Immunology 5 Transplantation Flashcards
what are the 2 main types of transplantation?
what is the main problem with transplantation?
rejection
what is rejection?
•Rejection refers to damage done by the immune system to a transplanted organ. (hypersensitivity reaction)
what is Autologous transplant?
•Autologous transplant refers to tissue returning to the same individual after a period outside the body, usually in a frozen state. (mainly for stem cells)
what is Syngeneic transplant?
•Syngeneic transplant refers to transplant between identical twins; there is usually no problem with graft rejection. Also called isograft.
what is Allogeneic transplant?
•Allogeneic transplant takes place between genetically nonidentical members of the same species; there is always a risk of rejection. (form another human)
what is Cadaveric transplantation?
•Cadaveric transplantation uses organs from a dead donor.
what is a Xenogeneic transplant?
•Xenogeneic transplant takes place between different species and carries the highest risk of rejection
summary of types of transplantations
Pig to human is the most commonly studied
Solid Organ Transplantation - Transplantation may be an option when what?
solid organs stop functioning
Several criteria must be met before transplantation - what are they?
- There must be good evidence that the damage is irreversible
- That alternative treatments are not applicable
- The disease must not recur
•The main problem with all solid organ transplants is the risk for ________
rejection
In Solid Organ Transplant Rejection:
•The chances of rejection must be minimized: how?
- The donor and recipient must be ABO compatible
- The recipient must not have anti-donor human leukocyte antigen (HLA) antibodies
- The donor should be selected with as close as possible HLA match to the recipient
- The patient must take immunosuppressive treatment (Length of immunosuppression varies between organs)
table showing the characteristic of different organ transplantations:
Cornea not vascularised so not accessible by immune cells so chances of graft rejection are low
Stem cells carry a high risk of rejection
Best results are with the highest matches between the donor and the recipient and that should be of the blood group, HLA at different loci
what is a hyperacute rejection?
- 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 acute rejection?
- Type IV (cell-mediated) delayed hypersensitivity reaction
- 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. (or any other organ)
what is the main cause of acute rejection? and how is it prevented?
- HLA incompatibility is the main cause. Minimising any HLA mismatch of the donor and recipient can reduce acute rejection
- 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 (More mismatches then low amount of surviving grafts and lower success rate)
- Could be antibody mediated rejection.
what is the Immunopathology of graft rejection?
(For acute graft rejection there is different 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
- Not all parts of the graft need to be attacked for rejection to occur
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
Can result form multiple acute attacks but also can happen by recurrence od pre-existing autoimmune disease which may of damaged the original organ in the recipient
what is tolerance?
•A state of unresponsiveness to molecules the immune system has the capacity to recognize and attack
what is tolerance In the context of transplantation?
•In the context of transplantation, this means that there is no response to alloantigens present on the transplanted tissue, but responses to pathogens are not affected
4 outcomes of transplant – 3 rejections and one tolerance
what is the problem with immunosuppresive drugs?
- 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
The problem with immunosuppressive drugs is that they are non-specific. People who get transplants are at higher risk of opportunistic infections which can sometimes be fatal
Now to reduce the risk of organ transplant rejection there should be tissue typing to maximise matching between recipient and donor
what tissue typing is avalible?
- HLA typing (HLA typing is compared to other donors)
- HLA cross matching
what is HLA cross matching?
(Lots of HLA types so cant type for all them)
they get donor B cells, get a blood sample from the donor as they express different classes of HLA
B cells are mixed with serum from the recipient as the serum will have antibodies and in this case if the serum has antibodies that react against the B cells this means there has been a mismatch and the transplantation cant take place
If no immediate reaction then no mismatch and procedure can proceed
table showing how selection of donor and recipient is done in kidney transplantation
B lymphocytes are preferable in the top box
History of good renal function
Screened to check no infection
Once taken form body should be put on ice immediately as longer it is kept from ice, worse the prognosis
Stem cell transplantation:
•Hematopoietic stem cells are used to restore ________ and ________ cells
myeloid
lymphoid
how is autologous SCT done? and what is the risk?
- In autologous SCT, marrow is removed, frozen, and reinfused after potent chemotherapy has been given
- Autologous transplants carry minimal immunologic risk
how is allogenic SCT done? and what is the risk?
- Allogenic SCT 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%
- The additional risks are due to Graft versus host disease (GVHD)
Allogenic SCT are only carried out in what situations?
- Hematologic 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)
whata re the sources of stem cells?
- 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
- Cord blood (umbilical, banks that store it) - contains a large number of stem cells, which can be frozen before use, immature lymphocytes are less likely to cause GVHD
how is Conditioning (of the recipient) done?
- High dose chemotherapy
- High dose radiotherapy
- Destroy the recipient’s stem cells and allows the engraftment of donor cells
(Also by removing existing immune cells reduces potential for rejection by immune cells)
what is Graft versus 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
what are the effects of GVHD?
- 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
Immunosuppressive Drugs:
what is the effects of corticosteroids?
- 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
Immunosuppressive Drugs:
T-Cell Signalling Blockade - what can be used?
Cyclosporine and tacrolimus work by interacting with proteins in the intracellular T-cell signalling cascade
Immunosuppressive Drugs:
Another target for immunosuppressive drugs for organ and stem cell transplantation is IL-2 blockage
IL-2 very important for T cell proliferation
what drugs can block it?
- Monoclonal antibodies against the IL-2 receptor (basiliximab and daclizumab) completely block IL-2 and have potent immunosuppressive effects. Only used to treat episodes of acute graft rejection. (high risk of infection)
- Rapamycin 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
Immunosuppressive Drugs:
what are antiproliferatives?
Azathioprine, mycophenolate mofetil, and methotrexate inhibit DNA production. These drugs prevent lymphocyte proliferation, but they are not specific for T cells and can cause myelotoxicity (bone marrow suppression)
Also drugs that stop the proliferation of T cells
Inhibit DNA production but not specific for just T cells and DNA is not unique to T cells
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
Without _________________ drugs, transplantations wouldn’t work
immunosuppressive
how is the numbers of transplants per annum changing?
Supply doesn’t meet demand
Not always possible to use donor due to mismatches
Xenotransplantation - Solution for shortage of allografts?
what is the 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
Complement inhibitors from other species do not inhibit human _________. As a result of this molecular incompatibility, xenotransplanted organs _______ complement
complement
activate
Transgenic pigs are being developed with reduced gal-α1,3-gal expression to _______ natural antibody binding and with human complement inhibitors to bypass molecular incompatibility
prevent
what are the problems with using pigs for xenotransplantation?
- 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
