Transplantation and Immunosuppressive Drugs Flashcards
What is transplantation?
Transplantation can be defined as the introduction of biological material (e.g organs, tissue, cells) into an organism
The problem with that is that the immune system has evolved to remove anything that it regards as non-self
What is an autologous transplant?
The transplantation from one part of an organism into another part of the same organism
- You may see an inflammatory response but there wouldn’t be any problems as it is self-transplanted into self
- E.g skin transplant from one site to another
What is a syngeneic transplant?
This is where donor material is transplanted into a recipient, however the donor and the recipient are genetically identical
- These should not generate an immune response as there is no genetic difference between donor + recipient
- E.g identical twins
What is an allogenic transplant?
Allogenic transplantation is when a donor donates part of their tissue to a recipient, but they are genetically different.
An example of this would be siblings/ relatives
Describe Xenogeneic transplants?
The transfer of tissue from an organism of one species to another
e.g Pig heart transplant into humans, however this is not common and there have only been a few cases where this happens with success
What are immune responses to transplants caused by?
Genetic differences between the donor and recipient
What is the most important consideration during transplantation?
MHC Genes
- The most important genetic differences are differences between the antigens forming the MHC
Where are MHC genes located?
On chromosome 6
- Most diverse region in the genome
How is HLA classified?
MHC I
- HLA-A, HLA-B, HLA-C
MHC II
- HLA-DRA, HLA-DRB, HLA-DPA, HLA-DQA, HLA-DQB
How can we match donor and recipient MHC?
Via next generation sequencing
What are the reasons for transplant rejection?
Either
- MHC protein is foreign
- Peptide in binding groove is foreign
- This can result in different rejection mechanisms
What is allorecogition?
Activation of T cells to react against transplant
Describe indirect allorecognition
Recipient T cells recognise a self-MHC molecule on a recipient cell with a bound peptide derived from the donor/foreign MHC molecule = T Cell Activation
Describe direct allorecognition
Recipient T cells recognise an intact allogenic (unmatched/foreign) MHC molecule expressed by a donor cell = T cell activation
Are dead or live donors more succesful for transplants?
- Live donors are more succesful
- This is because dead organ donors are more sensitive to MHC mismatch
- Organs from deceased donors are more likely to be in a inflamed condition due to ischaemia
- This is because dead organ donors are more sensitive to MHC mismatch
What are the types of graft rejection?
- There are three types of graft rejection
- Hyperacute rejection (pre-exisiting anti-donor Abs bind to antigens on donor tissue)
- Acute rejection (Direct allorecognition)
- Chronic rejection (Indirect allorecognition)
What is hyperacute rejection?
Pre-existing anti-donor antibodies rapidly bind antigens on donor tissue and result in
- Complement activation
- Antibody dependant cellular cytotoxicity (Fc receptors on NK cells)
- Phagocytosis (Fc receptors on macrophages)
What is the onset of hyperacute rejection?
Within a few hours
Which antigens do pre-existing anti-donor antibodies bind to in hyperacute rejection?
- Usually to ABO blood group antigens expressed on endothelial cells of blood vessels
- MHC I proteins
Where is hyperacute rejection most commonly seen?
In highly vascularised organs e.g kidney
What is the effector mechanism of preexisting anti-donor antibodies in hyperacute rejection?
- Antibodies will bind to ABO antigens expressed on endothelial cells
- This will lead to complement activation and accumulation of innate immune cells
- Endothelial damage = platelet accumulation and development of thrombi
- Tissue can die indirectly from this breakdown in the endothelial cells by ADCC and ADCP
What is acute rejection?
-
Direct allorecognition of foreign MHC
- Donor DC’s will migrate to secondary lymphoid tissue where they encounter effector T-cells = MHC mismatch
- Dendritic cells express both MHC I and MHC II meaning they activate both CD8+ and CD4+ T-cells
- CTL will increase inflammation and destroy the transplant
What is chronic rejection?
Indirect allorecognition
- Donor cells die
- Membrane fragments containing donor MHC are taken up by recipient/ host dendritic cells
- Donor MHC is processed into peptides which are presented by host MHC
- T cell response is generated to the peptide derived from the processed donor MHC
What is the onset of chronic rejection?
Can occur months or years after transplant
How can we transplant immune cells?
Haematopoietic Stem Cell Transfer (HSCT)
- Stem cells find their way to the bone marrow after infusion and regenerate there where they are cyropreserved with little damage
- Often autologous (will not cause an immune response)
What is the risk of transplanting immune stem cells from a donor to recipient (allogenic)?
Graft vs Host Disease (GVHD)
- Risk of donor immune cells attacking the host
- Can be lethal
How do we prevent graft vs host disease?
Removing T-cells from transplant or suppressing their function reduces GVHD
Explain a situation where grafting a donor immune system can be beneficial?
Graft vs Leukaemia
- Sometimes mismatch and donor leukocytes are beneficial
- Cancer cells are derived from self, and the immune system struggles to identify it as a foreign cell
- However, if you have a donor’s immune system transplanted it will be able to recognise the cancer as foreign and kill them because of the HLA mismatch
How can we maintain a non-autolgous transplant?
Immunosuppression drugs are essential to maintain a non-autologous transplant
What are the phases of treatment to immunosuppression following a transplant?
- Induction (Preventing the build-up of an immune response against transplant organ)
- Maintenance (will be altering dosage depending on the effectiveness of individual treatment)
- Rescue (if the immune response mounts towards the tumour)
What can immunosuppresant drugs be?
-
General immune inhibitors
- Corticosteroids
-
Cytotoxic
- Kill proliferating lymphocytes
- E.g mycophenolic acid, cyclophosphamide, methotrexate
- Kill proliferating lymphocytes
-
Immunosuppressive specific T cells
- Cyclosporin A, FK506
Using combinations are more effective than single dosage drugs and allows you to reduce the dosage of both drugs and reduce the side effects.
What is the course of immunosuppresants
Immunosuppressive drugs may need to be maintained indefinitely
What is cyclosporin?
Cyclosporin will block T-cell proliferation and differentiation
What infection can immunosuppressed patients be at risk of?
Transplant patients are more susceptible to infection and malignancy
- Immediate risk of CMV
What is the problem with immunosuppressive drugs?
They can lead to organ failure
- Cyclosporin nephrotoxicity in kidney transplant
What can be used to help patients that do not respond to immunosuppressive therapy?
Faecal material transplant
- Immunosuppresed patients (e.g cancer patients) can take FMT in order to promote effective anti-cancer immune responses
- The microbiome particularly of the intestine is involved in adaptive immune responses
