Transplantation Flashcards
Two barriers of transplantation?
- Rejection
- Tissue availability
What is the ABO system?
- One of many blood group antigens
- ABO - determined by a single gene encoding a glycosylation enzyme that modifies cell surface antigens
- Allele A - modifies H into A
- Allele B - modifies H into B
- Allele O - encodes a non-functional enzyme - no modification
What are IgM antibodies?
- Humans produce IgM antibodies against these carbohydrate structures - due to cross reaction with bacterial antigens
- Humans produce IgM against blood group carbohydrate you lack
- e.g., Group A has anti-B antibodies - so can’t be a donor.
(pic of compatibility on laptop)
Antibody compatibility - blood groups
A to B/ B to A = NO
A or B to O = YES
AB to any = YES - have no anti A or B antibodies
O to O only = YES - have anti A and B antibodies
Types of transplantation (3 points)
Autograft - a graft or tissue from one anatomical site to another in the same individual - autologous / syngeneic e.g., skin graft - no problems
Allograft - transplant from unrelated individual of the same species - (homograft) - cells are termed allogeneic - e.g., kidney transplant
Xenograft - transplant using tissue from different species - cells are termed xenogeneic - e.g., use of other animals organs
Types of rejection (3 types)
Acute rejection - Allografts - initially successful - without 10-14 days
Chronic rejection - with effective immunosuppression - allografts can last months/ years but degrade overtime
Hyperacute rejection - xenografts are rejected within hours
What is the major barrier to transplantation?
- MHC -Major histocompatibility complex
- How MHC was discovered
Name a key feature of acute rejection
- Animals given second allograft reject it even quicker
- Is a memory type response - similar to vaccination
- Is the T cells that mediate this rejection - MHC
What are the antigens in the allograft?
- Antigens that differ between members of the same species - alloantigens - generate alloreactive response
- MHC is major source of alloantigens
What provides the greatest source of diversity between donor and recipient? (1 point)
- MHC molecules - as are the most polymorphic molecules in the human population
How is the MHC polygenic, polymorphic and co-dominant?
Polymorphic - for a single gene - express both alleles from mother and father = co-dominant
Polygenic - express 3 different genes - all are expressed
= 6 different MHC class 1 genes
What are minor histocompatibility antigens?
- other genes that can effect rejection
- any polymorphic proteins
What is direct allorecognition?
- A way the donor MHC is recognised as an alloantigen
- E.G., Kidney transplant - immune cells are also transplanted as well as the organ - APCs, DCs - which migrate out of graft and to recipients lymph nodes - where they engage with T cells
- Likely to be a major source of acute rejection
- Greater the MHC mismatch - the faster and more strongly this occurs (more alloantigen is present)
- Donor DCs in graft will eventually die - but rejection persists revealing a second mechanism of rejection - indirect allorecognition
What is indirect allorecognition?
Allogeneic cells are processed directly by recipient APC and presented to recipient T cells
- Means T cells cannot attack graft directly - (different MHC)
- Instead - recepient T helper cells activate recipient macrophage (presenting graft peptides)
- Macrophage causes inflammation and tissue damage - may induce graft antibody responses - alloantibodies
How does the T cell activate macrophage in indirect allorecognition?
- Recipient macrophage ingests donor cell and presents allo-MHC derived peptide on recipient MHC
- T cell is activated by the macrophage - and in return T cell provides signals (IFN-gamma) - which activate the macrophage to undergo respiratory burst
- The activated macrophage damage the donor tissue
How does tissue damage occur to the graft?
4 points
- CD8 cells from direct recognition attack the graft directly
- CD4 cells from indirect recognition help B cells to make anti-graft antibodies against graft
- Antibodies bound to graft - lead to destruction via complement and via ADCC (macrophage and NK cells) - and aid further antigen presentation
- CD4 T cells from indirect recognition help macrophage become activated and damage tissue
Why are large numbers of T cells reactive to allo-MHC?
- T cells are positively and negatively selected during development for those TCR can bind to self-MHC but do not react with self-peptide
- T cells have not undergone thymic education yet for new tissue - but can still react quickly
- Quick activation may be due to Allo-MHC-peptide complex binding efficiently to some recipient TCRs - and therefore triggering T cell activation
- These Allo-MHC peptides are mimicing interactions between TCR and antigen
What is thymic education?
- T cells learning self from non-self
2 ways of improving outcomes of transplantation
- Better MHC matching
- immunosuppressive drugs
target:
- key steps in T cell activation
- Used to deplete grafts of immune cells - Alemtuzumab =CAMPATH1 (worlds first humanized antibody)
What causes hyperacute rejection from xenotransplant?
- Alpha-Gal epitope is present in pigs - but humans have anti- alpha-Gal antibodies
- Means pigs organs are rapidly coated in anti-alpha-Gal antibody - leading to complement -mediated destruction
- Pre-existing immunity to this epitope makes rejection very rapid
How can we minimise hyperacute rejection? (5 points)
- Genetically engineer pigs - to express complement regulators - CD55, CD59 etc
- Inactivate alpha1,3GT in pig germline
- Disrupt endogenous MHC class 1 and class 2 expression
- Add genes for negative regulators of immunity, clotting and inflammation
- Use extensive immunosuppressive drugs/antibodies
What are animal chimaeras?
- Using pluripotent stem cells to generate organs
- E.G., inject pluripotent stem cells into the embryo for rats deficient in pancreas development
- New rats are born with a mouse pancreas - can use cells from this new mouse to transplant into diabetic mouse - and it reverses diabetes
- Still requires immunosuppressives
- Still possibility of rejection
What is haemotopoietic stem cell transplantation (HSC)?
- HSC - immune system is removed to allow repopulation with donor-derived HSC
- For patients with immunodeficiency - e.g., following high dose chemotherapy
- Recipient is allogenic to donor HSC
- Rejection is aloo-rejection- known as graft versus host disease (GVHD) - potentially fatal
- Allo-rejection can be beneficial in leukaemia - to get rid of residual leukaemia cells
How is fetomaternal tolerance achieved?
- Foetal-maternal interface does not express MHC2 - and has low MHC1 and specialised MHC1 called HLA-G - which inhibits NK cells
- This limits allo-MHC reactions
- Placenta is rich in factors that suppress effector T cells and promote inhibitory regulatory T cells
- Uterine tissue also has mechanics to limit T cell attraction via chemokines
What is the role of CD47 mechanism at the foetal-maternal interface?
- CD47 is very highly expressed at interface between mother and foetus
- CD47 has low MHC1 and 2 expression + high expression of CD47 anti-phagocytic signals - SIRPA
- This has been shown to be true in other grafts too
