene generating a peptide not previously tolerised against
- Uptake and presentation of graft derived allopeptide
Allorecognition by T cells:
Direct and Indirect Recognition
Leccy
Types of graft rejection
- Hyperacute minutes
- Acute days to weeks
- Chronic months to years
Hyperacute Rejection: what is it, what is it caused by, and what happens?
Rapid rejection - occurs within minutes to hours
Pre-formed antibodies against the donor formed after sensitising events: pregnancy; blood transfusion; previous transplant
- Antibodies bind to graft blood vessel endothelium and recruit effector damage;
- Complement activation → inflammation → vascular damage (haemorrhage)
- Platelet aggregation & activation of clotting cascade → blockage of blood vessels
Acute Rejection
Sensitisation phase:
Allo-recognition and activation of CD4+ T helper cells
Generation of effector cells (DTH, B cells, CTLs)
Effector phase:
Attack on graft
Characteristic massive infiltration of T cells and macrophages
Chronic Rejection
vSlow progressive loss of graft function (years)
Eventually leads to blockage of vessels
Mechanism not fully understood (vascular & immune features;
cell-mediated and antibody mechanisms potentially involved)
Responds poorly to current immunosuppressive therapy
(half-life of a successful kidney graft remains ~10-15 yrs)
Immune Responses in Transplantation:
Graft versus Host Disease (GVHD)
leccy plus lowkey interesting
Strategies to Avoid/Prevent Graft Rejection
Avoidance (pre-transplant; avoid sensitisation)
* Organ retrieval
* Pre-screening & Matching
Prevention (during & following transplantation; supress/prevent effector responses)
* Immune suppression
Minimise damage to donated organs during procurement
* Consideration of the health of the graft begins immediately a potential donor is identified
* Optimal donor management - physiological optimisation, such as regulating chemical balances of brain-dead donor prior to organ removal
* Organ preservation - optimise surgical removal, perfusion, speed of delivery
Screening & matching:
* HLA typing
* Blood typing
* HLA-specific antibody screening
* Cross-matching (serum from recipient) - a functional assay that tests for anti-donor abs in a patient’s serum based on their ability to bind a sample of donor cells and mediate complement lysis.
Immunosuppression:
* Global immunosuppressive drugs - long-term global immune suppression may lead to increased risk of infections, malignancy, and drug associated toxicities (eg Nephrotoxicity by CsA)
* Specific immunosuppressive drugs - Cortiosteroids:
Prednisone - anti-inflammatory
Anti-mitotic agents:
Azathioprine
Agents targeting IL-2:
Cyclosporin → inhibits IL-2 synthesis
Rapamycin → inhibits IL-2 receptor signalling
Targeting lymphocyte trafficking:
Fingolimod → blocks exit from lymphoid tissue
* Biological agents as immunosuppressive - enable more specific targeting of immune suppression, rATG (rabbit derived anti-thymoglobulin):
Polyclonal induction agent → lymphocyte depletion, plus..
Monoclonal Antibodies (humanised):
Anti-CD52 → depletes lymphocytes
Anti IL2R → blocks IL2 signalling
Engineered CTLA4-Ig (Belatacept) → co-stimulation blockade → energy
- Induction Therapy
Drugs given at high dose before or at the time of the transplant to prevent sensitisation and inhibit initiation of alloresponses
- Maintenance Therapy
Lower dose of drugs to enable continued graft survival
Ideal immunosuppressive treatment
Combinations of drugs (biological and conventional) are optimised to maximise survival, but minimise harmful side effects (such as infections, malignancy and toxicity) by using lower doses of any individual agent
Different donor types and how quickly they can be done
Cadaveric - damage to organ may occur within minutes so extraction must be done quickly
Braindead - can take a few hours for surgery to be completed
Living donor -
leccy
Most ideal method to prevent transplant rejection
The ‘Holy Grail’ of Transplantation is Tolerance
‘Short-term therapy for long-term benefit’
→ re-educate for unresponsiveness to transplant antigens, leaving the remainder of the immune system intact and responsive to other antigens.
