Transplantation Flashcards
What are the 5 types of transplant?
Autologous transplant
-tissue returning to the same individual after a period outside the body, usually in a frozen state
Syngeneic transplant/isograft
-transplant between identical twins; there is usually no problem with graft rejection
Allogeneic transplant
-takes place between genetically nonidentical members of the same species; there is always a risk of rejection
Cadaveric transplantation
-uses organs from a dead donor
Xenogeneic transplant
-takes place between different species and carries the highest risk of rejection
What criteria must be met before solid organ transplant?
There must be good evidence that the damage is irreversible
That alternative treatments are not applicable
The disease must not recur
How can changes of solid organ rejection be reduced?
1) The donor and recipient must be ABO compatible
2) The recipient must not have anti-donor human leukocyte antigen (HLA) antibodies
3) The donor should be selected with as close as possible HLA match to the recipient
4) The patient must take immunosuppressive treatment
How can stem cells be donated?
Only live
What is a hyperactive rejection?
TYPE II, due to ABO or HLA mismatch
Within hours of transplantation
Preformed antibodies binding to either ABO blood group or HLA class I antigens on the graft
Antibody binding triggers a type II hypersensitivity reaction, and the graft is destroyed by vascular thrombosis
Hyperacute rejection can be prevented through careful ABO and HLA cross-matching and is now rare
What is an acute rejection?
Type IV (cell-mediated) delayed hypersensitivity reaction, HLA incompatibility is main cause
Takes place within days or weeks of transplantation
Donor dendritic cells stimulate an allogeneic response in a local lymph node and T cells proliferate and migrate into the donor kidney
Shortage of donor kidneys leads to using a partially mismatched kidney
The survival of the kidney is related to the degree of mismatching, especially at the HLA-DR loci
Could be antibody mediated rejection
What are the 2 immunological phases of graft rejection?
Afferent and effector phases
Describe the afferent and effector phases
Afferent phase:
-Donor MHC molecules on ‘passenger leucocytes’ (dendritic cells) within the graft are recognised by the recipient’s CD4+ T cells (allorecognition)
Effector phase:
-CD4+ T cells recruit effector cells responsible for the tissue damage of rejection; macrophages, CD8+ T cells, NK cells and B lymphocytes
What is chronic rejection?
Chronic rejection takes place months or years after transplant
An element of allogeneic reaction is often mediated by T cells, which can result in repeated acute rejection
Chronic rejection may be caused by recurrence of pre-existing autoimmune disease
How may tolerance of graft be aided and what are the issues with this?
Immunosuppressive drugs prevent rejection if given at the time of transplantation, but once the drugs are stopped, rejection still takes place
Immunosuppressive drugs also lack the specificity of true tolerance and thus prevent immune responses to infectious agents
Opportunist infections are a major limit to the use of potent immunosuppressive drugs
How is rejection prevented?
ABO typing
HLA typing
HLA cross-typing
What is HLA cross-typing?
After typing (as a final check) the B cells from the donor blood are mixed with recipient serum to find out if the recipient will produce antibodies against donor cells
Which HLA loci are most important when finding a match?
D
What is stem cell transplantation and what is it used for?
Haematopoietic stem cells are used to restore myeloid and lymphoid cells
When is autologous stem cell transplant carried out?
Marrow is removed, frozen, and reinfused after potent chemotherapy has been given
Autologous transplants carry minimal immunologic risk
How does allogenic stem cell transplantation compare with solid organ transplantation?
It is a much riskier procedure than most solid organ transplants
Even with well-matched donors and in the best of circumstances, the mortality rate can be as high as 20%
When is alleged SCT carried out?
Haematologic malignancy with no alternative treatment options
Cases when myeloid cell production is reduced or notably abnormal, such as in aplastic anaemia
Primary immunodeficiencies such as severe combined immunodeficiency (SCID)
Where are the sources of stem cells in the body?
Bone marrow
-Aspiration of a considerable amount of donor marrow under general aesthetic
Peripheral blood
-Harvested after treating the donor with colony-stimulating factors to increase the numbers of circulating stem cells
Umbilical cord blood
- Contains a large number of stem cells, which can be frozen before use
- Immature lymphocytes are less likely to cause GVHD
How can and a recipient be condition before an SCT and what is the purpose of this?
High dose chemotherapy
High dose radiotherapy
Destroy the recipient’s stem cells and allows the engraftment of donor cells
Do this even in autologous transplantation
What is the cause for high rates of allogenic SCT failure?
Graft vs. host disease
What is graft vs. host disease?
GVHD occurs when donor T cells respond to allogeneic recipient antigens
Mismatches in major or minor histocompatibility antigens
All patients who receive SCT are given immunosuppressive drugs to prevent GVHD, even if the donor and the recipient are HLA identical
Acute GVHD occurs up to 4 weeks after SCT
- Involvement of skin, gut, liver, and lungs is widespread
- When severe, acute GVHD carries a 70% mortality risk
Chronic GVHD occurs later and affects the skin and liver
What are some examples of immunosuppressive drugs?
Corticosteroids
T-cell signalling blockade e.g. cyclosporin
IL-2 blockade e.g. monoclonal antibodies, rapamycin
Anti-proliferatives e.g. azathioprine
How do low and high dose steroids work?
Low doses
-Act on antigen-presenting cells, preventing some of the early stages of graft rejection
Higher doses
-Effects on T cells and are used to treat episodes of rejection
How do T-cell signalling blockade immunosuppressants work?
E.g. Cyclosporine and tacrolimus
Work by interacting with proteins in the intracellular T-cell signalling cascade
How monoclonal antibodies against the IL-2 receptor work?
Completely block IL-2 and have potent immunosuppressive effects
Only used to treat episodes of acute graft rejection
E.g. basiliximab and daclizumab
How does rapamycin work (IL-2 blockade)?
Can be given orally and interacts with signalling events downstream of the IL-2 receptor
Rapamycin is less potent and easier to take than the monoclonal antibodies, so it is used to prevent graft rejection
How do anti-proliferatives work?
Inhibit DNA production
E.g. azathioprine, mycophenolate mofetil, and methotrexate
These drugs prevent lymphocyte proliferation, but they are not specific for T cells and can cause myelotoxicity (bone marrow suppression)
What are the side effects of cyclosporin?
Viral, fungal and bacterial infections Increased risk of getting certain cancers Nephrotoxic properties Diabetes Hypertension
The side effects of cyclosporin are thought to be largely due to its mode of action in inhibiting calcineurin
What are the side effects of rapamycin?
- Raised lipid and cholesterol levels
- Hypertension
- Anaemia
- Diarrhoea
- Rash
- Acne
- Thrombocytopenia
- Decreases in platelets and haemoglobin
What are the issues with xenograft?
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
Complement inhibitors from other species do not inhibit human complement. As a result of this molecular incompatibility, xenotransplanted organs activate complement
How are the issues with xenograft tackled?
Transgenic pigs are being developed with reduced gal-α1,3-gal expression to prevent natural antibody binding and with human complement inhibitors to bypass molecular incompatibility
Pigs are used because they are a similar size to humans and are easy to rear in captivity
Even with amendments, why might xenografts be rejected?
Acute rejection may occur because pig proteins elicit T-cell responses
Even pigs reared in microbe-free conditions are infected with endogenous retroviruses; these have never been known to infect humans, but there is a risk as pig viruses are more likely to infect recipients taking immunosuppressive drugs
