Immuno: Transplantation Flashcards
Which organ is most commonly transplanted?
- Kidneys
- Followed by Liver
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: effect 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
Where do the antigen-presenting cells that interact with host T cells come from?
From the recipient and the donor (the donor 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 other explanation might there be for graft failure other than rejection?
Immunosuppressive drugs may be nephrotoxic
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 T cell pathway is the main target for immunosuppressive drugs used in transplants?
- The main signal is between MHC and TCR
- Downstream, there are a number of pathways that involve calcineurin which result in cell proliferation
- Once activated, T cells will release IL2 which has autocrine and paracine effects on Th2 cells
- These are all targets for immunosuppression
What are the main immunosuppressive targets of B-cell mediated graft rejection?
- B cell activation
- Secretion of antibodies by plasma cells
- Effects of antibodies on endothelium
