Week 8 Flashcards
What is Histocompatibility?
The science of matching tissues to prevent immune reactions.
Where are the possible areas that haematopoeitic stem cell donations can be from?
Peripheral blood stem cells.
Umbilical cord blood stem cells.
Bone marrow
Where are Peripheral blood stem cells found?
Circulating in the arteries and veins of the donor.
How are peripheral blood stem cells collected from a donor?
They are collected by an aphaeresis machine: These remove blood from the donor, separates the stem cells and then returns the blood to the donor without the stem cells.
How must donors be treated if they are having peripheral stem cells removed for a donation and why?
Patients must be treated with GCSF.
Concentration of stem cells in the peripheral blood is low so clinicians must increase the concentration of circulating stem cells. GCSF does this by making their bone marrow produce more stem cells which then migrate to the peripheral blood.
When are umbilical cord blood stem cells collected?
At the time of child delivery.
What happens to Umbilical blood stem cells after they are removed ?
They are frozen and can then be later HLA types and matches with patients needing HSCT.
What are solid organ transplants?
The transplants of tissues and organs.
What are the main targets of rejection of solid organ transplants?
Human Leukocyte Antigens
What type of cells are likely to cause graft Vs host disease in solid organ transplants?
Intact donor immune cells
How can rejection episodes of graft vs host disease be controlled?
Topical drugs
What are the benefits of using topical drugs to control graft vs host disease rather than oral drugs?
They cause fewer side effects.
Why in the past, has the liver not always been matched before donation?
There is a very few number of livers available for donation and so clinical needs often outweigh the ability to wait for organs.
The liver is large and so is able to withstand the immunological response.
Why are livers now clinically matched before donations?
Many livers are transplanted partly from relatives. Only small parts of livers are required and will then grow to be full sized within the recipient.
What is composite tissue transplant?
Transplanting tissue that is composed of many tissues in the same transplant.
Give an example of a composite tissue transplant.
Limbs, face, genitals, uterus etc.
What is HLA Antigen typing?
Proofing of HLA present on patient or donor cells.
What does a HLA antibody screening detect?
anti-HLA antibodies.
If anti-HLA antibodies are are present before a transplant, what has stimulated them?
Transfusion or pregnancy
If anti-HLA antibodies are are present after a transplant, what has stimulated them?
Transplant tissues which can cause rejection of the graft.
What does HLA crossmatching test?
The compatibility of patient HLA antibody profile against a donor.
Outline what occurs during HLA crossmatching.
Recipient serum reacted against cells from the transplant donor immediately before the transplant. This is to see if there are any antibodies against the donor which could lead to rejection.
Define transplant.
To transfer an organ, tissue etc from one part of the body to another or from one person or animal to another.
Define Autograft
Transplant of tissue to the same person
Give examples of an Autograft
Skin graft, heart bypass, autologous bone marrow.
Define Allograft
Transplant of tissue/ organs between two genetically non-identical members of the same species.
Define Isograft
Transplant of tissue / organs between genetically identical members of the same species.
Define Xenograft
Transplant of tissues or organs between different species
What are the 3 main issue areas in transplantation?
Complexity
Conditioning / Preparation
Cost
What are the issues with complexity of transplantation?
It can take weeks - years to find the correct donor for each patient. Sometimes a donation which is less than perfect may need to be used just to keep a patient stable.
Complex surgery is often required.
What are the issues with conditioning and preparation of transplantation?
Patients must be assessed to check that they are safe and suitable to have transplants.
Secondary heath issues usually need to be addressed before transplants can take place.
What are the issues with cost of transplantation?
Cost implications are high due to preparation, surgery, after care and conditioning drugs. Often a decision must be made on cost Vs benefit.
If a person has an autoimmune disease in their own kidney, what must happen before they can have a kidney Transplant and why?
This must be controlled or the new kidney would just be killed by the same disease.
What is the most optimal timing for transplantation?
Early transplantation is usually best but different diseases sometimes give individual times when the transplant would be best based on disease progression.
What are the issues with transplantation in terms of infections?
All patients must undergo some kind of immunosuppression to dampen their immune system to the transplant. This can cause them to be at greater risk of getting infections.
What are the issues with transplantation in terms of rejection?
Parts of the immune system will recognise foreign antigens on the transplant and cause an immune response.
What are the issues with transplantation in terms of GvHD ?
It can be fatal.
It causes major complications is HSCT. In HSCT, a patients malignant cells are replaced with healthy donor cells. These donor cells can then initiate an immune response against the patient’s own cells.
How are complications with HSCT avoided in transplantation
By matching donors to HLA well.
What are the issues with transplantation in terms of relapse?
A patient may need a second transplant if the disease cannot be eliminated.
What are the issues with transplantation in terms of secondary disease?
When aggressive treatment is used to eliminate the original disease, this could cause a second disease.
Can kidney patients be kept stable on dialysis whilst waiting for a transplant?
Yes
Can heart and liver patients be kept stable on dialysis whilst waiting for a transplant?
No
What are the issues when a HLA matched donor is not available and a mismatched organ has to be used ?
More immunosuppressants are required to stop rejection which then means they are more likely to get infections due to having a weak immune system. Opportunistic infections are likely to occur.
Immunosuppressant drugs can also be toxic and damaging in high concentrations.
What chromosome are MHCs found on?
6
What do MHC molecules present and what is their overall purpose?
Self and non-self peptides to the T cell receptors to regulate the immune response.
How many MHC molecules are on each cell?
50-100000
What are the characteristics of MHC molecules?
Polygenic and Polymorphic
How are MHC molecules polygenic?
Made up of many genes
How are MHC molecules polymorphic ?
Exists in many different variations
What is the benefit of MHC molecules being variable?
Creates the molecular difference between individual and makes some major targets for the immune response.
What type of molecules are Human Leucocyte Antigens ?
MHC molecules that are glycoproteins
Name a specific MHC molecule?
Human Leucocyte Antigens
How does the possible variation in the beta pleated sheets in the structure of HLA aid its function?
Controls the range of peptides that can bind to HLA.
How does that possible variation in the alpha helices in the structure of HLA aid its function?
Determines which T cell receptors can bind to the HLA molecule.
What is MHC restriction?
The specific beta pleated sheets and alpha helices means that T cell receptors can only react with self-MHC molecules.
What are HLA class I expressed?
Virtually on somatic cells and on some nucleated cells.
(Myocardium, endocrine tissue, skeletal muscles).
How does the expression of HLA class I alter during an immune response?
Increases
Where is HLA class II expressed?
B lymphocytes Monocytes Macrophages Dendritic Cells Antigen presenting cells Vascular endothelium Kidney Glomerulus
How does HLA Class II alter during an immune response?
Increases extensively.
What is the biological role of HLA class I?
Present intracellular foreign peptide fragments to cytotoxic T cells and bind CD8.
What is the biological role of HLA class II?
They present extracellular endocytose polypeptide fragments to T-helper cells and bind to CD4.
What is the most polymorphic gene system known to man?
MHC
What are HLA genes inherited as?
Blocks of genes known as holotypes on chromosome 6.
How many HLA genes does each individual inherit and how do these interact?
Inherit 2 antigens at a given locus. They are CO-dominant.
Why is the HLA system the most important factor in transplantation?
- HLA is the primary non-self target of the immune response in transplantation due to its polygenic and polymorphic nature.
- HLA is the primary matching criteria for transplantation.
- Matching for HLA decreases incidence of rejection and GvHD in transplantation.
- Matching for HLA increases the engraftment and success rate of transplantation.
What are the 4 types of solid organ rejection?
Hyperacute
Accelerate
Acute
Chronic
How quickly after transplantation does hyper acute organ rejection occur?
Within hours or minutes
What causes Hyperacute organ rejection?
Pre-exitsting HLA or ABO antibodies in the host. Antibodies bind to HLA or ABO antigens on graft leading to complement activation, intravascular coagulation and graft necrosis.
How is hyper acute organ rejection prevented?
HLA matching
HLA antibody screening
Crossmatching
How quickly does accelerated organ rejection occur after transplantation?
Within 3 days
Describe the presence of HLA antibodies accelerated graft rejection
Can occur in the absence of pre-formed HLA antibodies
What causes accelerated organ rejection?
Pre-sensitisation to donor HLA in the host.
How is accelerated organ rejection prevented?
HLA matching
HLA antibody screening
Cross matching
How quickly does acute organ rejection occur after transplantation?
1 week to 3 months of transplantation
What is the most common type of organ rejection?
Acute
Describe the presence of HLA antibodies in acute organ rejection
Occurs in the absence of pre-formed and anti-HLA antibodies.
What causes acute organ rejection?
HLA mismatches
How is acute organ rejection prevented?
HLA matching
Immunosuppressants
Plasmapheresis
How quickly after transplantation does chronic organ rejection occur?
Within months or years
What characterises chronic organ rejection?
Arterial occlusions known as grafter arteriosclerosis which leads to ischaemia and cell death.
Outline the process of hyper acute rejection
Recipient antibodies exposed to donor antigens of the endothelium.
Causing complement activation.
Damage to endothelium.
Platelet activation and activation of the coagulation cascade and leukocyte accumulation.
Micro-thrombi and localised inflammation.
Vessel ischemia and graft necrosis.
Graft loss - death
What are the immunological causes of chronic graft loss?
Pre-existing antibodies.
MHC mismatching.
Macrophage infiltration ; vascular injury.
Ischemia repercussion injury.
What are the non-immunological causes of chronic graft loss?
Nephrotoxicity
Hyperfiltration
Hyperfusion
Hypertension
Organ ‘quality’
Underlying kidney disease
What are De-novo antibodies?
Newly formed antibodies which are formed in response to a transplant and are directed against foreign graft HLA.
What are the possible treatments of antibody mediated rejection?
Antibody removal - plasmapheresis.
Immunoadsorption
Intravenous IgG
How does intravenous IgG treat antibody mediated rejection?
Inhibits T cell proliferation, inhibition of cytokines, inhibition of complement
Name some other complications with transplantation?
Infection
Toxicity
Relapse
Secondary cancer
