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Immu 6: Transplant Flashcards

1
Q

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

A

HBO blood group
HLA

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2
Q

Which 3 HLA isotypes are considered the most immunogenic ?

What is the order of most to least immunogenic?

A

HLA-A
HLA-B
HLA-DR

DR > B > A

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3
Q

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

A
  • 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
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4
Q

Do we have pre-formed HLA-antibodies ?

A

No

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

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5
Q

What could cause a hyperacute rejection of an organ transplant ?

A

If you already had pre formed HLA-antibodies

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6
Q

List 3 ways antibodies cause killing of pathogens/graft ?

A

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

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7
Q

List 2 ways antibodies cause killing of graft via complement?

A

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.

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8
Q

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

A
  • Antibody mediated- Microcirculation inflammation (endothelium) - get capillaritis
  • T cell mediated - Tubulointerstitial inflammation - get tubulitis
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9
Q

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

Which is most sensitive and most commonly used?

A
  • 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 (MOST SENSITIVE AND COMMONLY USED) - 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
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10
Q

When do you screen for anti-HLA antibodies?

A
  1. Before transplant
  2. During transplant
  3. After
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11
Q

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

A

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

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12
Q

List 5 immunosuppressive agents used in transplants that target T cells ?

A
  • Cyclosporin, tacrolimus - Calcineurin inhibitor
  • Azathioprine, Mycophenolate mofetil - cell cycle inhibitor
  • Anti CD3 antibody (muromonab)- targets TCR
  • Daclizumab- anti-CD25 antibody
  • Alemtuzumab is an anti-CD52 monoclonal antibody that causes lysis of T cells
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13
Q

List 4 immunosuppressive agents used in transplants that target antibody mediated rejection ?

A
  • Rituximab- anti CD20 antibody
  • Eculizumab- Complement inhibitor
  • BAFF inhibitors- blocks cytokines
  • Proteasome inhibitors like Bortezomib can block the production of antibodies by plasma cells
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14
Q

Explain graft vs host disease ?

A

1- The recipients immune system is wiped out by radiation therapy.
2- The donor stem cells (bone marrow) 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

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15
Q

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

A

Immune response can attack tumours (graft vs tumour effect)

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16
Q

Which 2 drugs are commonly given for GVHD prophylaxis ?

A

Methotrexate
Cyclosporin

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17
Q

List 3 opportunistic infections that more regularly occur post transplant ?

A

CMV
PCP
BK virus

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18
Q

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

A

Muromonab (CD3 Mab)

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19
Q

Name the type of transplant between twins with identical HLA ?

A

Isograft

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20
Q

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

A

Allograft

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21
Q

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

22
Q

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

23
Q

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

A

phase 1: recognition of foreign antigen

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

24
Q

what are the 2 main components to rejection

A

T -cell mediated
Antibody mediated

25
Q

on which chromosome is HLA encoded

A

chromosome 6 by MHC

26
Q

on which cells are HLA class I and II encoded

A

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

27
Q

list the actions of activated T cells (5)

A
  • proliferation
  • produce cytokines (IL2 important)
  • provide help to CD8+ T cells
  • provide help for antibody production
  • recruit phagocytic cells
28
Q

what are typical histological features of T cell mediated rejection (3)

A
  • lymphocytic interstitial infiltration
  • ruptured tubular basement membrane
  • tubilitis
  • can also get arteritis
29
Q

describe the histology of kidney transplant rejection

A

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

30
Q

how do antibodies act in transplanation

A
  • 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
31
Q

how can we prevent graft rejection

A
  • 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
32
Q

list the standard transplant immunosuppression

A

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

33
Q

how do we treat episodes of acute rejection

A
  • cellular
    • STEROIDS
    • OKT3
    • ATG
  • antibody-mediated
    • IVIG
    • plasma exchange
    • anti C5
    • anti CD20
34
Q

describe haematopoietic SC transplantation

A

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

35
Q

list common post transplant malignancies (3)

A
  • kaposi sarcoma (HHV8)
  • lymphoproliferatve disease (EBV)
  • skin cancer
36
Q

How do you confirm if rejection is happening?

37
Q

Main cells involved in T-cell rejection

A

T cells and macrophages

38
Q

Most important drug to give if rejection seen 2 months after transplant

39
Q

Main cell type injured in antibody-mediated rejection

A

ENDOTHELIAL CELLS

40
Q

Tx of graft vs host disease

41
Q

Induction agents in immunosuppression for transplant (2)

Baseline immunosuppression after induction (3)

A

Induction

  • T-cell depleting: OKT3/ ATG, anti-CD52
  • Other: anti-CD25 (anti-IL2R)

Baseline after

  • Calcineurin inhibitor
    • mycophenolate mofetil OR azathioprine
  • +/- steroids
42
Q

ABO and HLA typing are important in which transplants (2)

In which is HLA not important (2)

A
  • important: bone marrow, kidney
  • not important: heart, lung
43
Q

How is trasplant mismatch calculated + written out?

A
  • Written as A:B:DR mismatches (even though DR>B>A in terms of degree of immunogenecity)
44
Q

2 examples of Calcineurin inhibitors (target T cell rejection)

A
  • Tacrolimus
  • Ciclosporin
45
Q

2 examples of Cell cycle inhibitors (target T cell rejection)

A
  • Mycophenolate mofetil
  • Azathioprine (old drug)
46
Q

2 examples of TCR targetters (target T cell rejection)

A
  • Anti-CD3 antibody (OKT3)
  • Anti-thymocyte globulin (causes lysis of T cells)
47
Q

anti-CD52 monoclonal antibody (target T cell transplant rejection)

A

Alemtuzumab

48
Q

anti-CD25 monoclonal antibody (target T cell transplant rejection)

A

Daclizumab

49
Q

1 complement inhibitors example (used to target antibody mediated transplant rejection)

A

Eculizumab

50
Q

1 Proteasome inhibitor example which is used to block the production of antibodies (used to target antibody mediated transplant rejection)

A

Bortezomib

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