Transplantation Flashcards
(47 cards)
What is an allograft?
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: BM 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 + graft survival
Improved surgical technique
Improved pre- + post-transplant patient management: Drug levels, Infections, cardiovascular disease, diabetes
Better understanding of transplant immunology: Prevention, dx + tx 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- all cells that will cause injury to graft have coordinated recruitment
What are the relevant protein variations in clinical transplantation?
HLA (human leukocyte antigens).
ABO blood group (for ABO-incompatible transplantation)
Others: minor histocompatibility genes.
What is the immunology of transplantation?
The immune system recognises someone else’s organ as foreign.
2 major components to rejection (may occur simultaneously):
- T cell-mediated rejection
- Antibody-mediated rejection (B cells)
What is HLA?
Major Histocompatibility complex (MHC) (chr 6).
Discovered after 1st attempts at transplantation (animal models + humans).
Cell surface proteins.
- HLA Class I (A,B,C): Expressed on all cells.
- HLA Class II (DR, DQ, DP): Expressed on antigen presenting cells but also can be up-regulated on other cells under stress.
Both have peptide binding groove to present antigen
What is special about HLA?
Highly polymorphic: 100s of alleles for each locus (e.g. A1, A2, A3–A372…).
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 + recipient improves transplant outcome.
The more mismatches, the worse the graft 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, IL-15)- autocrine effect increasing activation
Activation of CD4 helper + CD8 cytotoxic T cells
Help for antibody production by B cells
Recruit monocytes/macrophages
What cells are involved in the effector phase of T cell mediated rejection?
Cause inflammation in interstitium
“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 + nitrogen radicals
What can result from T cell mediated rejection?
Interstitial inflammation + tubulitis
Arteritis
What drugs can be used to manage T cell mediated rejection?
Target T cell activation pathway
Corticosteroids: anti proliferative
Daclizumab: Anti-CD25 monoclonal antibody
Mycophenolate mofetil: MPA inhibitor
Alemtuzumab: Anti-CD52 monoclonal antibody
OKT3, ATG: Anti-CD3 monoclonal antibody
Calcineurin inhibitors: Cyclosporine, tacrolimus
What are the phases of antibody mediated rejection?
Phase 1: B cells recognise foreign HLA.
Phase 2: Proliferation + 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 + B glycoproteins on RBCs but also endothelial lining of blood vessels in transplanted organ.
Naturally occurring anti-A + 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.
