Immuno 7: Transplant

Question 1

What are the 2 most important protein variations that determine donor organ compatibility ? (Least likely to be rejected)

Answer 1

HBO blood group

HLA

Question 2

Which 3 HLA isotypes are considered the most immunogenic ?

Answer 2

HLA-A
HLA-B
HLA-DR

Question 3

How can transplanted organs cause a T-cell mediated immune response ?

Answer 3

If there is a mismatch in HLA molecules APC cells present foreign HLA to naive T cells in the lymph nodes
The CD4+ T cells activate Cytotoxic CD8+ T cells and macrophages

Question 4

Do we have pre-formed HLA-antibodies ?

Answer 4

No

Unless you have previously had a transplant, received a blood transfusion or been pregnant

Question 5

What could cause a hyperacute rejection of an organ transplant ?

Answer 5

If you already had pre formed HLA-antibodies

Question 6

List 3 ways antibodies cause killing of pathogens/graft ?

Answer 6

1- Neutralising by binding directly to pathogen or toxin
2- Opsonising the pathogen/graft so Phagocytes can clear it
3- Binding to pathogen/graft so NK cells can recognise FC receptor of antibody and destroy the pathogen/graft

Question 7

List 2 ways antibodies cause killing of graft via complement?

Answer 7

1- Antibody binds to HLA molecule on endothelium of the graft. The Fc region can activate the classical complement cascade leading to formation of the membrane attack complex which ends in cell lysis

2- Antibody binds to HLA molecule on endothelium of graft. The activation of complement cascade recruits NK cells and other mononuclear cells which kill the graft cells.

Question 8

How does Antibody mediated transplant rejection look different to T cell mediated transplant rejection on histology ?

Answer 8

Antibody mediated- Microcirculation inflammation (endothelium)
T cell mediated - Tubulointerstitial inflammation

Question 9

What are the 3 main types of anti-HLA assays to screen for antibodies against the graft ?

Answer 9

Cytotoxicity assay- looks at whether the recipients serum will kill the lymphocytes of the donor in the presence of complement. Positive cross match suggest cell lysis

Flowcytometry- looks at whether the recipients serum binds to the donors lymphocytes, bound antibody is detected by flourescently labelled anti-human immunoglobulin

Solid phase assays- uses recombinant proteins of all the HLA molecules in fluorescent beads. Looks at which bead fluoresces to see which HLA molecules are causing an immune reaction

Question 10

What is the role of IL2 in T cell mediated immune response to graft ?

Answer 10

IL2 is a cytokine that causes autocrine and paracrine activation of T cells

Question 11

List 3 immunosuppressive agents used in transplants that target T cells ?

Answer 11

Cyclosporin- Calcineurin inhibitor
Azathioprine- cell cycle inhibitor
Anti CD3 antibody (muromonab)- targets TCR
Daclizumab- anti-CD25 antibody

Question 12

List 3 immunosuppressive agents used in transplants that target antibody mediated rejection ?

Answer 12

Rituximab- anti CD20 antibody
Eculizumab- Complement inhibitor
BAFF inhibitors- blocks cytokines

Question 13

Explain graft vs host disease ?

Answer 13

1- The recipients immune system is wiped out by radiation therapy.
2- The donor stem cells set up a new immune system in the recipients bone marrow
3- The new immune system can start attacking the hosts organs because they recognise the self antigens as foreign

Question 14

What is one possible benefit that can occur as a result of graft vs host disease ?

Answer 14

Immune response can attack tumours (graft vs tumour effect)

Question 15

Which 2 drugs are commonly given for GVHD prophylaxis ?

Answer 15

Methotrexate

Cyclosporin

Question 16

List 3 opportunistic infections that more regularly occur post transplant ?

Answer 16

CMV
PCP
BK virus

Question 17

Which mouse monoclonal antibody can suppress T cells by targeting CD3 and is used in case of organ transplant rejection ?

Answer 17

Muromonab (CD3 Mab)

Question 18

Name the type of transplant between twins with identical HLA ?

Answer 18

Isograft

Question 19

Name the type of transplant between a donor and recipient from the the same species who are not identical ?

Answer 19

Allograft

Question 20

Name the type of transplant where the donor and recipient are from different species ?

Answer 20

Xenograft

Question 21

Name the type of transplant where the donor uses their own tissue for transplant ?

Answer 21

Autograft

Question 22

what are the 3 phases of the immune response to transplanted graft

Answer 22

phase 1: recognition of foreign antigen

2: activation of antigen-specific lymphocytes
3: effector phase of graft rejection

Question 23

what are the 2 main components to rejection

Answer 23

T -cell mediated

Antibody mediated

Question 24

on which chromosome is HLA encoded

Answer 24

chromosome 6 by MHC

Question 25

on which cells are HLA class I and II encoded

Answer 25

I - A,B,C - expressed on all cells | II - DR, DP, DQ - expressed on APC but can also be upregulated on other cells under stress

Question 26

list the actions of activated T cells

Answer 26

``` proliferation produce cytokines (IL2 important) provide help to CD8+ T cells provide help for antibody production recruit phagocytic cells ```

Question 27

what are typical histological features of T cell mediated rejection

Answer 27

lymphocytic interstitial infiltration ruptured tubular basement membrane tubilitis

Question 28

describe the histology of kidney transplant rejection

Answer 28

interstitial inflammation and tubulitis lots of lymphocytes BM and tubular epithelium has been ruptured by lymphocytes inflammatory cells also attack the endothelium ofblood vessels - arteritis

Question 29

how do antibodies act in transplanation

Answer 29

antibodies bind to antigens (HLA) on the endothelium of the blood vessels in the transplanted organ these antibodies can fix complement which assembles to form membrane attack complexes (MAC) results in endothelial cell lysis also recruits inflammatory cells - within capillaries of the kidney - capillaritis results in graft fibrosis antibodies against graft endothelial epitopes can also cause damage by cross-linking the MHC molecules and activating them

Question 30

how can we prevent graft rejection

Answer 30

AB/HLA typing especially important for bone and kidney transplants screening for antibodies: - cytotoxicity assays (will recipients serum kill donor lymphocytes) - flow cytometry (will recipients serum bind to donor lymphocytes) - solid phase assays

Question 31

describe immunosuppression for transplants (targeting T cells

Answer 31

steroids to prevent T cell mediated rejection calcineurin inhibitors eg: tacrolimus, cyclosporine cell cycle inhibitors: mycofenolate mofetil, azathioprine targeting TCR: anti CD3 antibody, anti thymocyte antibody almtuzumab - anti CD52 monoclonal antibody that causes lysis of T cells Dacluzumab - anti CD25 monoclonal antibody which targets the cytokine signal

Question 32

describe immunosuppression for transplants (targeting antibody mediated rejection)

Answer 32

Deplete B cells using rituximab (anti CD20) BAFF inhibitors target cytokines that promote B cell activation and growth proteasome inhibitors block production of antibodies by plasma cells complement inhibitors eg eculizumab

Question 33

list the standard transplant immunosuppression

Answer 33

induction agent - OXT3/ATG, anti CD52, anti CD25 | baseline immunosuppression: calcineurin inhibitor + mycofenolate mofetil/ azathioprine +- steroids

Question 34

how do we treat episodes of acute rejection

Answer 34

cellular - steroids/ OKT3/ATG | antibody-mediated - IVIG, plasma exchange, anti C5, anti CD20

Question 35

describe haematopoietic SC transplantation

Answer 35

used for haem and lymphoid cancers GVHD - prophylaxis = methotrexate/ cyclosporine rash, n+v, abdo pain, diarrhoea, jaundice

Question 36

list common post transplant malignancies

Answer 36

``` kaposi sarcoma (HHV8) lymphoproliferatve disease (EBV) ```