B22. Transplantation Flashcards
Transplantation
• Transplantation can be done with cells, tissues or organs as a translocation within the body or between individuals (donor and recipient).
• The tissue transplanted is called a graft.
o Autograft - own tissue
o Syngraft, isograft - genetically identical individuals (inbred animals, twins)
o Allograft - different individuals of same species
o Xenograft - different species (e.g. pig liver to hu)
• 2 things before transplantation start o genetic distance btw donor and recipient: PCR e.g.
o immunosuppression: must always be used! Even if it genetically identical! MCH molecules may have small differences due to mutations even if from the same clone.
• In vitro growing - injection of stem cells
• Xenotransplantations are becoming more frequent than hu transplantations - high need for organs and tissues.
• Genetically modified animals expressing hu MHCcan be used. The big problem is that the different species are carrying different organism. Pathogens not harming one species may harm another. Pig vs humans.
• Split technique can be used - use of only one kidney or one lobe of the liver. Also vitro growing of organs.
• Strongly inbred animals are fairly generically homogenic, to many troubles should not be encountered during transplant
• Allografts - from different individuals of the same species. Have a good plan for the transplantation and do a genetic survey - select the best donor. The outcome will depend on the before and after treatment of the animal. 7-10 days are usually the time needed for the first signs of tissue rejection —> follow the rules of the primary immune response.
• Xenograft - diff species are used. heart valves, liver from pig to humans. Heart valves —> MHC complexes are easy to take off and there is not a lot of vessels.
• Pig liver - in case of emergencies some hospitals keep pig livers to filter the toxic materials. It does not last for more than 10-20 minutes, but it is enough for saving the patient and clear the toxins in the blood. This is because of the activation of the complement system by atb.
• Xenotransplants during history was not successful - bone marrow from baboon into a HIV patient made him survive for 12 years, but this is the exception.
• If the immune system doesn’t work anything can be transplanted!
• Everything that is vascularised and is transplanted will meet atb, non vascularised tissues does not have atg! Neither will highly differentiated tissues. Atg are induced by sugar components and will cross react with atb.
Transplantation reactions , 2 main types
• Host vs graft reaction
o immune system of the recipient destroys the graft
o a complete attack will result in destruction of the transplanted tissue
• Graft vs host
o a tissue containing a lot of lymphoid cells may attack the recipient!
o baboon marrow for e.g. will be instantly and continuously activated
o these organs must be immunosuppressed! Immunosuppress the donor! Lymphocytes can also be removed form the organ —> mobile cells that can be rinsed out from the organ, and keep the organ in a maintenance medium.
o not as important as host vs graft
Transplant pre-thoughts
• Check genetic distance and before the transplantation immunosuppression of the recipient (or donor) should be done for several days (if there is time).
• Check for MHC, mHC (minor HC) usually takes to long time and to much money since they are not that important. Any thing can serve as a mHC - they can influence the outcome but the effect can never be as big as MHC. The reaction may be more severe but they cannot reject the organ their own.
• Tc and NK will attack the graft directly
• NK will not find self atg, lower activity than Tc
• Tc will survey the organ and kill it. The transplantation reaction after 7-10 days are due to Tc and atb.
• Th and B cells will also join the killing of the grafts by atb production
• Atg presentation
o direct by graft cell MHC I and II
o indirect by graft components (atg) presented by host MHC
Tissues not rejected
- Cornea and brain have no direct link to lymphoid system
- If inflammation is inhibited there is a good chance the graft will be accepted. If inflammation develop blood vessels will open up and let more atg through the tissues.
- Highly differentiated tissues, no MHC expression or easily removed
- No lymphoid tissues or link to lymphoid system —> livers have a better outcome than kidney transplantation, only limited lymphoid access to the liver
- Sperm, not rejected contains immunosuppressive materials. In the embryo there is a more direct connection to mothers blood stream in rodents and primates.
- The embryo is actually an allograft with 50% difference of genetic material. No MHC expression until implantation, and MHC like proteins on the surface to avoid NK, blocking atb covering the placenta. Fetus also produce local immunosuppressive materials that will not be produced later in life.
Rejection
• Mechanism of rejection: Soluble MHC atg are carried to lymph nodes, activation and chemotaxis of macrophages, NK, T and B cells. Cytotoxic reactions are done by Tc and NK, atb production (ADCC, complement activation) causing tissue damage.
• Hyper acute, xenografts with cross reacting atb. Also allografts if transplantation is repeated (first failed transplantation will immunise the animal and produce atb) and if immune suppression is not proper.
• Acute, after transplantation again on the same animal after a longer time - no circulating atb any more but memory cells will be activated within 2-5 days and the reaction will be much stronger.
• Late acute, Delayed Type hypersensitivity may participate several weeks after transplantation occurred —> Th behave as Tc and destroy the tissues. Not as efficient or toxic, but still can induce apoptosis.
• Chronic, immunosuppression is maintained for a while, but when it starts to decrease the rejection starts.
o Immunosuppression cannot be maintained forever, it is very destructive!
o Check this carefully after transplantation and look for fever and other clinical signs.
o If suppression is maintained for long enough there will be a time when it can be completely stopped.
o High dose atg + suppression = exhaustion of the immune system and the graft will be completely tolerated. Note that this time cannot be determined, trials and clinical signs are different for each patient.
o Vascularisation should be completed. DTH is an important part.
The outcome of a transplantation will depend on: the MHC compatibility, the immune suppression of the patient and the graft preparation (removal of MHC).
MHC compatibility tests
- PCR, answer 1-7d
- Serology, MHC proteins are checked directly with monoclonal ab. Rapid and efficient testing. Reaction takes 2h.
- MLR (mixed lymphocyte reaction), mix blood from recipient and donor and see if activated - bigger and division if activation.
