Immuno 5: Transplantation Flashcards
What are some allografts that can be done? Which of these are most common?
- • Solid organs (kidney, liver, heart, lung, pancreas) → MOST COMMON
- • 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
Which organ is the most commonly transplanted? What is its half life?
o 1st most common transplanted organs = KIDNEYS (average 1⁄2 life of a kidney is 12 years)
o 2nd most common = LIVER
What are the phases of Immune Response to Transplanted Graft?
- Phase 1: recognition of foreign antigens
- Phase 2: activation of antigen-specific lymohocytes
- Phase 3: effector phase of graft rejection
What are the most relevant protein variations in clinical transplantation?
- ABO blood group
- HLA (on chromosome 6 by MHC; n.b. HLA can mean the proteins OR the genes)
- other minor histocompatibility genes
What are the 2 major forms/components of graft rejection?
- T cell-mediated rejection
- Antibody-mediated rejection
What is the difference between HLA Class I And HLA class II?
- 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 upregulated on other cells under stress
Describe HLA
- 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
Which HLA class subtypes are most important to match? What does the number of mistmatches relate to?
Most important to match = DR > B > A
- most immunogenic of A, B, C, DR, DQ
- The number of mismatches is a major determinant of the risk of rejection and graft survival
How many mismatches are there here? What is the max number of mismatches
How many alleles are matched in parent to child donations? What about sibling to sibling?
How is donor and recipient HLA type determined?
tissue typing
PCR-based DNA sequence analysis for HLA alleles determines the individuals genotype
Summarise phase 1 of T cell mediated rejection of a graft
- To activate alloreactive T cells, the T cells require:
- Presentation of foreign HLA antigens in MHC by APCs (both DONOR and HOST APC cells are involved)
- Co-stimulatory signals
- These actions occur in the lymph nodes – APCs pick up antigens from donor MHC and activate T cells in nodes
- This leads to effector phase of rejection → inflammation caused leads to graft dysfunction (i.e. raised creat)
- A biopsy can serve to determine if rejection is occurring
Summarise phase 2 of T cell mediated rejection of a graft
- Proliferation
- Product cytokines (IL2 is important)
- Provide help to CD8+ cells
- Provide help for antibody production
- Recruit phagocytic cells
Effects cells have inside the transplanted organ:
o Cytotoxic T cells:
§ Granzyme B (toxin)
§ Perforin (punch holes)
§ Fas-ligand (apoptosis)
o Macrophages:
§ Phagocytosis
§ Proteolytic enzymes production
§ Cytokine release
§ O2 and N2 radicals production
Summarise phase 3 of T cell mediated rejection of a graft
• 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 are the Histological Features of T cell-mediated Rejection?
What is another cause of failed graft function, other than rejection?
failed graft function may not always be due to rejection… some immunosuppressive drugs given are nephrotoxic → reduced function
What are the 3 phases of antibody-mediated rejection?
- Phase 1: exposure to foreign antigen
- Phase 2: proliferation and maturation of B cells with antibody production
- Phase 3: effector phase – antibodies bind to graft endothelium (capillaries of glomerulus and around tubules)
Can antibodies against ABO occur without exposure? What about anti-HLA antibodies?
Whilst anti-ABO blood group ABs naturally occur, anti-HLA antibodies are not naturally occurring
- Can be pre-formed due to previous exposure to epitopes (e.g. previous transplantation, pregnancy, transfusion)
- Can be post-formed (after transplantation)
Where are ABO antigens found?
A and B glycoproteins on RBCs but also endothelial lining of blood vessels in transplanted organ
What are the monosaccharides found on on A, B, AB, O antigens?
What are the antigens in blood and antibodies in plasma for A, B, AB, O blood groups?
Explain phase 3 of antibody-mediated graft rejection
Phase 3 (antibodies in transplantation):
- Antibodies bind to antigens (HLA) on the endothelium of the blood vessels in the transplanted organ
- Antibodies fix/activate complement which assembles to:
- Form MAC → endothelial cell lysis
- Recruit inflammatory cells to the microcirculation
- Antibodies can crosslink the MHC molecules, thus activating them
- The antibodies can also directly recruit mononuclear cells, NK cells and neutrophils → capillaritis
What are the actions of antibodies in transplant rejection?
Action of Antibodies in Infection – the same mechanisms occur in transplant rejection:
- Neutralise toxins
- Opsonise (aid phagocytosis)
- Antibody-dependant cellular cytotoxicity
-
Complement activation (which leads to):
- MAC lysis
- Opsonise (aid phagocytosis)
- Inflammation
in image, top box = complement independent, bottom = complement dependent
What is a Cardinal feature of antibody-mediated rejection?
Cardinal feature of antibody-mediated rejection = capillaritis = inflammatory cells in capillaries of the kidney → injury
