Transplantation and Immunosuppressive Drugs Flashcards
What is the definition of transplantation?
➝ The introduction of biological material (organs, tissues, cells) into an organism
What is an autologous transplant?
➝ transplantation of tissue from one part of the organism to another part of the same organism
What is an example of an autologous transplant?
➝ Skin graft
What is a syngeneic transplant?
➝ donor material transplanted into the recipient when the donor and recipient are genetically identical
What is an allogenic transplant?
➝ Donors and recipients are from the same species but genetically different
What is a xenogenic transplant?
➝ donor and recipient are different species
What are immune responses to transplant caused by?
➝ genetic differences between the donor and recipient
What are human MHC proteins called?
➝ human leukocyte antigen
On what chromosome is HLA found?
➝ chromosome 6
How many MHC Class I alleles are there?
➝ 3
➝ A, B, C
How many MHC Class II alleles are there and what structures do they form?
➝ 3
➝ heterodimers of two proteins
Which cells in the body express both MHC class I and II?
➝ White blood cells
What are the MHC Class II alleles?
➝ DRA ➝ DRB ➝ DPA ➝ DPB ➝ DQA ➝ DQB
What is needed to define epitopes on HLA?
➝ next generation sequencing
What do T cells recognise?
➝ short peptide fragments that are presented to them by MHC proteins
What can professional APCs do with external proteins?
➝ internalise them and cross present them on the MHC class I pathway
What does MHC class II bind?
➝ Fragments of proteins which have been taken up by endocytosis
What does MHC Class I bind?
➝ Fragments of intracellular proteins
What is the function of CLIP?
➝ Maintains the shape of the HLA until the peptides are ready to bind
Describe indirect allo-recognition?
➝ The recipient cell has self HLA on its cell if the cell expresses the self peptide as normal cells do there is no immune response
➝ the TCR will be quiescent
➝ When self HLA presents a peptide (eg influenza peptide) an immune response will occur against the influenza
➝ if the recipient has a transplantation and the self HLA can present a peptide from the donor HLA molecule there is indirect allo-recognition
What is indirect allo-recognition?
➝ TCR of recipient detecting non-self peptide on self HLA
Describe direct allo-recognition?
➝ A recipient has transplanted tissue which contain donor immune cells
➝ If they have been perfectly matched the donor HLA is the same as the recipient HLA and there is no reaction
➝ when there is an unmatched donor there is direct allo-recognition
➝ the TCR from the recipients T cells will detect the MHC
➝ even if the peptide isn’t recognised as foreign (because it is from a conserved region) the unmatched HLA activates the T cells
What is direct allo-recognition?
➝ TCR of the recipient reacting to donor HLA molecules
How many MHC loci are usually matched?
➝ 4/6 MHC class II loci
Why are live donors better than dead donors?
➝ Recipients will have a history of disease which results in a degree of inflammation
➝ organs from deceased donors are likely to be inflamed due to ischemia
What are the three types of graft rejection?
➝ Hyperacute rejection
➝ Acute rejection
➝ Chronic rejection
When does hyperacute rejection occur?
➝ within a few hours of transplant
What organs does hyperacute rejection usually occur with?
➝ highly vascularised organs
How does hyperacute rejection occur and what is needed?
➝ requires pre-existing antibodies usually to ABO blood group antigens or MHC I proteins
➝ ABO antigens are expressed on endothelial cells of blood vessels
What are the three ways antibodies to MHC can arise?
➝ Pregnancy
➝blood transfusion
➝ previous transplant
What does recognition of the Fc region lead to?
➝ Complement activation
➝ antibody dependent cellular cytotoxicity (Fc receptors on NK cells)
➝ Phagocytosis (Fc receptors on macrophages)
How do thrombi develop in hyperacute rejction?
➝ Antibodies bind to endothelial cells
➝ Complement fixation
➝ Accumulation of innate immune cells
➝ Endothelial damage, platelets accumulate, thrombi develop
What causes acute rejection?
➝ T cell response develops as a result of MHC mismatch
Describe how transplants are destroyed by acute rejection?
➝ Dendritic cells migrate to secondary lymphoid tissue where they encounter circulating effector T cells
➝ Macrophages and CTL increase inflammation and destroy the transplant
When does chronic rejection occur?
➝ months or years after the transplant
What does chronic rejection result from?
➝ Indirect allorecognition of foreign MHC/HLA
Describe how chronic rejection occurs?
➝ Blood vessel walls thickened, lumina narrowed and loss of blood supply
➝ correlates with the presence of antibodies to MHC-I
➝ Donor derived cells die
➝ membrane fragments containing donor MHC are taken up by host dendritic cells
➝ donor MHC is presented into peptides which are presented by host MHC
➝ T cell response is generated to the peptide derived from the processed donor MHC
What is a HSCT?
➝ haematopoietic stem cell transfer
What is graft vs host disease?
➝ if the transplanted tissue is immune cells there is the risk of donor immune cells attacking the host
What reduces graft vs host disease?
➝ Removing T cells from the transplant or suppressing their function
What is graft vs leukaemia?
➝ Sometimes mismatch and donor leukocytes can be beneficial which removes the original leukemia
What is essential to maintaining a non-autologous transplant?
➝ Immunosuppression
What are the three categories of immunosuppressant?
➝ General immune inhibitors
➝ Cytotoxic (kill proliferating lymphocytes)
➝ inhibit T cell activation
What is an example of general immune inhibitors?
➝ Corticosteroids
What are three examples of cytotoxic drugs used in immunosuppression?
➝ Mycophenolic acid
➝ cyclophosphamide
➝ methotrexate
What are three examples of drugs that inhibit T cell activation?
➝ Cyclosporin
➝ tacrolimus
➝ rapamycin
How does cyclosporin work?
➝ inhibits IL-12 production
How does mycophenolic acid work?
➝ Blocks lymphocyte proliferation through inhibition of DNA synthesis in T and B cells
How does rapamycin work?
➝ Blocks lymphocyte proliferation by inhibiting IL-2 signalling
How does anti IL-2 receptor antibody work?
➝ Inhibits T cell proliferation by blocking IL-2 binding
How does anti CD3 monoclonal antibody work?
➝ depletes T cells by targeting them for destruction
What is an example of a combination immunosuppressive regime?
1) steroids - prednisolone
2) cytotoxic
3) immunosuppressive specific
What is an immediate risk for transplant patients?
➝ more susceptible to infection and malignancy such as CMV
What can immunosuppressive drug toxicity lead to?
➝ organ failure
➝ e.g cyclosporin nephrotoxicity
What is the microbiome involved in?
➝ regulating adaptive immune responses
How can anti-cancer immune responses be improved?
➝ FMT (fecal matter transplant)
