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
- Deceased donors slightly lower ~ 10 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 blood group
- HLA
Which chromosome is HLA encoded on?
Chromosome 6
What are the two major types of rejection?
- T cell-mediated rejection
- Antibody-mediated rejection
What are the alleles of HLA class I and class II?
- Class I - A, B, C
- Class II - DR, DQ, DP
Describe the basic structure of HLA Class I and Class II.
Class I
- 3 alpha domains
- 1 beta-2 microglobulin domain
- 1 transmembrane domain
Class II
- 2 alpha domains
- 2 beta domains
- 2 transmembrane domains
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)
Which HLA alleles are most immunogenic?
A, B and DR
What is 1:1:0 in terms of mismatches
For A, B and DR
Others e.g. DQ are still antigenic
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 phases of T-cell mediated rejection.
Describe the effector phase of T-cell mediated graft rejection.
Activated CD8+ T-cells
- Release toxins to kill target cells - granzyme B
- Punch holes in target cells - perforin
- Induce apoptosis - Fas ligand
CD4+ T-cells recruit and activate macrophages which:
- Phagocytose cells
- Release proteolytic enzymes
- Produce inflammatory cytokines
- Release oxygen and nitrogen free radicals
What are the typical histological features of T-cell mediated rejection?
- Lymphocytic interstitial infiltration
- Tubulitis - WBCs within the tubular epithelium
- Arteritis - WBCs within vascular wall
What are the 3 signals of T-cell activation?
- Antigen/MHC interaction with TCR
- Co-stimulatory molecular expression - CD80/86 interaction with CD28
- IL-2
What other explanation might there be for graft failure other than rejection?
Immunosuppressive drugs may be nephrotoxic
Where are AB antigens expressed?
On erythrocytes AND endothelial cells
What are the three phases of antibody-mediated rejection?
- Phase 1: B-cells recognise to foreign HLA
- Phase 2: proliferation and maturation of B cells with anti-HLA antibody production
- Phase 3: effector phase - antibodies bind to graft endothelium = intravascular disease
What is a key difference between the production of anti-AB and anti-HLA antibodies?
- Anti-AB antibodies are naturally occuring (pre-formed)
- Anti-HLA antibodies are not naturally occuring but can be pre-formed due to previous exposure to epitopes (e.g. previous transplant, pregnancy) or post-formed (after transplantation)
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 occlusion of the microcirculation leading to graft fibrosis and necrosis
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 binds 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
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
Corticosteroids affect numerous pathways
Name two drugs that target TCR.
- Muromonab-CD3 (OKT3) - anti-CD3 antibody
- Anti-thymocyte globulin
Name an anti-CD52 antibody
Alemtuzumab
Name an anti-CD25 antibody
Basiliximab / Daclizumab - binds to CD25 (alpha subunit of IL-2 receptor)
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
What is rituximab?
Anti-CD20 - depletes B-cells
Give an example of a BAFF inhibitors and explain how it works.
Belimumab
- BAFF is required for B-cell survival
- Without BAFF, B-cells undergo apoptosis
Name a proteasome inhibitor and describe how it works.
Bortezomib
- Inhibits degradition of pro-apoptosis proteins
- Eventually leads to apoptosis
Name a complement inhibitor.
Eculizumab - targets C5
Outline the components of modern transplant immunosuppression regimes.
What is the managment of immunosuppressant associated
- Drug toxicity
- Viral infection
- Post-tranplant lymphoproliferative disease
Reduce immunosuppressant drug treats all
Post-tranplant lymphoproliferative disease may also require chemotherapy
Briefly describe the pathophysiology of graft-versus-host-disease.
- During SCT, the host immune system is eradicated and replaced by autologous or allogeneic bone marrow
- In allogeneic stem cell transplant, donor lymphocytes can attack host tissues
NOTE: if there is a malignancy, the graft can kill these cells (graft-versus-leukaemia)
How can GvHD be prevented?
Methotrexate with ciclosporin
List some symptoms of GVHD.
- Skin - maculopapular rash (pruritic and painful)
- GI - diarrhoea/bloody stools, abdominal pain, nausea and vomiting
- Liver - jaundice, deranged LFTs
List some opportunistic infections that are more common in transplant recipients.
- CMV
- BK virus
- PCP
List some malignancies that are more common in transplant recipients.
- Kaposi sarcoma (HHV8)
- Lymphoproliferative disease (EBV)
- Skin cancer
