Immunology: Transplantation Flashcards
What methods can be used to reduce risk of rejection and graft-versus-host disease?
- Immunosuppressive drugs
- Tissue-typing technology
Define the term ‘autologous transplant’
Autologous transplant refers to tissue returning to the same individual after a period outside the body, usually in a frozen state.
Define the term ‘allogeneic transplant’
Allogeneic transplant takes place between genetically nonidentical members of the same species; there is always a risk of rejection.
How can the chances of rejection be minimised? (4)
- 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.
Why is immunosupression not required for corneal transplant?
The cornea does not become vascularised
Rejection can be subdivided into acute and hyperacute rejection.
What is hyper-acute rejection?
- This occurs within hours of transplantation
- Pre-formed antibodies binding to either ABO blood group or HLA class 1 antigens on the graft
- Antibody binding triggers a type 2 hypersensitivity reaction and the graft is destroyed yb vascular thrombosis
- However, hyperacute rejection can be prevented through careful ABO and HLA cross-matching and is now rare.
Rejection can be subdivided into acute and hyperacute rejection.
What is acute rejection?
- This occurs days or weeks after transplantation and is the delayed type 4 hypersensitivity reaction
- HLA incompatibility is the main cause. Minimising any HLA mismatch of the donor and recipient can reduce acute rejection but this is an issue with organ donor shortages
Describe the pathogenesis of graft rejection
There are 2 key phases: afferent phase and effector phase.
Afferent:
- Donor MHC molecules on dendritic cells (antigen presenting cells) within the graft are recognised by the recipients CD4+ T-cells (helper cells) - allorecognition
Effector:
- CD4+ T-cells recruit effector cells responsible for the tissue damage of rejection such as macrophages, CD8+ T cells (killer cells), NK cells and B cells
Not all parts of the graft need to be attacked for rejection to occur.
What is chronic rejection?
This takes place months or years after a 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.
What is tissue typing?
Tissue typing is a procedure in which the tissues of a prospective donor and recipient are tested for compatibility prior to transplantation.
2 ways of doing this are:
- HLA typing
- HLA cross-matching
Sources of stem cells (3)
Bone marrow
Peripheral blood - harvested after treating the donor with colony-stimulating factors to increase the numbers of circulating stem cells.
Umbilical cord blood - contains large number of stem cells and also immature lymphocytes which are less likely to cause GVHD
What is conditioning in the context of transplantation?
- The treatments used to prepare a patient for stem cell transplantation.
- A conditioning regimen may include high dose chemotherapy +/- high dose radiotherapy.
- The aim is to destroy the recipient’s own stem cells/remaining cancer cells and to weaken their immune system to help keep the body from rejecting the donated cells after transplant
What is GVHD?
- 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.
Which immunosuppressive drugs are commonly used before transplant?
Corticosteroids:
- Low dose - acts predominantly on antigen-presenting cells, preventing some of the early stages of graft rejection
- Higher dose - have direct effects on T cells and are used to treat episodes of rejection
T-cell signalling blockade drugs such as cyclosporine and tacrolimus - work by interacting with proteins in the intracellular T-cell signalling cascade
IL-2 blockade drugs such as monoclonal antibodies against the IL-2 receptor (basiliximab) or Rapamycin
Antiproliferatives - azathioprine, methotrexate etc - inhibit DNA production so prevent lymphocyte proliferation (part of the response to the antigen). These are not specific for T cells and can cause myelotoxicity (bone marrow suppression)
Side effects of cyclosporin
- Infections
- Increased risk of certain cancers
- Nephrotoxicity
- DM
