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YEAR 5: Immunopathology > Immuno: Transplantation > Flashcards

Immuno: Transplantation Flashcards

1
Q

Which organ is most commonly transplanted?

A
  • Kidneys
  • Followed by Liver
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2
Q

What is the average half-life of a transplanted kidney?

A

12 years

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3
Q

What are the three phases of an immune response to a graft?

A
  • Phase 1: recognition of foreign antigens
  • Phase 2: activation of antigen-specific lymphocytes
  • Phase 3: effect phase of graft rejection
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4
Q

What are the most relevant cellular proteins that can determine compatibility?

A

ABO

HLA

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5
Q

Which chromosome is HLA encoded on?

A

Chromosome 6

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6
Q

What are the two major components of rejection?

A
  • T cell-mediated rejection
  • Antibody-mediated rejection
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7
Q

Describe the basic structure of HLA Class I and Class II.

A
  • Class I: have three alpha domains and a beta-2 microglobulin domain, has one transmembrane domain
  • Class II: has two alpha and two beta domains, had two transmembrane domains
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8
Q

Which alleles encode HLA Class I and Class II?

A
  • Class I: A, B and C
  • Class II: DP, DQ, DR
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9
Q

Where are HLA Class I and Class II expressed?

A
  • Class I: all cells
  • Class II: antigen-presenting cells (can be upregulated at times of stress)
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10
Q

What is the benefit of having high variability in the peptide-binding groove of MHC?

A

Can present a wide variety of antigens

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11
Q

What is the disadvantage of the variability in the peptide-binding groove of MHC with regards to transplants?

A

This means that the host immune system can react with the slightly different MHC of the donor leading to rejection.

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12
Q

Which HLA alleles are most immunogenic?

A

A, B and DR

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13
Q

Where do the antigen-presenting cells that interact with host T cells come from?

A

From the recipient and the donor (the donor organ will contain many APCs)

NOTE: a lot of these interactions will happen in lymph nodes

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14
Q

Which test is used to give a definitive diagnosis of graft rejection?

A

Biopsy

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15
Q

Describe the effector phase of T-cell mediated graft rejection.

A
  • T cells tether, roll and arrest on the endothelial cell surface
  • They will migrate across into the interstitium and start attacking the tubular epithelium
  • Macrophages (recruited by T cells) may also be seen in the interstitium
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16
Q

What are the typical histological features of T-cell mediated rejection?

A
  • Lymphocytic interstitial infiltration
  • Ruptured tubular basement membrane
  • Tubulitis (inflammatory cells within the tubular epithelium)
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17
Q

What other explanation might there be for graft failure other than rejection?

A

Immunosuppressive drugs may be nephrotoxic

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18
Q

What are the three phases of antibody-mediated rejection?

A
  • Phase 1: eposure to foreign antigen
  • Phase 2: proliferation and maturation of B cells with antibody production
  • Phase 3: effector phase - antibodies bind to graft endothelium
19
Q

What is a key difference between the production of anti-AB and anti-HLA antibodies?

A
  • Anti-AB antibodies are naturally occuring (pre-formed)
  • Anti-HLA antibodies are not naturally occuring but can be pre-formed due to previous exposure to epitopes (e.g. previous transplant, pregnancy) or post-formed (after transplantation)
20
Q

Outline the pathophysiology of antibody-mediated transplant rejection.

A
  • Antibodies bind to HLA on the endothelium of blood vessels within the transplanted organ
  • The antibodies fix complement which leads to formation of MAC and endothelial cell lysis
  • Binding of complement also recruits inflammatory cells
  • This leads to inflammation of the microcirculation (capillaritis)
  • This leads to procoagulant tendencies and closure of the microcirculation leading to graft fibrosis
  • Antibodies can also cross-link MHC molecules and activate them
21
Q

What are the main histological features of antibody-mediated transplant rejection?

A
  • Presence of inflammatory cells within the capillaries of the graft (HALLMARK)
  • Immunohistochemistry can show fixation of complement fragments on the endothelial cell surface
22
Q

What are the three main approaches to preventing graft rejection?

A
  • AB/HLA typing
  • Screening for antibodies
  • Overcoming organ mismatch tissues
23
Q

Which technology is used for AB/HLA typing?

A

DNA sequencing using PCR

24
Q

At what stages of transplantation will screening for antibodies be performed?

A
  • Before transplantation
  • At the time of transplant (once an organ has been assigned)
  • After transplantation (check for new antibody formation)
25
Q

Name and describe three assays for anti-HLA antibodies.

A
  • Cytotoxic Assays: tests whether patient serum binds donor lymphocytes in the presence of complement
  • Flow Cytometry: tests whether patient serum binds donor lymphocytes irrespective of complement
  • Solid Phase Assays: beads containing all the possible HLA epitopes are mixed with the patient’s serum. This determines which HLA types the patient has antibodies against. Having many antibodies against different HLA epitopes suggests that the patient is highly sensitised.
26
Q

How can organ mismatch issues be overcome?

A
  • Improve transplantation across tissue barriers
  • More donors
  • Organ exchange programmes
  • Xenotransplantation and stem cell research
27
Q

What T cell pathway is the main target for immunosuppressive drugs used in transplants?

A
  • The main signal is between MHC and TCR
  • Downstream, there are a number of pathways that involve calcineurin which result in cell proliferation
  • Once activated, T cells will release IL2 which has autocrine and paracine effects on Th2 cells
  • These are all targets for immunosuppression
28
Q

Name two calcineurin inhibitors.

A

Tacrolimus

Ciclosporin

29
Q

Name two cell cycle inhibitors

A

Mycofenolate mofetil

Azathioprine

30
Q

Name two drugs that target TCR.

A

Anti-CD3 antibody (OKT3)

Anti-thymocyte globulin

31
Q

Name an anti-CD52 antibody and state its effect.

A

Alemtuzumab - causes lysis of T cells

32
Q

Name an anti-CD25 antibody and state its effect.

A

Daclizumab - targets cytokine signalling

33
Q

What are the main immunosuppressive targets of B-cell mediated graft rejection?

A
  • B cell activation
  • Secretion of antibodies by plasma cells
  • Effects of antibodies on endothelium
34
Q

What is rituximab?

A

Anti-CD20 - causes depletion of B cells

35
Q

How do BAFF inhibitors work?

A

Target cytokines (BAFF) that promotes B cell activation and growth

36
Q

Name a proteasome inhibitor and describe how it works.

A
  • Bortezomib
  • Blocks the production of antibodies by plasma cells
37
Q

Name a complement inhibitor.

A

Eculizumab

38
Q

Outline the components of modern transplant immunosuppression regimes.

A
  • Induction agent (e.g. OKT3, anti-CD52, anti-CD25)
  • Baseline immunosuppression (e.g. calcineurin inhibitor, mycofenolate mofetil, azathioprine, steroids)
  • Treatment of acute rejection
    • Cellular: steroids, OKT3
    • Antibody-mediated: IVIG, plasma exchange, anti-CD20
39
Q

Briefly describe the pathophysiology of graft-versus-host-dsiease.

A
  • During SCT, the host immune system is eradicated and replaced by autologous or allogeneic bone marrow
  • In allogeneic stem cell transplant, the donor lymphocytes can react with host tissues

NOTE: if there is a malignancy, the graft can kill these cells

40
Q

How can GVHD be prevented?

A
  • Methotrexate/ciclosporin
41
Q

List some symptoms of GVHD.

A
  • Rash
  • Nausea and vomiting
  • Abdominal pain
  • Diarrhoea/bloody stools
  • Jaundice
42
Q

List some opportunistic infections that are more common in transplant recipients.

A
  • CMV
  • BK virus
  • PCP
43
Q

List some malignancies that are more common in transplant recipients.

A
  • Kaposi sarcoma (HHV8)
  • Lymphoproliferative disease (EBV)
  • Skin cancer

YEAR 5: Immunopathology (12 decks)

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