Transplantation Flashcards
What is rejection?
Rejection = damage done by immune system to a transplanted organ
What are the different kinds of transplant?
- Autologous transplant
- Tissue returning to the same individual after a period outside the body, usually in a frozen state
- Syngeneic transplant
- Transplant between identical twins
- Allogeneic transplant
- Between genetically non-identical members of the same species
- Cadaveric transplantation
- Uses organs from dead donor
- Xenogeneic transplant
- Between two different species
- Carries highest risk of rejection
What can transplants be seperated into?
- Solid organ transplantation
- Stem cell transplantation
What are exampels of solid organs that can be transplanted?
- Heart
- Lung
- Liver
- Pancreas
- Cornea
- Trachea
- Kidney
- Most common
- Skin
- Vascular tissue
What is the most common kind of transplant?
Kidney
What criteria must be met before transplantation?
- Good evidence damage is irreversible
- Alternative treatments not applicable
- Disease must not recur
What is the main risk of transplantation?
Rejection
How can the risk of rejection be minimised?
- Donor and recipient must have compatible ABO
- Recipient mist not have anti-donor human leukocyte antigen (HLA) antibodies
- Donor should be selected with as close as possible HLA match to recipient
- Patient must take immunosuppressive treatment
- Varies depending on organ
What are the different kinds of rejection?
- Hyperacute rejection
- Acute rejection
- Chronic rejection
Describe the timing of hyperacute rejection?
- Within hours
Describe the mechanism of hyperacute rejection?
- Preformed antibodies binding to either ABO blood group or HLA class I antigens on graft
- Antibody binding triggers a type II hypersensitive reaction, and graft destroyed by vascular thrombosis
What hypersensitivity is involved in hyperacute rejection?
Type II
How can hyperacute rejection be prevented?
- Careful ABO and HLA cross-matching
Describe the timing of acute rejection?
- Within few days or weeks of transplantation
Describe the mechanism of acute rejection?
- Type IV (cell-mediated delayed hypersensitive reaction
- Donor dendritic cells stimulate an allogeneic response in local lymph node and T cells proliferate and migrate to donor kidney
What hypersensitivity is acute rejection?
Type IV
What is the main cause of acute rejection?
- HLA incompatibility
- Main cause
Describe the timing of chronic rejection?
- Months or years after transplant
What are the causes of chronic rejection?
- Recurrence of pre-existing autoimmune disease
- Recurrence of acute attacks
Describe the mechanism of chronic rejection?
- Element of allogenic rejection, often mediated by T cells, which can result in repeated acute rejection
What are the different phases of graft rejection and what happens?
- Afferent phase
- Donor MHC molecules on ‘passenger leucocytes’ (dendritic cells) within graft are recognised by recipients CD4+ T cells
- Effector phase
- CD4+ T cells recruit effector cells responsible for the tissue damage of rejection
- Macrophages, CD8+ T cells, NK cells and B cells
- CD4+ T cells recruit effector cells responsible for the tissue damage of rejection
What does tolerance in the context of transplantation mean?
In the context of transplantation, means no response to alloantigen’s present on transplanted tissue but responses to pathogens not affected
How is tolerance achieved in transplantation?
Achieved with immunosuppressant drugs:
- Prevent rejection if given at the time of transplantation
- Once stopped, rejection still takes place
- Lacks specificity of true tolerance and thus also prevents immune response to infectious agents
- Opportunist infections are major limit to use of potent immunosuppressive drugs
What is tissue typing?
Tissue typing = procedure in which tissues of prospective donor and recipient are tested for compatibility
What are the 2 different steps in tissue typing?
- HLA typing
- Typed at the A, B and DR loci
- HLA cross matching
- Information put into registry of donors and compared
- If identify match, further typing occurs
- Matching test done to confirm as typing rarely perfect match
- B cells from donor taken (as expressed class 1 and 2 of HLA), then mixed with serum from recipient (has antibodies), looking for no reaction
What is stem cell transplantation?
Haematopoietic stem cells used to restore myeloid and lymphoid cells
What does SCT stand for?
Stem cell transplantation
What are the different kinds of stem cell transplantation?
- Autologous SCT
- Marrow removed, frozen and reinfused after potent chemotherapy given
- Minimal immunologic risk
- Allogenic SCT
- Much riskier procedure than most solid organ transplants
- Mortality rate of 20% even with well-matched donors
- Only carried out in
- Hematologic malignancy with no alternative treatment
- Cases when myeloid cell production is reduced, such as aplastic anaemic
- Primary immunodeficiency’s such as severe combined immunodeficiency
- Much riskier procedure than most solid organ transplants
When is allogenic SCT carried out?
- Hematologic malignancy with no alternative treatment
- Cases when myeloid cell production is reduced, such as aplastic anaemic
- Primary immunodeficiency’s such as severe combined immunodeficiency
Where are different sources of stem cells?
- Bone marrow
- Aspiration of considerable amount of donor marrow under GA
- Peripheral blood
- Harvested after treating the donor with colony-stimulating factors to increase number of circulating stem cells
- Cord blood
- Contains large numbers of stem cells, which can be frozen before use
- Immature lymphocytes less likely to cause graft versus host disease
- Can only be used for child or small adult
What is done to destroy recipients own stem cells to allow engraftment of donor cells?
Conditioning is done to destroy recipients stem cells and allow engraftment of donor cells, achieved by:
- High dose chemotherapy
- High dose radiotherapy
What is graft versus host disease?
Occurs when donor T cells respond to allogeneic recipient antigens:
- Mismatch in major or minor histocompatibility antigens
How is graft versus host disease prevented?
- All patients given SCT are given immunosuppressive drugs, even if donor and recipient are HLA identical
What does GVHD stand for?
Graft versus host disease
When does acute GVHD become chronic?
>4 weeks after stem cell transplant
What organs are involved in GVHD?
- Acute GVHD (occurs up to 4 weeks after SCT)
- Skin, gut, liver and lungs
- Chronic GVHD
- Skin and liver
Describe the prognosis of GVHD?
- When severe, 70% mortality risk
What are the side effects of cyclosporine?
- Increased risk of infection
- Increased risk of certain cancers
- Nephrotoxic properties
- Diabetes
- Hypertension
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 problems with xenotransplantation?
- Primates assemble different sugar side chains from other species
- Galactose-a1, 3-galactose is sugar present in all cells of most non-primate species
- Immune system recognises this as all human possess antibodies against it following exposure to gut bacteria
- These antibodies bind onto xenotransplanted organs, activating complement and triggering hyperacute rejection
- Complement inhibitors from other species do not inhibit human complement, so xenotransplanted organs activate complement
What are different classes of immunosuppresive drugs?
- Corticosteroids
- At low doses – act on antigen-presenting cells preventing some of early stages of graft rejection
- Higher doses – direct effect on T cells and can treat episodes of rejection
- T-cell signalling blockade
- Drugs – cyclosporine, tacrolimus
- Mechanism – interacts with proteins in the intracellular T-cell signalling cascade
- IL-2 blockade
- Monoclonal antibodies against IL-2 receptor
- Drugs – basiliximab, daclizumab
- Mechanism – completely block IL-2 having potent immune suppression effects
- Indication – only used to treat episodes of acute graft rejection
- Rapamycin
- Administration – orally
- Mechanism – interacts with signalling events downstream of IL-2 receptor
- Indication – less potent than monoclonal antibodies so used to prevent graft rejection
- Monoclonal antibodies against IL-2 receptor
- Antiproliferatives
- Drugs – azathioprine, mycophenolate mofetil and methotrexate
- Mechanism – inhibit DNA production, prevention lymphocyte proliferation
- Side effects – myelotoxicity (bone marrow suppression)
For T cell signalling blockade drugs:
- drug names
- mechanism
For IL-2 blockade drugs:
- names
- mechanism
- indication
For rapamycin:
- administration
- mechanism
- indication
For antiproliferatives:
- names
- mechanism
- side effects
What is myelotoxicity?
Bone marrow suppression
