27- Transplantation and Immunosuppressive Drugs

Question 1

what is transplantation?

Answer 1

the introduction of biological material (e.g. organs, tissue, cells) into an organism

Question 2

what is autologous transplantation?

Answer 2

transplantation of biological material from a person to another part of same person (e.g. skin grafts)

Question 3

what is syngeneic transplantation?

Answer 3

transplantation of biological material from donor to recipient – different people but genetically identical (e.g. twins)

Question 4

what is allogenic transplantation?

Answer 4

donors and recipients are from the same species but genetically different (e.g. siblings)

Question 5

what is xenogeneic transplantation?

Answer 5

donor and recipient are different species (e.g. heart valve transplantation using porcine or bovine valves)

Question 6

what is the importance of histocompatibility and epitope matching in transplants?

Answer 6

tissue compatibility between donor and recipient is crucial for successful transplants - immune responses against transplants are driven by differences in MHC antigens

HLA genes are the most polymorphic genes, have 1000s of variants, hard to match HLA alleles and specific epitopes

Question 7

importance of MHC epitopes in transplantation?

Answer 7

epitopes are the part of an antigen that is recognized by the immune system to stimulate an immune response

donor MHC epitopes are recognized by the recipient’s immune system

T-cell epitopes are peptide fragments from donor MHC molecules

B-cell epitopes are regions on donor MHC molecules recognized by antibodies

if the recipient’s immune system sees donor MHC epitopes as foreign, it may reject the transplant

Question 8

what is allorecognition?

Answer 8

immune system recognising and responding to antigens from another individual of the same species

Question 9

what is direct allorecogntiion?

Answer 9

recipient T cells recognising donor MHC molecules presented by donor APCs

mismatched HLA leads to activation of recipient immune system to attack donor tissue

Question 10

what is indirect allorecognition?

Answer 10

recipient T cells recognise donor-derived peptides presented on recipient APCs

presence of foreign/ donor peptide activates recipient immune response

Question 11

why is it better to use live donors over dead donors?

Answer 11

live donors are better

dead donors will have a history of diseases resulting in a degree of inflammation and ischaemia - inflammation may activate immune responses

it’s better to have an MHC live donor mismatch than a dead donor’s inflamed organ

Question 12

three types of rejection mechanisms?

Answer 12

hyperacute
acute
chronic

Question 13

when does hyperacute rejection occur?

Answer 13

within a few hours of transplantation, often with highly vascularised organs like the kidneys as more immune cells and antibodies pass through them

Question 14

mechanism for hyperacute rejection

Answer 14

pre-existing antibodies to non-self ABO antigens (expressed on blood vessel endothelial cells) or MHC-1 molecules from the donor - antibodies bind to antigens

Fc portion of bound antibodies stick out - triggers:
1. antibody-dependent cellular cytotoxicity = Fc-gamma-R3 receptors on NK cells bind to Fc region on antibodies, activates NK cytotoxic activity and the release of cytotoxic granules via the formed immunological synapse

2. activates complement cascade - via C3 and C5 convertases - promotes MAC formation for cell lysis, triggers inflammation and recruiting immune cells, activates phagocytosis
3. triggers phagocytosis with macrophage Fc receptor and antibody-Fc region binding

damage causes blood clot/ thrombi formation, contributes to tissue damage and death = ultimately transplant rejection

Question 15

pre-existing antibodies against non-self ABO antigens or MHC-1 molecules - from where?

Answer 15

pregnancy
blood transfusion
previous transplants

Question 16

what triggers acute rejection?

Answer 16

direct allorecognition

Question 17

mechanism for acute rejection

Answer 17

inflammation of transplanted organ affects organ’s resident dendritic cells/ APCs

donor APCs migrate to secondary lymphoid organs to present donor peptides to self effector T cells = immune response

macrophages and CD8+ T cells are activated to destroy the transplant

Question 18

when does chronic rejection occur?

Answer 18

months/years after transplant

Question 19

mechanism for chronic rejection?

Answer 19

donor-derived cells from transplant die overtime

membrane fragments from dying cells containing donor peptides/MHC are released, internalised and presented by self-APCs to self-T cells = indirect allorecognition of donor peptides

activates immune response by effector T cells - antibodies against donor peptides are produced, bind to donor antigens on transplant organ’s endothelial cells = induces inflammation

recruited effector CD8+ cells and macrophages induce damage, reduce blood supply to transplant organ by thickening vessel walls and narrowing lumen

chronic inflammation and lack of blood supply = tissue damage and death of graft

Question 20

describe haemopoietic stem cell transfer

Answer 20

blood and bone marrow transplant used to infuse HSCs into patient - helps regenerate healthy HSCs

autologous or allogenic transplant - as long as there’s HLA matching

process:
HSCs are collected from blood or bone marrow, infused into the patient and migrate to bone marrow to engraft and begin hemopoiesis - produce new blood cells. differentiate into various blood cell lineages

Question 21

what is graft vs host disease?

Answer 21

transplanted donor immune cells attacking the host, as they see recipient cells as non-self

transplant targets the host - occurs especially when transplanting immune cells

Question 22

how can graft vs host disease be useful

Answer 22

useful in leukaemia - engrafting/ transplanted graft cells can identify and kill leukaemia cells, prevents disease relapse

Question 23

importance in immunosuppression in transplant medicine?

Answer 23

essential to maintain allogenic/ non-autologous transplant

Question 24

what are the three phases of immunosuppressive treatment?

Answer 24

induction
maintenance
rescue

Question 25

methotrexate as an immunosuppressant?

Answer 25

kills proliferating T and B lymphocytes

Question 26

cyclosporin as an immunosuppressant?

Answer 26

blocks T cell proliferation and differentiation, allows transplants to survive longer in recipient

quite cytotoxic, significant side effects

Question 27

what two main immunosuppressive regimes are used in the induction phase?

Answer 27

antibody induction therapy
- lymphocyte depleting rabbit ATG that prevents T cell proliferation & activation
- basiliximab which targets the IL-2 pathway

triple drug regimen
- calcineurin inhibitor, an antiproliferative agent, and corticosteroid = at higher doses during induction

Question 28

how is ATG used as an immunosuppressant? how does it work?

Answer 28

mainly during induction phase for immunosuppression, also used during T-cell mediated rejection for rescue phase

prevents T cell proliferation & activation

Question 29

what immunosuppressive regimen is used during the maintenance phase?

Answer 29

triple drug regimen at lower doses, tapering off at risk of transplant rejection

Question 30

what drugs are involved in the triple drug regimen?

Answer 30

calcineurin inhibitor (calcineurin helps activate T cells)
an antiproliferative agent
a corticosteroid

tacrolimus, mycophenolate mofetil, and prednisone is the most common

Question 31

what is the rescue phase implemented with immunosuppressants?

Answer 31

if rejection occurs - treatment depends on whether it’s T-cell or B-cell mediated rejection

Question 32

immunosuppressive rescue drugs used during T-cell mediated rejection?

Answer 32

ATG and high dose steroids

Question 33

immunosuppressive rescue drugs used during B-cell mediated rejection?

Answer 33

i.v. immunoglobulin
anti-CD20 monoclonal antibody with high-dose steroids = anti-CD20 binds to CD20 on B cells and depletes them

Question 34

example of IL-2 antagonist?

Answer 34

basiliximab

Question 35

example of calcineurin inhibitors?

Answer 35

cyclosporine - inhibit IL-2 production = prevent T cell activation and proliferation

Question 36

risk of immunosuppressive therapy?

Answer 36

suppresses recipient immune responses, affects their ability to tackle infection or tumorigenesis

more susceptible to infection and malignancy

some have severe side effects - e.g. cyclosporin can induce nephrotoxicity in kidney transplant

Question 37

importance in intestinal microbe in immunosuppressed patients?

Answer 37

immunosuppressed patients not responding to cancer immunotherapy - undergo faecal transplant, changes gut microbiome = promotes effective anti-cancer immune responses

intestinal microbiome is important in regulating adaptive immune responses, may be implicated in transplant outcomes