Transplantation and Immunosuppressive Drugs Flashcards
What does transplantation mean
Transplantation is the introduction of biological material (eg organs, tissue, cells) into an organism
What are the types of donor relationships
- Autologous and syngeinic donations
- genetically identical
- no immune reactions
- donation to and from same part of body
What is an example of an autologous transplant
Skin grafts from one part to another part of the body
What is an example of an syngeneic transplant
From one identical twin to another twin
What is allogenic transplantation
Same species but genetically different
What is xenogeneic transplantation
Transplantation between different species entirely
What is the cause of transplantation rejection
- Immune responses to transplant are caused by genetic differences between the donor and the recipient
- The most important are differences between the antigens forming the major histocompatibility complex (MHC)
What is the importance of epitopes on donor MHC
- B-cell epitopes on donor MHC
- T-cell epitopes derived from donor MHC
- 1000’s of HLA alleles but perhaps only 100’s of epitopes
- Next-generation sequencing is required to assassin the difference between the HLA of the recipient and donor
How is MHC recognised in a transplant
Both the MHC protein and the peptide in its binding groove may be foreign
What is Indirect allo-recognition
- Where a self HLA and non-self peptide is present there is T cell activation
- Cause lysis of cell
What is direct allo-recognition
- Where a unmatched HLA and peptide causes T cell activation
How do we ensure transplant survival
- try to match 4/6 MHC class 2 loci
- Reduces likelihood of future transplants and problems with future transplant
Describe the possibility of using Live vs Dead donors
- Recipients will have a history of disease which will have
resulted in a degree of inflammation - Organs from deceased donors are also likely to be in
inflamed condition due to ischemia - Transplant success is less sensitive to MHC mismatch
for live donors
What are the types of graft rejections
- Hyperacute rejection
- Acute rejection
- Chronic rejection
What is hyper-acute rejection
- Within a few hours of transplant
- Most commonly seen for highly vascularised organs
(e.g. kidney) - Requires pre-existing antibodies, usually to ABO
blood group antigens or MHC-I proteins - (ABO antigens are expressed on endothelial cells of
blood vessels) - Antibodies to MHC can arise from pregnancy, blood
transfusion or previous transplants
How does antibodies cause damage to transplanted tissue
- Recognition of Fc region leading to
- Complement activation
- Antibody-dependent cellular cytotoxicity
(Fc Receptors on NK cells) - Phagocytosis
(Fc Receptors on macrophages)
How does antibodies cause damage in hyper acute rejection
- Antibodies bind to endothelial cells
- complement fixation
- accumulation of innate immune cells
- Endothelial damage, platelets accumulate, thrombi develop
Describe acute reaction
- Inflammation results in activation of organ’s resident dendritic cells
- T cell response develops as a result of MHC mismatch
Describe the direct allorecognition response in acute rejection
- Inflammation results in activation of organ’s resident dendritic cells
- DC migrate to secondary lymphoid tissue where they encounter circulating effector T cells
- Macrophages and CTL increase inflammation and destroy transplant
Describe chronic rejection
- Can occur months or
years after transplant - Blood vessel walls thickened, lumina narrowed – loss of blood supply
- Correlates with presence of antibodies to MHC-I
Describe the indirect allorecognition response in chronic rejection
- Donor-derived cells die
- Membrane fragments containing donor MHC are taken up by host DC
- Donor MHC is processed into peptides which are presented by host MHC
- T cell and antibody responses is generated to the peptide derived from processed donor MHC
What is Haematopoetic stem cell transfer
- Previously called bone marrow transplant, now
renamed as source is often blood - Often autologous
- Until 1980 only HLA identical siblings could be used as donors due to the risk of rejection or graft versus host disease
What is meant by Graft vs Host disease
- When transplanted tissue is immune cells themselves, there is the risk of
donor immune cells attacking the host – GVHD - Can be lethal – best approach is prevention
- Removing T cells from transplant or suppressing their function reduces
GVHD
Describe the graft vs leukemia response
- Sometimes mismatch and donor leukocytes can be
beneficial - removing original leukaemia - Graft versus leukaemia response
- Development of GVL may prevent disease relapse
Why is immunosuppression important
- essential to maintain non-autologous transplants
What are the 3 phases of immunosuppression treatment
- Induction
- Maintenance
- Rescue
What are some types of immunosuppressants used
- General immune inhibitors (e.g. corticosteroids)
- Cytotoxic – kill proliferating lymphocytes (e.g. mycophenolic
acid, cyclophosphamide, methotrexate) - Inhibit T-cell activation (cyclosporin, tacrolimus, rapamycin)
Describe the use of cyclosporin
- Blocks T cell proliferation and differentiation
- improved patient and graft survival rates dramatically from 30%-50% to 80% at 1 year.
- Next generation therapies less toxic and effective at lower doses
Describe the use of combination immunosuppressive regimes
- (1) Steroids – e.g. prednisolone
- (2) Cytotoxic – e.g. mycophenolate motefil
- (3) Immunosuppressive specific for T cells
– e.g. cyclosporin A, FK506,
Describe the Induction phase of immunosuppressive regimes
Antibody induction therapy:
- Lymphocyte depleting rabbit Anti-thymocyte globulins (ATG) is the most
commonly used antibody for induction therapy, followed by basiliximab and
alemtuzumab.
Triple drug regimen:
- a calcineurin inhibitor, an antiproliferative agent, and corticosteroid.
- Tacrolimus, mycophenolate mofetil, and prednisone is the most common regimen.
Describe the maintenance phase of immunosuppressive regimes
Use of triple drug regimen at lower doses
Describe the Rescue phase of immunosuppressive regimes
- T-cell mediated rejection (TCMR) is treated with ATG and steroids (eg,
methylprednisolone 250-1000 mg per dose). - B-cell mediated rejection (BCMR) may be treated with Intravenous
immunoglobulin or anti-CD20 antibody and steroids.
How do we monitor immunosuppressive therapy
- There is currently no immunosuppressive that will prevent
transplant rejection whilst maintaining other immune responses - Transplant patients more susceptible to infection and malignancy
– Immediate risk e.g. CMV - Immunosuppressive drug toxicity can lead to organ failure eg
cyclosporin nephrotoxicity in kidney transplant.
How does intestinal microbiome affect transplants and immunosuppressed patients
- The microbiome, particularly of the intestine, is involved
in regulating adaptive immune responses - Immunosuppressed patients (e.g. cancer patients) can
take FMT – faecal material transplant – in order to
promote effective anti-cancer immune responses - May be implicated in transplantation outcomes
