Transplantation Flashcards
Most relevant proteins in transplantation
ABO blood group
HLA
Two major forms of rejection
T cell-mediated rejection
Antibody-mediated rejection
HLA classes
o HLA Class I (A, B and C) – expressed on ALL cells
Thought to be the most immunogenic
o HLA Class II (DR, DQ, DP) – expressed on APCs (also be upregulated on other cells under stress)
Most important HLA classes to match
Most important to match = DR > B > A
Features of HLA receptors
They are highly polymorphic with hundreds of alleles for each locus
High degree of variability from the areas of protein lining the peptide-binding groove which allows us to present a wide variety of antigens in that peptide-binding groove to the cells of the immune system
T cell mediated rejection
• Phase 1:
T cells require:
Presentation of foreign HLA antigens in MHC by APCs (both DONOR and HOST APC cells are involved)
Co-stimulatory signals
Occur in the lymph nodes
Causes inflammation and graft dysfunction
Phase 2 o Proliferation o Product cytokines (IL2 is important) o Provide help to CD8+ cells o Provide help for antibody production o Recruit phagocytic cells
Phase 3
Migration to area
Rolling, attachment, adhesion, diapedesis
Histological Features of T cell-mediated Rejection
o Lymphocytic interstitial infiltration
o Ruptured tubular basement membrane
o Tubulitis (inflammatory cells within the tubular epithelium)
o Macrophages, recruited by the T cells
Antibody Mediated Rejection
o Phase 1: exposure to foreign antigen
o Phase 2: proliferation and maturation of B cells with antibody production
o Phase 3: effector phase – antibodies bind to graft endothelium (capillaries of glomerulus and around tubules)
o Antibodies bind to antigens (HLA) on the endothelium of the blood vessels in the transplanted organ
o Antibodies fix/activate complement which assembles to:
Form MAC endothelial cell lysis
Recruit inflammatory cells to the microcirculation
o Antibodies can crosslink the MHC molecules, thus activating them
o The antibodies can also directly recruit mononuclear cells, NK cells and neutrophils capillaritis
• Action of Antibodies in Infection – the same mechanisms occur in transplant rejection:
o Neutralise toxins
o Opsonise (aid phagocytosis)
o Antibody-dependant cellular cytotoxicity
o Complement activation (which leads to):
MAC lysis
Opsonise (aid phagocytosis)
Inflammation
Histology of Antibiody mediated rejection
o Inflammatory cell infiltrate o Capillaritis (inflammatory cells in the microcirculation – a cardinal feature of antibody mediated rejection)
Screening for anti-HLA antibodies
BEFORE, AT TIME (at organ assignment) and AFTER TRANSPLANT – 3 assays used:
Cytotoxicity assays:
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
o Flow cytometry:
Inspects if recipient’s serum binds to the donor’s lymphocytes
Detection of bound AB by fluorescently labelled anti-human immunoglobulin
o Solid phase assays (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
o Three signals to activate T-cells
APC MHC to T-cell TCR (main signal)
APC CD80/CD86 to T-cell CD28 (CD80/86 to CTLA4 suppresses immune reactions)
Cytokine IL-2 to T-cell CD25 (after T-cell activation, autocrine IL-2 is released to further activate)
Modern Transplant Immunosuppression Regimen:
o Induction agent: e.g. OXT3/ATG, anti-CD52, anti-CD25
o Baseline immunosuppression: calcineurin inhibitor + mycophenolate mofetil / azathioprine ± steroids
o Treatment of episodes of acute rejection:
Cellular: steroids, OKT3, ATG
Antibody-mediated: IVIG*, plasmapheresis, anti-C5, anti-CD20
Pathogenesis of GvHD
During SCT, the host immune system is eliminated (using total body irradiation and drugs)
It is then replaced by own (autologous) or HLA-matched donor (allogeneic) bone marrow
Allogeneic SCT leads to reaction of donor lymphocytes against host tissues
• Related to a degree of HLA-incompatibility
If there is a malignancy (e.g. leukaemia), the graft can help kill these cells (graft-versus-tumour)
GvHD symptoms and treatment
o Symptoms – looks like slow-onset anaphylaxis with jaundice… Rash Nausea and vomiting Abdominal pain Diarrhoea/bloody stool Jaundice
o GvHD Prophylaxis = Methotrexate/cyclosporine
o GvHD treatment = steroids