Transplantation and Immunosuppressive Drugs

Question 1

Transplantation - define

Answer 1

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

Question 2

Immune responses - cause

Answer 2

Immune responses to transplant are caused by genetic differences between the donor and the recipient

Question 3

Importance of epitopes on donor MHC

Answer 3

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

Question 4

T cells recognise

Answer 4

T cells recognise short peptide fragments that are presented to them by major histocompatibility (MHC) proteins

Question 5

MHC class I - bind what and seen by what

Answer 5

Fragments of intracellular proteins

T cell receptor on Cytotoxic T cells, with assistance from CD8

Question 6

MHC class II - bind what and seen by what

Answer 6

Fragments of proteins which have been taken up by endocytosis
T cell receptor on helper T cells, with assistance from CD4

Question 7

Describe relation of self HLA/peptide

Answer 7

Self HLA + self peptide = no T-cell activation

Self HLA + non self peptide = T-cell activation

Question 8

Describe relation of matched HLA/peptide

Answer 8

Matched HLA + peptide = no T-cell activation

Unmatched HLA + peptide = T-cell activation

Question 9

Live vs dead donors

Answer 9

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

Question 10

Types of graft rejection

Answer 10

Hyperacute rejection

Acute rejection

Chronic rejection

Question 11

Hyperacute rejection - when

Answer 11

Within a few hours of transplant

Most commonly seen for highly vascularised organs (e.g. kidney)

Question 12

Hyperacute rejection - requires

Answer 12

Requires pre-existing antibodies, usually to ABO blood group antigens or MHC-I proteins
(ABO antigens are expressed on endothelial cells of blood vessels)

Question 13

Antibodies to MHC can arise from

Answer 13

Antibodies to MHC can arise from pregnancy, blood transfusion or previous transplants

Question 14

How can antibodies cause damage to transplanted tissue?

Answer 14

Recognition of Fc region leading to -

Complement activation

Antibody dependent cellular cytotoxicity
(Fc Receptors on NK cells)

Phagocytosis
(Fc Receptors on macrophages)

Question 15

Hyperacute rejection - describe action

Answer 15

Antibodies bind to endothelial cells

complement fixation

accumulation of innate immune cells

Endothelial damage, platelets accumulate, thrombi develop

Question 16

Acute rejection - describe

Answer 16

Inflammation results in activation of organ’s resident dendritic cells

T cell response develops as a result of MHC mismatch

Question 17

Describe immune response after inflammation

Answer 17

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

Question 18

Chronic rejection - describe

Answer 18

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

Question 19

Chronic rejection results from

Answer 19

Chronic rejection results from indirect allorecognition of foreign MHC/HLA

Question 20

Chronic rejection - effects

Answer 20

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

Question 21

Graft Versus Host Disease - define

Answer 21

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

Question 22

Graft Versus Host Disease - prevention

Answer 22

Removing T cells from transplant or suppressing their function reduces GVHD

Question 23

Graft versus Leukemia - when is it useful

Answer 23

But sometimes mismatch and donor leukocytes can be beneficial - removing original leukemia
Graft versus leukemia response
Development of GVL may prevent disease relapse

Question 24

Immunosuppression - function

Answer 24

Essential to maintain non-autologous transplant

Induction, maintenance and rescue phases of treatment

Question 25

Immunosuppressants for transplant can be what

Answer 25

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)

Question 26

Cyclosporin - functions

Answer 26

Breakthrough drug for transplant

Blocks T cell proliferation and differentiation

Inhibit production of IL-2

Question 27

Cyclosporin - comparison w/next gen therapies

Answer 27

Next generation therapies less toxic and effective at lower doses

Question 28

Mycophenolic acid - function

Answer 28

Blocks lymphocyte proliferation through inhibition of DNA synthesis in T and B cells

Question 29

Rapamycin - function

Answer 29

Blocks lymphocyte proliferation by inhibiting IL-2 signalling

Question 30

Steroids - function

Answer 30

General anti-inflammatory effects,

Question 31

Anti-CD3 monoclonal antibody - function

Answer 31

Depletes T cells by targeting them for destruction

Question 32

Anti-IL-2 receptor antibody - function

Answer 32

Inhibits T cell proliferation by blocking IL-2 binding. May also promote phagocytosis and complement activation

Question 33

Combination immunosuppressive regimes - list

Answer 33

(1) Steroids – e.g. prednisolone
(2) Cytotoxic – e.g. mycophenolate motefil
(3) Immunosuppressive specific for T cells – e.g. cyclosporin A, FK506,

Question 34

Immunosuppressive therapy monitoring - explain why not present

Answer 34

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

Question 35

Immunosuppressive drug toxicity can lead to

Answer 35

Immunosuppressive drug toxicity can lead to organ failure eg cyclosporin nephrotoxicity in kidney transplant.