Transplantation And Immunosupressive Drugs Flashcards
What are the two types of donor-recipient relationships?
Autologous and Syngeneic — Donors and recipients are genetically identical
Allogenic — donors and recipients are from the same species but are genetically different
Xenogeneic - donor and recipient are different species
What is histocompatibility?
Tissue compatibility between donor and organs
Immune responses are caused by genetic differences between the donor and recipient
Most important antigens are MHC
What is the importance of epitopes on donor MHC?
B cell epitopes on donor MHC
T cell epitopes derived from donor MHC
Less variation of epitopes than HLAs
Next generation sequencing required
Describe what occurs during MHC2 loading
Antigen is internalised by a phaglysosome
The antigen is lysed into peptides
These peptides then bind to MHC2 and are presented on the surface of the cell
Recognised by T helper cells and assistance from CD4
What is the function of helper T cells?
Information no support for other immune cells via cytokine production
what is the function of cytotoxic T cells?
Highly pacific killer cells
What exactly is recognised as foreign in transplants?
both the MHC and peptide in its binding grove may be defined as foreign
What occurs during indirect T cell activation?
Self HLA and self peptide will not activate T cells
Self HLA And NON Self peptide will activate T cells
What occurs during direct T cell activation?
Matches HLA and peptide on the downpour cell - no T cell activation
Unmatched. (Non-self) HLA and peptide - T cell activation
What is the correlation between HLA mismatch and graft survival?
Increased number of mismatches means a lower survival half life
What is the difference between live and dead donors?
Organs from dead donors are likely to be inflamed condition due to ischemia and possibly having a history of disease
Transplant success is less sensitive too MHC mismatch for live donors
What is hyper acute rejection?
Within a few hours of transplant.
Most commonly seen for highly vascularised organs (kidney)
Require pre existing antibodies (ABO blood group antigens OR MHC1 proteins)
Antibodies to MHC can arise from pregnancy, blood transfusion or previous transplants
What is acute rejection?
Inflammation of donor organ results in activation of organs dendritic cells
T cell response developes as a response of MHC mismatch
What is 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 MHC1
How can 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)
Describe what occurs during hyper acute rejection
- Antibodies bind to endothelial cells
- Complement fixation
- Accumulation of innate immune cells
- Endothelial damage, platelets accumulate, thrombi develop - phagocytosis and lysis
Describe what occurs in acute rejection?
- Inflammation results in activation of organs resident DC
- DC migrate to secondary lymphoid tissue - encounter circulating effector T cells
- Macrophages and CTL increase inflammation and destroy transplant
Describe what occurs during 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 graft vs host disease (GVHD)?
When the transplanted tissue is immmune cells themselves (eg. Haematopoietic transplant), there is a risk of donor immune cells attacking the host
Can be lethal - best approach is prevention
Removing T ells from transplant or suppressing their function reduces GVHD
What is graft versus leukaemia?
Sometimes mismatch and donor leukocytes can be beneficial - removing original leukaemia
May prevent relapse - as the graft sees leukaemia as non-self — stronger immune response to tumour cells
What are the 3 phases of immunosupression?
Induction
Maintenance
Rescue phases of treatment
What are 3 examples of immunosuppressants for transplant?
General immune inhibitors
Cytotoxic - kill proliferating lymphocytes
Inhibit T cell activation
IMMUNOSUPPRESSIVES MAY NEED TO BE MAINTAINED INDEFINITELY
What is cyclosporin?
Breakthrough drug for transplantation
Blocks T cell proliferation and differentiation
Improves patient and graft survival rates
What is included in combination immunosuppressive regimes?
- Steroids
- Cytotoxic
- Immunosuppressive specific for T cells
What occurs in the induction phase of immunosuppressants?
Antibody induction therapy
- lymphocyte depleting rabbit anti-thymocyte globulins (ATG) is the most commonly used antibody for induction therapy.
Triple drug regime
- calcineurin inhibited, a anti proliferative agent and corticosteroid
What occurs in the maintenance phase of immunosuppressants?
Triple drug regime at lower doses
What occurs in the rescue phase of immunosuppressants?
T cell mediated rejection is treated with ATG and steroids
B cell mediated rejection may be treated with intavenous immunoglobulin or anti-CD20 antibody and steroids
What are the limitations of immunosuppressive therapy?
Currently no immmunosupressive that will prevent transplant rejection whilst maintaining other immune responses
Transplant patients are more susceptible to infection and malignancy
Immunosuppressive drug toxicity can lead to organ failure
How can the intestinal microbiome be a effective anti cancer treatment for transplantation outcomes?
The microbiome and intestine is involved in regulating the adaptive immune response
FMT - feel material transplant in immunosupressed patients can promote effective anti-cancer immune responses
May be implicated in transplant outcomes
