Transplantation and Immunosuppressive Drugs Flashcards
Define transplantation
The introduction of biological material such as organs, tissues and cells into an organism
Why is it difficult to transplant?
The immune system has evolved to remove anything it regards as non-self.
Where was the first transplant?
The first transplantation is the cornea which happened in 1905 and the reason this was able to occur so early is because the eye is an immunoprivileged site.
Define autologous
When there is transplant from one part of the organism into another part of the same organism e.g. skin transplant from one area to the other.
Define syngeneic
When there is transplant between a donor into a recipient, when both the donor and the recipient are genetically identical. Therefore, this usually doesn’t generate any immunological problems either for example, identical twins.
Define allogenic
When the donor and the recipient are from the same species but are genetically different. This is the most common type of transplant carried out e.g. relatives so may have a closest genetic match possible.
Define xenogeneic
When the donor and the recipient are from different species. This isn’t common.
What is histocompatibility?
Tissue compatibility
Why is it important to match MHC?
- The most important differences are between the antigens forming the MHC complexes.
- The human MHC is called HLA (human leukocyte antigen), every human has different HLA and therefore it is the biggest problem in transplant.
- It is the most diverse area in the human genome.
- The immune responses to transplant are caused by genetic differences between the donor and the recipient
Describe the genetics of HLA
- Found on chromosome 6
- Can be split into class I and class II
- Class I is made up of 3 genes: A, B, and C; also all nucleated cells express MHC I
- Class II is made up of 3 genes which are heterodimers: DP, DQ and DR. Only immune cells express MHC II.
How is matching HLA done?
Between the donor and recipient for MHC is done via sequencing and seeing if the HLA alleles match. This is used to match the epitopes on the MHC, some MHC may different between the 2 people, however the epitopes (alleles) may be the same e.g. B cell epitopes on donor MHC and T cell epitopes dervied from donor MHC.
Describe the interaction between APC and MHC complexes
- APC and normal cells express class I MHC complexes which activate CD8
- APC express class II MHC complexes which activate CD4
- The antigen binds to the peptide binding groove.
- The binding groove is variable so different antigens are able to bind.
- TCR detects the combination of the peptide and the MHC.
Describe the interaction between T cells and MHC Class I
- T cells recognise short peptide fragments (antigens) that are presented to them via MHC.
- The infected cell which could be nucleated, or APC will have the pathogen intracellular in the cytosol.
- The viral infected cell will contain a proteasome which will breakdown the viral proteins into peptides.
- Professional APCs like dendritic cells can internalise external proteins, peptides or viruses and present them on the MHC I pathway.
Describe the interaction between T cells and MHC class II
Only professional APCs like macrophages can express MHC II
- The APC takes up the bacteria which is extracellular into an endosome where it is broken down.
- They then get process in the phagolysosome and get broken down into peptides via the low pH.
- Eventually, this peptide will meet with the MHC II molecule which will contain the CLIP fragment.
- The CLIP fragment will leave the MHC II molecule and bind to the HLA-DM.
- This allows the antigen to bind to the MHC II molecule and get expressed on the surface for CD4 cells.
What is the function of CD4 T cells?
Produce helper responses which, are vital for antibody production and cytotoxic CD8 responses.
What is the function of helper T cells?
Provide information and support for other immune cells via cytokine production.
What are cytotoxic T cell?
Highly specific killer cells
Describe the importance between transplant and MHC proteins
- In transplants, both the MHC molecule and the peptide in its binding groove may be foreign.
- And it can detect the combination of both as foreign.
- Therefore, this leads to different types of rejections.
- There could be direct recognition of the HLA or indirect recognition.
What is indirect T cell activation?
- Normally, the recipient cells (for example APC) will express a self-peptide which the TCR will bind to and release it is self and therefore not get activated.
- If it does get activated by self-cells, it leads to autoimmune diseases.
- However, after a transplant, the HLA molecule can express the donor peptide as non-self and there is indirect allorecognition.
- Therefore, in summary indirect allorecognition is due to TCR of recipient detecting non-self peptides from self-HLA.
What is direct T cell activation?
- Transplant tissue contains donor immune cells including HLA molecules which may be identical to the recipient self-HLA molecule if the match is perfect, which means there should be no immune response.
- However, sometimes another type of allorecognition occurs which is when the HLA molecule is unmatched to the recipient and you get direct TCR from recipient recognise it.
- This occurs even if the peptides present on the groove are recognised as self.
- Therefore, in summary direct allorecognition occurs when TCR of recipient T cells react with non-self donor HLA molecule.
Why is it important to match 4/6 MHC class II loci?
It reduces likelihood of future transplants and problems with future transplants. As the number of mismatches increases, the half-life decreases.
What is the difference between live and dead donors?
Donor material from a deceased person are also likely to be in inflammed condition due to ischaemia which can lead to immune responses against that organs. Transplant success is less sensitive to MHC mismatch for live donors.
What are the 3 types of graft rejections?
Based on the direct and indirect allorecognitions:
- Hyperacute rejection
- Acute rejection
- Chronic rejection
What are hyperacute rejection?
- Happens within a few hours of rejection
- Most commonly seen in highly vascularised organs such as the kidneys
- Requires pre-exisitng antibodies, usually to ABO blood group (expressed on endothelial cells of blood vessels) antigens or MHC I proteins (arise from pregnant, blood transfusion or previous transplant).
How can antibodies cause damage to transplanted tissue?
- The pre-exisiting antibody will detect the antigen on the donor tissue. The variable region (Fab) of the antibody will bind to the antigen, and the constant region (Fc) will bind to the innate immune cells.
- This will lead to complement activation, antibody dependent cellular cytotoxicity, activation of NK cells and gamma delta T cells which will target the cell count antibody to die.
- It will also lead to phagocytosis by macrophages which is very quick.
Why is phagocytosis of the transplanted tissue quick?
- The antibodies are already pre-existing.
- The antibodies can bind to endothelial cells, lead to complement fixation, accumulation of innate immune cells and cause endothelial damage, platelets accumulate and thrombi development.
What is acute rejection?
This is inflammation which results in activation of the dendritic cells in the donor organs. T cells response develops as a result of MHC mismatch.
Give an example of direct allorecognition
- The donor dendritic cells, migrate form the organ to secondary lymphoid tissue where they encounter recipient circulating effector T cells.
- The T cells will recognise the non-self HLA on the dendritic cells, and both CD4 and CD8 cells will get activated.
- Those cells will then migrate to the donor organ which will have inflammatory environment and they will target every cell that expresses the HLA in the donor tissue and destroy it.
Which cells in acute rejection increase inflammation and destroy the transplant?
Macrophages and CTLs
What is chronic rejection?
This can occur months or years after transplant. There are antibodies against MHC I. The blood vessel wall thickens, lumina narrows and there is loads of blood supply. This is an example of non-direct allorecognition.
How is an immune response activated in chronic rejection?
- Some donor derived cells will die.
- They will then get taken up by recipient APCs.
- This will breakdown the proteins of those cells into fragments and express them on their MHCs as foreign peptides.
- Recipient CD8 cells will then bind to them and activate an immune response.
What is haemtopoietic stem cell transfer (HSCT)?
This is when the recipient doesn’t have an immune response and is being provided with one through transplanting immune cells. This used to be stem cells from the same patient but now it is bone marrow transplant from one patient to the other.
What are the issues with transplanting stem cells?
Lead to infections or graft versus host disease because the donor immune system attacks the recipient.
What do the human stem cells do after transplant?
They can find their way to bone marrow after infusion and regenerate there. They can be cryopreserved with little damage.
How can the graft affect the host causing disease (graft vs host disease)? How can the disease be overcome?
- When transplanted tissue is immune cells themselves, there is the risk of donor immune cells attacking the host.
- This can be lethal.
- By removing the T cells from transplant or suppressing their function reduces this.
What is the correlation between a graft and leukaemia?
- Sometimes mismatch and donor leukocytes can be beneficial such as during removing original leukaemia.
- The development of GVL may prevent disease relapse.
- The reason this works and the self-immune system doesn’t is because cancer derives from self-cells.
- Therefore, the body’s own immune system doesn’t always attack it as it would with a virus for example.
Why is immunosuppression important?
It is important to maintain non-autologous transplant.
What are the phases of immunosuppression?
- Induction
- Maintenance
- Rescue phase of treatment
What are examples of immunosuppressants?
- General immune inhibitors such as corticosteroids
- Cytotoxic and so kill proliferating lymphocytes such as mycophenolic
- Inhibit T cell activation such as cyclosporin
Immunosuppressives may need to be maintained indefinitely.
What is cyclosporin?
This was a breakthrough drug of transplant.
What is the action of cyclosporin?
It blocks T cell proliferation and differentiation. However, it is very toxic.
- Next generation therapies are less toxic and effective at lower doses.
Action of cyclosporin and FK506
Inhibit production of IL-2
Action of mycophenolic acid
Blocks lymphocyte proliferation through inhibition of DNA synthesis in T and B cells
Action of Rapamycin
Blocks lymphocyte proliferation by inhibiting IL-2 signalling
Action of steroids
General anti-inflammatory effects
Action of Anti-CD3 monoclonal antibody
Depletes T cells by targeting them for destruction
Action of Anti-IL-2 receptor antibody
Inhibits T cell proliferation by blocking IL-2 binding. May also promote phagocytosis and complement activation.
What are some combination immunosuppressive regimes?
Steroids such as prednisolone.
Cytotoxic such as mycophenolate motefil. Immunosuppressive specific for T cells such as cyclosporin.
What are the immunosuppressives that prevent transplant rejection whilst maintaining other immune responses?
There is currently no immunosuppressives.
What are transplant patients at risk of?
Transplant patients more susceptible to infection and malignancy, they have an immediate risk of CMV.
What does immunosuppressive drug toxicity lead to?
It can lead to organ failure for example, cyclosporin nephrotoxicity in kidney transplant.
What in the intestine is involved in regulating adaptive immune responses?
The microbiome, particularly of the intestine is involved in regulating adaptive immune responses.
Why are immunosuppressed patients given faecal material transplant?
Can take faecal material transplant in order to promote effective anti-cancer immune responses. This may be implicated in transplantation outcomes.
