Immuno 7: Transplant Flashcards
What are the 2 most important protein variations that determine donor organ compatibility ? (Least likely to be rejected)
HBO blood group
HLA
Which 3 HLA isotypes are considered the most immunogenic ?
HLA-A
HLA-B
HLA-DR
How can transplanted organs cause a T-cell mediated immune response ?
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
Do we have pre-formed HLA-antibodies ?
No
Unless you have previously had a transplant, received a blood transfusion or been pregnant
What could cause a hyperacute rejection of an organ transplant ?
If you already had pre formed HLA-antibodies
List 3 ways antibodies cause killing of pathogens/graft ?
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
List 2 ways antibodies cause killing of graft via complement?
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.
How does Antibody mediated transplant rejection look different to T cell mediated transplant rejection on histology ?
Antibody mediated- Microcirculation inflammation (endothelium)
T cell mediated - Tubulointerstitial inflammation
What are the 3 main types of anti-HLA assays to screen for antibodies against the graft ?
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
What is the role of IL2 in T cell mediated immune response to graft ?
IL2 is a cytokine that causes autocrine and paracrine activation of T cells
List 3 immunosuppressive agents used in transplants that target T cells ?
Cyclosporin- Calcineurin inhibitor
Azathioprine- cell cycle inhibitor
Anti CD3 antibody (muromonab)- targets TCR
Daclizumab- anti-CD25 antibody
List 3 immunosuppressive agents used in transplants that target antibody mediated rejection ?
Rituximab- anti CD20 antibody
Eculizumab- Complement inhibitor
BAFF inhibitors- blocks cytokines
Explain graft vs host disease ?
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
What is one possible benefit that can occur as a result of graft vs host disease ?
Immune response can attack tumours (graft vs tumour effect)
Which 2 drugs are commonly given for GVHD prophylaxis ?
Methotrexate
Cyclosporin
List 3 opportunistic infections that more regularly occur post transplant ?
CMV
PCP
BK virus
Which mouse monoclonal antibody can suppress T cells by targeting CD3 and is used in case of organ transplant rejection ?
Muromonab (CD3 Mab)
Name the type of transplant between twins with identical HLA ?
Isograft
Name the type of transplant between a donor and recipient from the the same species who are not identical ?
Allograft
Name the type of transplant where the donor and recipient are from different species ?
Xenograft
Name the type of transplant where the donor uses their own tissue for transplant ?
Autograft
what are the 3 phases of the immune response to transplanted graft
phase 1: recognition of foreign antigen
2: activation of antigen-specific lymphocytes
3: effector phase of graft rejection
what are the 2 main components to rejection
T -cell mediated
Antibody mediated
on which chromosome is HLA encoded
chromosome 6 by MHC
on which cells are HLA class I and II encoded
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
list the actions of activated T cells
proliferation produce cytokines (IL2 important) provide help to CD8+ T cells provide help for antibody production recruit phagocytic cells
what are typical histological features of T cell mediated rejection
lymphocytic interstitial infiltration
ruptured tubular basement membrane
tubilitis
describe the histology of kidney transplant rejection
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
how do antibodies act in transplanation
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
how can we prevent graft rejection
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
describe immunosuppression for transplants (targeting T cells
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
describe immunosuppression for transplants (targeting antibody mediated rejection)
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
list the standard transplant immunosuppression
induction agent - OXT3/ATG, anti CD52, anti CD25
baseline immunosuppression: calcineurin inhibitor + mycofenolate mofetil/ azathioprine +- steroids
how do we treat episodes of acute rejection
cellular - steroids/ OKT3/ATG
antibody-mediated - IVIG, plasma exchange, anti C5, anti CD20
describe haematopoietic SC transplantation
used for haem and lymphoid cancers
GVHD - prophylaxis = methotrexate/ cyclosporine
rash, n+v, abdo pain, diarrhoea, jaundice
list common post transplant malignancies
kaposi sarcoma (HHV8) lymphoproliferatve disease (EBV)
