Immunology 3 - Transplantation Flashcards
What are the 2 types of transplantation?
- Life saving - liver, heart, small bowel
2. Life enhancing - if other life supportive methods less good (e.g. kidney - dialysis / pancreas)
What are the different types of transplantation
- Autografts - within the same individual - e.g. CABG, reconstructive
- Isografts - between genetically identical individuals of the same species (identical twins)
- Allografts - between different individuals of the same species (most common)
- Xenografts - between individuals of different species
- Prosthetic graft
What are the 2 types of allograft donor
- Deceased donor - divided into donor after brainstem death and donor after circulatory death
- Living donor - bone marrow, kidney, liver. Can be genetically related donor or unrelated
Describe DBD - Donor after brain stem death
Majority of organ donors - brain injury caused death before terminal apnoea resulted in cardiac arrest.
e.g. IC haemorrhage road traffic accident.
Organs harvested and cooled to minimise ischaemic damage
Describe DCD - donor after circulatory death
Death diagnosed and confirmed using cardiorespiratory criteria
Longer period of warm ischaemia time
In deceased donors, what must be excluded before using the organ
- Viral infection
- Malignancy
- Drug abuse, OD
- Disease of transplanted organ
Removed organs = rapidly cooled and perfused (maximum cold time for kidney = 60h)
Transplantation allocation is based on?
- Equity - time on waiting list, urgency
2. Efficiency - patient survival, etc
Name 3 elements to consider when allocating organs
- Waiting time
- HLA match and age combined
- Donor-recipient age difference
How does the half life of kidney transplants vary?
If living donor - lasts longer (2x) than deceased donor (roughly 15 years)
What are the 2 main groups of molecules that cause rejection
- ABO blood group
2. HLA on Chr 6
A and B proteins are located on RBC. Where else are they located
Endothelial lining of blood vessels in transplanted organ
Describe ABO incompatible transplantation
- Antibodies removed in recipient (plasma exchange)
- Good outcome - even if antibody comes back
- Done in kidney, heart, liver transplants
How do T cells recognise antigens
They recognise T cells in the context of HLA molecules presented by APCa
What are the 2 types of HLA
- Class 1 - A, B, C - expressed on all cells
- Class 2 - DR, DQ, DP; expressed on APCs but also unregulated on other cells
They are highly polymorphic - lots of alleles for each locus. Each individual has 2 types for each HLA molecule
How do MHC Class 1 and Class 2 molecules differ
Peptide binding groove:
In MHC Class 1 -both alpha chains (1 & 2)
In MHC Class 2 - alpha (1) and beta (1)
(Class 1 also has a b2-microglobulin chain)
Which are the highly polymorphic HLA molecules
HLA-A, HLA-B, HLA-C, HLA-DR
Explain the mismatching in parent - child.
wb sibling to sibling
Parent to child = equal to or greater than 3/6 matches
Sibling to sibling:
25%= 6 mismatches 50% = 3 mismatches 25% = 0 mismatches
What is rejection
- Exposure to foreign HLA molecules –> results in an immune reaction to foreign epitopes —> rejection.
Can cause immune graft damage and failure
What is the treatment for rejection
Immunosuppressive drugs
Describe the different types of rejection
- Hyperacute rejection (rare) - rapidly after graft implanted
- Acute rejection - few weeks/months after transplant
- Chronic rejection - slow deterioration
- T-cell mediated rejection
- Antibody mediated rejection
Describe T cell mediated rejection
T cell recognises foreign HLA epitopes on APCs. T cells recognise these foreign antigens on local secondary lymphoid organs - lymph nodes.
Then T cells circulate to graft and encounter the HLA molecule that will stimulate them on the surface of the endothelium of the graft.
T cells undergo tethering, rolling, arrest, diapedesis, through endothelial cell lining into interstitium - start attacking tubule with HLA epitopes they recognise - causing tubulitis (in kidney)
CD4 helper cells recruit which other 2 cells as part of the infiltrate?
Cytotoxic T cells and macrophages
Describe antibody-mediated rejection
B cell dominant (obvs)
Antibody against graft HLA (mainly) or AB antigen (rarely)
Antibodies may arise:
- Pre-transplantation (“sensitised”)
- Post transplantation (“de novo”)
How do antibodies destroy infections?
Activates complement, activates macrophages (Fc receptors)
Antibody rejection is mainly ….
Intravascular
T cell rejection is mainly?
Tubulointerstitial
What are signs of deteriorating graft function
Kidney - rise in creatinine, fluid retention, hypertension
Liver - rise in LFTs, coagulopathy
Lung transplant - breathlessness, pulmonary infiltrate
How do we try and prevent rejection
- Maximise HLA compatibility
2. Life-long immunosuppressive drugs
Which immunosuppressive drugs target T cells?
Calcineurin inhibitors: e.g. cyclosporine, tacrolimus
Cell cycle / nucleotide synthesis inhibitors: azathioprine
and steroids which have a more generic action
Also induction agents - reduce the number of antibodies - e.g. anti-CD52 mAb
IL-2 inhibitors - anti-IL2 receptor drugs
Which immunosuppressive drugs target B cells?
We only target B cells if patient has antibodies against graft
Can do splenectomy or plasma exchange or intravenous immunoglobulin (IVIG)
Can use:
- anti-CD20 drugs
- Bortezomib (proteosome inhibitor - kills of antibody producing plasma cells)
- Anti-C5 drugs (drugs inhibiting complement activation)
Name 3 opportunistic viruses that may arise post transplantation
- Cytomegalovirus
- BK Virus
- Pneumocytis carinii
Name some common pst transplantation malignancies
- Skin cancer
- Post transplant lymphoproliferative disorder - EBV driven
- Others
