Transplantation and Immunosuppressive Drugs Flashcards
Transplantation - define
Transplantation is the introduction of biological material (eg organs, tissue, cells) into an organism
The immune system has evolved to remove anything it regards as non-self
Immune responses - cause
Immune responses to transplant are caused by genetic differences between the donor and the recipient
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 required
T cells recognise
T cells recognise short peptide fragments that are presented to them by major histocompatibility (MHC) proteins
MHC class I - bind what and seen by what
Fragments of intracellular proteins
T cell receptor on Cytotoxic T cells, with assistance from CD8
MHC class II - bind what and seen by what
Fragments of proteins which have been taken up by endocytosis
T cell receptor on helper T cells, with assistance from CD4
Describe relation of self HLA/peptide
Self HLA + self peptide = no T-cell activation
Self HLA + non self peptide = T-cell activation
Describe relation of matched HLA/peptide
Matched HLA + peptide = no T-cell activation
Unmatched HLA + peptide = T-cell activation
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
Types of graft rejection
Hyperacute rejection
Acute rejection
Chronic rejection
Hyperacute rejection - when
Within a few hours of transplant
Most commonly seen for highly vascularised organs (e.g. kidney)
Hyperacute rejection - requires
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
Antibodies to MHC can arise from pregnancy, blood transfusion or previous transplants
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)
Hyperacute rejection - describe action
Antibodies bind to endothelial cells
complement fixation
accumulation of innate immune cells
Endothelial damage, platelets accumulate, thrombi develop
Acute rejection - describe
Inflammation results in activation of organ’s resident dendritic cells
T cell response develops as a result of MHC mismatch
Describe immune response after inflammation
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
Chronic rejection - describe
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
Chronic rejection results from
Chronic rejection results from indirect allorecognition of foreign MHC/HLA
Chronic rejection - effects
Membrane fragments containing donor MHC are taken up by host DC
Donor MHC is presented into peptides which are presented by host MHC
T cell response is generated to the peptide derived from processed donor MHC
Graft Versus Host Disease - define
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
Graft Versus Host Disease - prevention
Removing T cells from transplant or suppressing their function reduces GVHD
Graft versus Leukemia - when is it useful
But sometimes mismatch and donor leukocytes can be beneficial - removing original leukemia
Graft versus leukemia response
Development of GVL may prevent disease relapse
Immunosuppression - function
Essential to maintain non-autologous transplant
Induction, maintenance and rescue phases of treatment
Immunosuppressants for transplant can be what
Immunosuppressants for transplant can be -
General immune inhibitors (e.g. corticosteroids)
Cytotoxic – kill proliferating lymphocytes (e.g. mycophenolic acid, cyclophosphamide, methotrexate)
Inhibit T-cell activation (cyclosporin, tacrolimus, rapamycin)
Cyclosporin - functions
Breakthrough drug for transplant
Blocks T cell proliferation and differentiation
Inhibit production of IL-2
Cyclosporin - comparison w/next gen therapies
Next generation therapies less toxic and effective at lower doses
Mycophenolic acid - function
Blocks lymphocyte proliferation through inhibition of DNA synthesis in T and B cells
Rapamycin - function
Blocks lymphocyte proliferation by inhibiting IL-2 signalling
Steroids - function
General anti-inflammatory effects,
Anti-CD3 monoclonal antibody - function
Depletes T cells by targeting them for destruction
Anti-IL-2 receptor antibody - function
Inhibits T cell proliferation by blocking IL-2 binding. May also promote phagocytosis and complement activation
Combination immunosuppressive regimes - list
(1) Steroids – e.g. prednisolone
(2) Cytotoxic – e.g. mycophenolate motefil
(3) Immunosuppressive specific for T cells – e.g. cyclosporin A, FK506,
Immunosuppressive therapy monitoring - explain why not present
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
Immunosuppressive drug toxicity can lead to organ failure eg cyclosporin nephrotoxicity in kidney transplant.
