IMMUNO: Transplantation Flashcards
What are the first and second most transplanted organs?
- 1st most common transplanted organs = KIDNEYS (average ½ life of a kidney is 12 years)
- 2nd most common = LIVER
What proportion of the world population has kidney disease?
5%, 7% or 11%?
11%
5years on what are the chances of survival of a patient on CKD starting dialysis?
35, 55 or 85%?
35% chance of 5 year survival
What are the phases of T cell immune response to transplanted grafts?
- Phase 1: recognition of foreign antigens
- Phase 2: activation of antigen-specific lymphocytes
- Phase 3: effector phase of graft rejection
What are the most relevant protein variations in clinical transplantation? Which one is the most important?
- ABO blood group
- HLA (on chromosome 6 by MHC; n.b. HLA can mean the proteins OR the genes) - MOST IMPORTANT
- Other minor histocompatibility genes
What are the two major forms/components of rejection?
- T cell-mediated rejection
- Antibody-mediated rejection
What is the difference between HLA class I and II?
MHC (chromosome 6)
-
HLA Class I (A, B and C) – expressed on ALL cells
- Thought to be the most immunogenic
- HLA Class II (DR, DQ, DP) – expressed on APCs (also be upregulated on other cells under stress)
Features:
- polymorphic with hundreds of alleles for each locus
- high degree of variability lining the peptide-binding groove = allows us to present a wide variety of antigens i
- number of mismatches is a major determinant of the risk of rejection
Which HLA are most important to match in transplantation?
DR>B>A
What happens in phase II of T cell mediated immune activation to transplantation?
- To activated alloreactive T cells, T cellls require:
- Presentation of foreign HLA antigens in MHC by APCs (both DONOR and HOST APC cells are involved)
- Co-stimulatory signals
- This occurs in lymph nodes and causes the effector phase of rejection –> inflammation caused leads to graft dysfunction (i.e. raised Cr).
- Biopsy can be done to diagnose.
What does 1,0,0 mean in terms of HLA matching?
1 mistmatch at HLA-A
0 mismatches at HLA-B
2 mismatches in HLA-DR
Maximum is 2 mismatches in each = 6
How are mismatches counted? Try below.
This would be written as 1,1,0.
What happens in the phase 2 of T cell mediated immune reaction to a transplant?
Action of activated T cells e.g.
- Proliferation
- Production of cytokines (IL2 is important)
- Providing help to CD8+ cells
- Providing help for antibody production
- Recruitment of phagocytic cells
What technique is used for HLA tissue typing?
PCR
Where does phase 2 vs phase 3 of immune T cell-mediated reaction to transplantation happen?
Phase 2 - lymph nodes
Phase 3 - within graft
How do cytotoxic T cells and macrophages affect the transplanted organ?
Cytotoxic T cells:
- Granzyme B (toxin)
- Perforin (punch holes)
- Fas-ligand (apoptosis)
Macrophages:
- Phagocytosis
- Proteolytic enzymes
- Cytokine release
- O2 and N2 radicals
What is shown?
T cell mediated tubulitis.
- Lymphocytic interstitial infiltration
- Ruptured tubular basement membrane
- Tubulitis (inflammatory cells within the tubular epithelium)
- Macrophages, recruited by the T cells
NB: Immunohistotyping can be used to mark which type of cells e.g. T cells, are present.
What is seen here?
Infiltration of immune cells and closing of kidney tubules due to T cell mediated graft rejection.
- N.B. failed graft function may not always be due to rejection… some immunosuppressive drugs given are nephrotoxic –> reduced function
What happens in phase 3 of immune T cell-mediated reaction against transplants?
- Effector phase:
- The T cells will tether, roll and arrest on the endothelial cell surface
- They will then crawl through into the interstitium and start attacking the tubular epithelium
What is shown in this antibody mediated rejection?
- Glomerulus with capillary loops
- Many cells within lumen of these loops
- This is intravascular primarily
- Called glomerulonephritis
- There is also capillaritis
Describe the use of cytotoxic assays for anti-HLA diagnosis.
- Inspects if recipient’s serum will kill the lymphocytes of the donor, in the presence of complement
- Positive crossmatch suggests that there is cell lysis (i.e. +ve is a bad thing)
Describe the use of flow cytometry for anti-HLA Ab detectiion.
- Inspects if recipient’s serum binds to the donor’s lymphocytes
- Detection of bound AB by fluorescently labelled anti-human immunoglobulin
- A broad test to look at whether antibodies bind antigen irrespective of whether they bind complement
Describe the use of solid phase assays for anti-HLA Ab detection.
Uses a series of beads containing all the possible HLA epitopes
- Recipient’s serum is mixed with beads and fluorescently labelled immunoglobulin is used to determine which HLA epitopes the antibodies bind to (can also give an indication of the strength of the reaction)
- Patients that have antibodies to lots of different types of antibodies are regarded as highly sensitised
List 4 drugs used as management in transplantation with T cell-mediated rejection.
- Steroids (prevent general T-cell mediated rejection)
- Inhibitors of cell signalling / Calcineurin inhibitors (i.e. Tacrolimus, Cyclosporine)
- Anti-proliferative agents (i.e. Mycophenolate mofetil, Azathioprine)
- Inhibitors of cell surface receptors (i.e. Anti-CD3 antibody (OKT3), ATG / Anti-thymocyte globulin)
List 4 management drugs used in management of antibody mediated rejection.
- Rituximab (anti-CD20) = B cell depletion
- BAFF inhibitors (target cytokines that promote B cell activation and growth)
- Proteasome inhibitors (i.e. bortezomib) = block production of antibodies by plasma cells
- Complement inhibitors (i.e. eculizumab, anti-C5) = block complement binding to endothelial cells
