Transplantation Flashcards
- What is the average half-life of a transplanted kidney?
12 years
- What are the three phases of an immune response to a graft?
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 cellular proteins that can determine compatibility?
ABO
HLA
- Which chromosome is HLA encoded on?
Chromosome 6
- What are the two major components of rejection?
T cell-mediated rejection
Antibody-mediated rejection
- Describe the basic structure of HLA Class I and Class II.
Class I: have three alpha domains and a beta-2 microglobulin domain, has one transmembrane domain
Class II: has two alpha and two beta domains, had two transmembrane domains
- Which alleles encode HLA Class I and Class II?
Class I: A, B and C
Class II: DP, DQ, DR
- Where are HLA Class I and Class II expressed?
Class I: all cells
Class II: antigen-presenting cells (can be upregulated at times of stress)
- What is the benefit of having high variability in the peptide-binding groove of MHC?
Can present a wide variety of antigens
- What is the disadvantage of the variability in the peptide-binding groove of MHC with regards to transplants?
This means that the host immune system can react with the slightly different MHC of the donor leading to rejection
- Which HLA alleles are most immunogenic?
A, B and DR
- What are the actions of activated T cells?
Proliferation Production of cytokines (IL2 is important) Provide help for CD8+ T cells Provide help for antibody production Recruit phagocytes
- Where do the antigen-presenting cells that interact with host T cells come from?
From the recipient and the donor (the donated organ will contain many APCs)
NOTE: a lot of these interactions will happen in lymph nodes
- Which test is used to give a definitive diagnosis of graft rejection?
Biopsy
- Describe the effector phase of T-cell mediated graft rejection.
T cells tether, roll and arrest on the endothelial cell surface
They will migrate across into the interstitium and start attacking the tubular epithelium
Macrophages (recruited by T cells) may also be seen in the interstitium
- What are the typical histological features of T-cell mediated rejection?
Lymphocytic interstitial infiltration
Ruptured tubular basement membrane
Tubulitis (inflammatory cells within the tubular epithelium)
- What are the three 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
- What is a key difference between the production of anti-AB and anti-HLA antibodies?
Anti-AB antibodies are naturally occurring (pre-formed)
Anti-HLA antibodies are not naturally occurring but can be pre-formed due to previous exposure to epitopes (e.g. previous transplant, pregnancy) or post-formed (after transplantation)
- Briefly describe the mechanisms by which antibodies help combat infection.
They can bind to the surface of microbes and directly neutralise it
They can opsonise microbes and attract inflammatory cells via Fc receptors
They cause cell death through antibody-dependent cellular cytotoxicity or phagocytosis
Complement can bind to immunoglobulins on the surface of microbes leading to direct lysis of microbes
- Outline the pathophysiology of antibody-mediated transplant rejection.
Antibodies bind to HLA on the endothelium of blood vessels within the transplanted organ
The antibodies fix complement which leads to formation of MAC and endothelial cell lysis
Binding of complement also recruits inflammatory cells
This leads to inflammation of the microcirculation (capillaritis)
This leads to procoagulant tendencies and closure of the microcirculation leading to graft fibrosis
Antibodies can also cross-link MHC molecules and activate them
- What are the main histological features of antibody-mediated transplant rejection?
Presence of inflammatory cells within the capillaries of the graft (HALLMARK)
Immunohistochemistry can show fixation of complement fragments on the endothelial cell surface
- What are the three main approaches to preventing graft rejection?
AB/HLA typing
Screening for antibodies
Overcoming organ mismatch issues
- Which technology is used for AB/HLA typing?
DNA sequencing using PCR
- At what stages of transplantation will screening for antibodies be performed?
Before transplantation At the time of transplant (once an organ has been assigned) After transplantation (check for new antibody formation)
- Name and describe three assays for anti-HLA antibodies.
Cytotoxic Assays: tests whether patient serum kills donor lymphocytes in the presence of complement
Flow Cytometry: tests whether patient serum binds donor lymphocytes irrespective of complement
Solid Phase Assays: beads containing all the possible HLA epitopes are mixed with the patient’s serum. This determines which HLA types the patient has antibodies against. Having many antibodies against different HLA epitopes suggests that the patient is highly sensitised.
- How can organ mismatch issues be overcome?
Improve transplantation across tissue barriers
More donors
Organ exchange programmes
Xenotransplantation and stem cell research
