Transplantation Flashcards
What criteria must be met for a transplant?
- Tissue/organ undergone an Irreversible Pathological Process which either Threatens Patient’s Life or Significantly Hampers QoL
- Alternative treatment is not available
- Disease must not recurre
What are the 4 major types of graft?
Xenograft - From an animal
Allograft - From another person
Isograft - From someone genetically identical
Autograft - From yourself
Define Histocompatibility?
State in which the donor and recipient share the same (or sufficiently similar) alleles of HLA genes that they express the same MHC proteins and so would not attack the graft
Where are HLA alleles found?
on chromosome 6
Each person has 2 sets of alleles and they are co-dominantly expressed
How are HLA alleles inherited
As Haplotypes (meaning 2 half sets, one from each parent)
Hence each person is 1/2 identical to each parent and so has a 1/4 chance of being identical to a sibling
What are the major requirements for tissue typing?
HLA match, particularly:
- HLA-A
- HLA-B
- HLA-DR
And ABO blood group
What do HLA-A & HLA-B code for?
MHC 1
Found on all nucleated cells, present intracellular antigens and recognised by CD8+ T cells
What does HLA-DR code for?
MHC 2
Found on APCs, presents extracellular antigens and recognised by CD4+ T cells
What are privileged sites?
Places with little to no blood flow and so no immunity. They don’t require tissue matching or immunosuppression
E.g. Cornea
What are the major causes of rejection?
- HLA/ABO incompatible
- Pre-formed immunity (sensitized to donor antigen)
- Failed Immunosuppression (incl non-compliance)
- Infections or environmental triggers
How do we categorize rejection?
Immediate
Acute
Chronic
how do you prevent someone rejecting an organ?
ABO matching
Tissue Typing (HLA)
Prophylactic Immunosuppresants
Other than rejection what else can go wrong in a transplant?
Infection Neoplasia Drug SEs Recurrence of disease Surgical/ ethical complications Graft vs host disease
What are the types of immunosuppresants used in organ transplant?
- CCS
- T-cell blockade: cyclosporin and tacrolimus
- IL-2 blockade: monoclonal antibodies and rapamycin
- Antiproliferatives
What’s the difference between graft rejection and Graftvshost disease?
In rejection the host attacks the graft
In GvH, white cells in the donated tissue attack the host’s body
So what is required for GvH disease?
Graft must contain immunocompetent cells
Recipient must have defective immunity (pretty likely since you’re smacking them with immunosuppresants)
HLA mismatch
What can we do to prevent GvH?
Tissue Typing (HLA)
Can do Donor Marrow T cell Depletion
What kind of donors are associated with the longest life, least rejection and best health?
1) Living Donors (Related or unrelated)
2) Living donors altruistic
3) Brain Death Donors (DBD)
4) Cadaveric Death Donors (DCD)
So 4 are the least healthy transplants and 1 the most
what are privileged transplantation sites?
Tissues which do not receive much blood supply and therefore require less mismatching
What are the types of graft rejection
- Hyperacute : within minutes
- Accelerated: 2-5 days
- Acute : 7-21 days
- Chronic: months to years
What are hyper acute graft rejection due to?
Hyperacute:
- Preformed antibodies binding to ABO or HLA antigens on graft.
- Triggers a type 2 hypersensitivity
what is accelerate graft rejection due to?
presence of T-cells which are presensitised to the donor
what is acute graft rejection due to?
newly sensitised T cells to donor
what is chronic rejectoion due to?
Multifactorial
usually related to T cells
Classification of GVHD?
Acute: can last up to 4 weeks post transplant
- affects skin, gut, liver and lungs
Chronic: occurs later and can affect skin and liver
Immunopathology of graft rejection?
1- Afferent phase: donor MHC molecules on “passenger leucocytes” within the graft are recognized by recipients CD4+ T Cells (ALLORECOGNITION)
2- Efferent phase : CD4+ cells recruit effector cells responsible for tissue damage of rejection e.g. macrophages, CD8+ cells, NK cells, B lymphocytes
What are the two mechanisms of graft rejection?
Direct: T cell recognises unprocessed allogenic MHC on graft APC
Indirect: presentation of a processed peptide of allogenic MHC bound to self MHC
Types of stem cell presentation?
Autologous: self stem cells which have been frozen, conditioned and rein fused
Allogenic: much riskier
when are allogenic stem cells preferred?
- Hamatological malignancy
- Aplastic anaemia
- primary immunodeficiency
Sources of stem cells?
- Bone marrow
- Peripheral blood
- Cord blood
How can stem cells be conditioned?
- high dose chemo
- high dose RT
- Destroy recipients stem cells and allow engraftment of donor cells
How does CCS work?
- At low doses they predominantly act on antigen-presenting cells, preventing some of the early stages of graft rejection.
- Higher doses of corticosteroids have direct effects on T cells and are used to treat episodes of rejection.
What are the two types of IL-2 blockade?
1- Monoclonal antibodies against IL-2 receptor :
•used to treat ACUTE episodes of graft rejection
• completely blocks IL-2
•vey potent immunosuppressive drug
•e.g. basiliximab, daclizumab..
2- Rapamycin
•Less potent than monoclonal antibodies and easier to take
•Used to prevet graft rejection
•Blocks pathway further down
Main problem with xenotransplantation?
- Primates assemble different sugar side chains from other species.
- Galactose-α1,3-galactose (gal-α1,3-gal) is a sugar present on the cells of most non-primate species.
- The immune system can recognize gal-α1,3-gal, and all humans possess antibodies against it following exposure to gut bacteria.
- Antibodies against gal-α1,3-gal bind onto xenotransplanted organs, activate complement, and trigger hyperacute rejection.
