Transplantation Flashcards
What is an allograft?
The transplant of an organ, tissue, or cells from one individual to another individual of the same species who is not an identical twin.
Which parts of the body can be transplanted in an allograft?
Solid organs: Kidney, liver, heart, lung, pancreas
Small bowel
Free cells: Bone marrow stem cells, pancreas islets
Temporary: Blood, skin (burns)
Privileged sites: Cornea
Framework: Bone, cartilage, tendons, nerves
Composite: Hands, face
How can transplant outcomes be improved?
Patient survival and graft survival
Improved surgical technique
Improved pre- and post-transplant patient management
Drug levels: Infections, cardiovascular disease, diabetes
Better understanding of transplant immunology: Prevention, diagnosis and treatment of graft rejection
What are the different stages of immune response to a transplanted graft?
Phase 1: Recognition of foreign antigens.
Phase 2: Activation of antigen-specific lymphocytes.
Phase 3: Effector phase of graft rejection.
What are the relevant protein variations in clinical transplantation?
Most relevant protein variations in clinical transplantation:
- ABO blood group (for ABO-incompatible transplantation).
- HLA (human leukocyte antigens).
Some other determinants – minor histocompatibility genes.
What is the immunology of transplantation?
The immune system recognises someone else’s organ as foreign.
Two major components to rejection:
- T cell-mediated rejection
- Antibody-mediated rejection (B cells)
What is HLA?
Major Histocompatibility complex (MHC) (chromosome 6). Discovered after first attempts at transplantation (animal models and humans). Cell surface proteins.
- HLA Class I (A,B,C): Expressed on all cells.
- HLA Class II (DR, DQ, DP): Expressed on antigenpresenting cells but also can be upregulated on other cells under stress.
What is special about HLA?
Highly polymorphic – hundreds of alleles for each locus (for example: A1, A2, A3 – A372 and rising…).
Presentation of foreign antigens on HLA molecules to T cells is central to T cell activation.
How does HLA contribute to infections and neoplasia?
To maximise diversity in defense against infections/neoplasia, each individual has a variety of HLA.
Each individual’s HLA are derived from a large pool of population varieties.
How does HLA affect transplantation?
The variability in HLA in the population provides a source for immunisation against the transplanted organ.
“Mismatches”
What is the nomenclature for HLA mismatches?
Work out number of mismatches based on differences
What is the relationship between HLA mismatches and transplant outcome?
Minimising HLA differences between donor and recipient improves transplant outcome.
How is tissue typing (determining HLA in individuals) conducted?
PCR-based DNA sequence analysis for HLA alleles determines the individuals genotype
What is T cell mediated rejection?
Phase 1: Presentation of donor HLA by a professional antigen presenting cell (APC), in the context of recipient HLA.
Phase 2: T-cell activation, inflammatory cell recruitment.
Phase 3: Effector phase (organ damage).
Explain T cell activation.
Proliferation
Production of cytokines (Il-2)
Help for CD8+ cytotoxic T cell activation
Help for antibody production by B cells
Recruitment of monocyte/macrophage lineage cells
What cells are involved in the effector phase of T cell mediated rejection?
“Cytotoxic” T cells:
- Release of toxins to kill target: Granzyme B
- Punch holes in target cells: Perforin
- Apoptotic cell death: Fas -Ligand
Monocyte/macrophages:
- Phagocytosis
- Release of proteolytic enzymes
- Production of cytokines
- Production of oxygen radicals and nitrogen radicals
What can result from T cell mediated rejection?
Interstitial inflammation and tubulitis
Arteritis
How can T cell mediated rejection be managed?
Corticosteroids
Daclizumab: Anti-CD25 monoclonal antibody
Mycophenolate mofetil: MPA inhibitor
Alemtuzumab: Anti-CD52 monoclonal antibody
OKT3, ATG: Anti-CD3 monoclonal antibody
FK506: Cyclosporine, tacrolimus inhibitor
What are the phases of antibody mediated rejection?
Phase 1: B cells recognise foreign HLA.
Phase 2: Proliferation and maturation of B cells with anti-HLA antibody production.
Phase 3: Effector phase; antibodies bind to graft endothelium: intra-vascular disease.
How are anti-HLA antibodies formed?
Anti-HLA antibodies are not naturally occurring.
- Pre-formed: Transplantation, pregnancy, transfusion.
- Post-formed: Arise after transplantation.
Other antibodies:
- Anti-A or anti-B antibodies (naturally occurring)
- Non HLA antibodies
What are ABO blood groups?
A and B glycoproteins on red blood cells but also endothelial lining of blood vessels in transplanted organ.
Naturally occurring anti-A and anti-B antibodies.
When is screening for anti-HLA antibodies conducted?
Before transplantation.
At time of transplantation: When a specific deceased donor kidney has been assigned to the patient.
After transplantation, repeat measurements to check for new antibody production.
What are three types of assay to test for anti-HLA antibodies?
Cytotoxicity assays
Flow cytometry
Solid phase assays
What is being tested for in a cytotoxic crossmatch?
does the recipient serum kill the donor’s lymphocytes in the presence of complement? – detection of cell death using vital dyes.
What is being tested for in flow cytometry?
Does the recipient’s serum bind to the donor’s lymphocytes (bound antibody detected by fluorescently-labelled anti-human Ig)?
What is being tested for in solid phase assays?
Does the recipient’s serum bind to recombinant single HLA molecules attached to a solid support such as beads (bound antibody detected by fluorescently-labelled anti-human Ig)?
How can antibody mediated rejection be managed?
Remove antibodies with plasma exchange
Intravenous Ig
How is rejection detected?
Monitor transplant function (creatinine) + screen for antibodies.
If creatinine goes up: take a biopsy to confirm and classify rejection.
What does this show?
Drug toxicity
Decrease IS drug
What does this show?
Viral infections
Decrease IS drug
What does this show?
Vascular disease
BP control + Vascular stent
What does this show?
Post-transplant Lymphoproliferative Disease
IS drug
Chemotherapy
What does this show?
Recent glomerulonephritis
