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IMMUNO - Abbie > 5. Transplantation > Flashcards

5. Transplantation Flashcards

1
Q

What is the most commonly transplanted organ?

A

Kidneys

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2
Q

What is the second most common transplanted organ?

A

Liver

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3
Q

What is the average half life of a kidney transplant?

A

12 years

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4
Q

What are the phases of the immune response to transplanted graft?

A

Phase 1: recognition of foreign antigens, phase 2: activation of antigen-specific lymphocytes, phase 3: effector phase of graft rejection. The immune system recognises someone else’s organ as foreign

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5
Q

What are the most relevant protein variations in clinical transplantation?

A

ABO blood group and HLA

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6
Q

Where is HLA coded?

A

Coded on chromosome 6 by MHC

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7
Q

What is the difference between HLA and MHC?

A

sometimes HLA is used to refer to the proteins and MHC refers to the genes but they are often used interchangeably

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8
Q

There are some other minor histocompatility genes - true or false?

A

True

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9
Q

What are two major components to rejection?

A

T-cell mediated rejection, antibody-mediated rejection

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10
Q

What is HLA and why are they vital?

A

Discovered after the first failed attempts are human organ transplant. They are cell surface proteins. The presentation of foreign antigens on HLA molecules to T cells is a vital part of T cell activation.

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11
Q

Where is HLA class I expressed?

A

HLA Class I (A, B and C) - expressed on ALL cells

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12
Q

Where is HLA Class II expressed?

A

HLA Class II (DR, DQ, DP) - expressed on antigen-presenting cells but can also be upregulated on other cells under stress

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13
Q

How is there a high degree of variability between HLA?

A
  1. HLA are highly polymorphic with hundreds of alleles for each locus
  2. The areas of protein lining the peptide-binding groove are responsible for the high degree of variability between HLA
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14
Q

Why has there evolved to be a high degree of variability between HLA?

A

The high variability has evolved so that we are able to present a wide variety of antigens in that peptide-binding groove to the cells of the immune system

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15
Q

Why may the high degree of variability between HLA be an issue?

A

The variability in antigens is an issue in transplantation because they provide a key difference that the immune system can react with

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16
Q

Which HLA loci are thought to be the most immunogenic?

A

A, B and DR

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17
Q

What is a major determinant of the risk of rejection?

A

Number of mismatches

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18
Q

What do T cells require to initiate activation of alloreactive T cells?

A
  1. T cells require presentation of the foreign HLA antigens by a professional antigen presenting cell, in the context of HLA, to initiate activation of alloreactive T cells
  2. There are several co-stimulatory signals
  3. This engagement stimulates activation of T cells that are specific for the epitope being presented
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19
Q

What are the actions of activated T cells?

A

Proliferation, produce cytokines (IL2 is important), provide help to CD8+ cells, provide help for antibody production, recruit phagocytic cells

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20
Q

What are the antigen-presenting cells involved in activating T cells in a transplant patient?

A

The antigen-presenting cells involved in activating T cells is a combination of both the donor AND the recipient antigen-presenting cells. Because when you give someone an organ (e.g. kidney) it will contain a bunch of APCs from the donor

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21
Q

Where do most of the interactions between the donor and recipient APCs take place?

A

Lymph nodes

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22
Q

What happens when the APCs pick up antigens from the donor’s HLA molecule and migrate to the lymph nodes?

A

They migrate to the lymph nodes where they will come into contact with migrating naïve T lymphocytes which subsequently become activated and home to the graft organ. This will eventually result in the effector phase of rejection

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23
Q

What happens as a result of the inflammation of the rejection process?

A

The inflammation caused by this process will lead to graft dysfunction (i.e. a raise in creatinine)

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24
Q

How to determine whether what is happening is rejection?

A

Biopsy

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25
Q

Summarise the effector phase:

A
  1. The T cells will tether, roll and arrest on the endothelial cell surface. 2. They will then crawl through into the interstitium and start attacking the tubular epithelium
  2. Typical Histological Features of T cell-mediated Rejection will be seen:
    • Lymphocytic interstitial infiltration
    • Ruptured tubular basement membrane
    • Tubulitis (inflammatory cells within the tubular epithelium)
  3. Macrophages, recruited by the T cells, may also be seen in the interstitium and the tubules
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26
Q

What are typical histological features of T cell mediated rejection?

A
  1. Lymphocytic interstitial infiltration
  2. Ruptured tubular basement membrane
  3. Tubulitis (inflammatory cells within the tubular epithelium).
    (4. Macrophages, recruited by the T cells, may also be seen in the interstitium and the tubules)
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27
Q

Summarise T-cell mediated rejection

A
  1. To activate alloreactive T cells, foreign HLA antigens by a professional APC must be presented
  2. Activated T cells proliferate, produce cytokines, help CD8+ cells and antibody production, recruit phagocytic cells
  3. The APCs will pick up antigens from the donor’s HLA molecule and migrate to the lymph nodes where they will come into contact with migrating naïve T lymphocytes which subsequently become activated and home to the graft organ
  4. This will result in effector phase of rejection
  5. Inflammation will lead to graft dysfunction
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28
Q

What is the histology of kidney transplant rejection?

A
  • There are a lot of lymphocytes
  • The basement membrane of the tubular epithelium has been ruptured by lymphocytes
  • The inflammatory cells can also attack the endothelium of blood vessels leading to arteritis
  • This same process can occur in any transplanted organ
29
Q

A fail in graft function is NOT always due to rejection, what may be another reason?

A

Some of the drugs given to dampen the immune response are nephrotoxic and may be responsible for reduced graft function (this can be treated by reducing drug levels)

30
Q

What are three phases of antibody-mediated rejection?

A

Three phases are: Phase 1: exposure to foreign antigen,
Phase 2: proliferation and maturation of B cells with antibody production,
Phase 3: effector phase - antibodies bind to graft endothelium (capillaries of glomerulus and around tubules)

31
Q

We have naturally occurring anti-A and anti-B antibodies. Whereas anti-HLA antibodies are NOT naturally occurring. How can they be pre-formed or post-formed?

A
  1. They can be pre-formed due to previous exposure to epitopes (e.g. previous transplantation, pregnancy, transfusion)
  2. Or they can be post-formed - formed after transplantation
32
Q

What is the action of antibodies in infection? (What do antibodies fix to? What happens when they opsonise? What does it lead to? What does complement lead to? What do receptors on inflammatory cells do?)

A

The same mechanisms occur in transplant rejection

  1. Antibodies can fix to the surface of microbes and directly neutralise it
  2. Antibodies opsonise microbes and attract inflammatory cells that have receptors on their surface for the Fc portion of the antibody
  3. This can lead to cell death either through phagocytosis or antibody-dependent cellular cytotoxicity
  4. Complement can bind to immunoglobulins on the surface of microbes which can lead to direct lysis of microbes
  5. There are also receptors for complement on inflammatory cells, so complement binding can result in inflammatory cell recruitment and phagocytosis
33
Q

What is the action of antibodies in transplantation? (What do antibodies bind to? What happens when they fix complement?How are inflammatory cells recruited? What other cells are recruited? What is capillaritis? How can this lead to graft fibrosis? What do antibodies against graft endothelial epitopes lead to?

A

Similar processes take place to infection.

  1. Antibodies will bind to antigens (HLA) on the endothelium of the blood vessels in the transplanted organ
  2. These antibodies can then fix complement which assembles to form membrane attack complexes (MAC) resulting in endothelial cell lysis
  3. Binding of complement can also recruit inflammatory cells to the microcirculation
  4. The antibodies can also directly recruit mononuclear cells, NK cells and neutrophils
  5. One of the cardinal features of antibody-mediated rejection is the presence of inflammatory cells within the capillaries of the kidney which then cause endothelial injury. This is called capillaritis
  6. These processes will result in procoagulant tendencies and closure of the microcirculation leading to graft fibrosis
  7. Antibodies against graft endothelial epitopes can also cause damage by cross-linking the MHC molecules and activating them
34
Q

Histology of antibody-mediated rejection:

A
  1. The little capillaries in between the tubules contain inflammatory cells.
  2. This is inflammation of the microcirculation (whereas in T cell mediated rejection you get inflammatory cells in the tubular epithelium and the interstitial space)
  3. Immunohistochemistry looking for fixation of complement fragments on the endothelial cell surface may also be useful
35
Q

Summarise rejection:

A
  1. Can be T-cell mediated, antibody-mediated or both
  2. Both cause graft dysfunction (e.g. raised creatinine, raised LFTs)
  3. Graft biopsy - management and outcome are different depending on type of rejection
36
Q

What can be done to prevent or treat graft rejection?

A

AB/HLA typing, screening for antibodies, overcoming organ mismatch issues

37
Q

How does AB/HLA typing work?

A
  1. DNA sequencing using PCR is how people are typed
  2. Part of the allocation procedure
  3. Encourage living donation from blood relatives
38
Q

What is HLA matching more important for and less important for?

A

HLA matching is particularly important for bone marrow and kidney transplantation. It is less important in heart and lung transplants

39
Q

When to screen for antibodies?

A
  1. Before transplantation
  2. At the time of transplantation (once an organ has been assigned)
  3. After transplantation (repeat measurement to check for new antibody formation)
40
Q

When screening for antibodies, there are three types of assays - what are they?

A

Cytotoxic assays, flow cytometry, solid phase assays

41
Q

What does a cytotoxic assay look at?

A

Looks at whether the recipient’s serum will kill the lymphocytes of the donor in the presence of complement. Positive crossmatch suggests that there is cell lysis.

42
Q

What does a flow cytometry look at?

A
  • Looks at whether the recipient’s serum binds to the donor’s lymphocytes
  • Bound antibody is detected by fluorescently-labelled anti-human immunoglobulin
  • This is broad and looks at whether the antibodies bind antigen irrespective of whether they bind complement
43
Q

What do solid phase assays look at?

A
  • This uses a series of beads containing all the possible HLA epitopes
  • The recipient’s serum is mixed with these beads and fluorescently-labelled immunoglobulin is used to determine which HLA epitopes the antibodies bind to
  • It can also give an indication of the strength of the reaction
    (NOTE: patients that have antibodies to lots of different types of antibodies are regarded as highly sensitised)
44
Q

Can mismatch positive transplantation take place?

A

Mismatch positive transplantation can take place but it requires a lot of preparation with the use of plasma exchange and IVIG

45
Q

How to overcome organ mismatch issues?

A
  1. Improve transplantation across tissue barriers
  2. More donors
  3. Organ exchange programmes
  4. Future: xenotransplantation (animals), stem cell research
46
Q

How are T-cells targeted in immunosuppression?

A
  1. Main signal is between MHC and the TCR.
  2. Downstream there are a number of pathways, especially involving calcineurin. These pathways result in cell proliferation
  3. There are also a number of costimulatory signals that can also be targeted
  4. Once the cell is activated, it releases various cytokines (e.g. IL2) which can have an autocrine or a paracrine effect on T cells. This cytokine signal can also be targeted
47
Q

Are steroids given in immunosuppression?

A

Steroids are normally given as part of a standard immunosuppression regime to prevent T-cell mediated rejection

48
Q

Which calcineurin inhibitors are commonly used for immunosuppression?

A

Tacrolimus, cyclosporine

49
Q

Which cell cycle inhibitors are used for immunosuppresion?

A

Mycofenolate mofetil, azathioprine (old drug)

50
Q

Which drugs target TCR for immunosuppression?

A

Anti-CD3 antibody (OKT3), anti-thymocyte globulin. These cause apoptosis of T cells

51
Q

How does alemtuzumab work? (Used in immunosuppression)

A

Alemtuzumab is an anti-CD52 monoclonal antibody that causes lysis of T cells

52
Q

How does daclizumab work? (used in immunosuppression)

A

Daclizumab is an anti-CD25 monoclonal antibody which targets the cytokine signal

53
Q

When targeting antibody-mediated rejection for immunosuppression, what are the main targets?

A
  1. B cell activation
  2. Secretion of antibodies by plasma cells
  3. Effect of antibodies on endothelium
54
Q

Which drug causes B cell depletion?

A

B cells can be depleted using rituximab (anti-CD20)

55
Q

How do BAFF inhibitors work in immunosuppresion (antibody-mediated rejection)?

A

BAFF inhibitors target cytokines that promote B cell activation and growth

56
Q

How does bortezemib work in immunosuppression?

A

Proteasome inhibitors such as bortezemib can block the production of antibodies by plasma cells

57
Q

How does eculizimab work in immunosuppression?

A

Complement binding to the surface of endothelial cells can be blocked using complement inhibitors such as eculizimab

58
Q

In modern transplant immunosuppression, give some examples of induction agents:

A

OXT3/ATG, anti-CD52, anti-CD25

59
Q

When are induction agents given in modern transplant immunosuppression?

A

This is given at the time of transplantation or just before in order to prepare the patient to receive the foreign organ

60
Q

What is given for baseline immunosuppression in modern transplant immunosuppression?

A

Calcineurin inhibitor + mycofenolat mofetil or azathioprine with or without steroids

61
Q

How do you treat episodes of acute rejection?

A
  1. Cellular e.g. steroids, OKT3/ATG.

2. Antibody-mediated: IVIG, plasma exchange, anti-C5, anti-CD20

62
Q

How might IVIG reduce antibody production, during treatment of episodes of acute rejection?

A

IVIG can reduce antibody production through feedback and it can displace troublesome antibodies so that they cannot exert their harmful effects

63
Q

What is haematopoietic stem cell transplantation used for?

A

Used for haematological and lymphoid cancers. May be used in acquired or inherited deficiencies in marrow cells such as errors of metabolism or immunodeficiencies

64
Q

How does graft-versus-host disease occur?

A
  1. During the process of SCT, the host immune system is eliminated (using total body irradiation and drugs)
  2. It is then replaced by own (autologous) or HLA-matched donor (allogeneic) bone marrow
  3. Allogeneic stem cell transplantation leads to reaction of donor lymphocytes against host tissues
  4. Related to a degree of HLA-incompatibility
  5. If there is a malignancy (e.g. leukaemia), the graft can help kill these cells (graft-versus-tumour)
65
Q

What can be used as GVHD prophylaxis?

A

Methotrexate/cyclosporine

(It is thought that the damage to the GI tract by the irradiation and cytotoxic drugs before the transplant has an important role in liberating antigens which will subsequently be presented to the donor’s immune cells)

66
Q

What are the symptoms of GVHD?

A

Rash, nausea and vomiting, abdominal pain, diarrhoea/bloody stool, jaundice

67
Q

What is the treatment for GVHD?

A

Steroids

68
Q

Post-transplantation infections?

A
  1. Increased risk of conventional infections

2. Also increased risk of opportunistic infection e.g. CMV, BK virus, PCP

69
Q

What are post-transplantation malignancies?

A
  1. Viral-associated malignancies are much more common, e.g. Kaposi sarcoma (HHV8), lymphoproliferative disease (EBV)
  2. Skin cancer is 20 x more common
  3. Risk of other cancers is also increased

IMMUNO - Abbie (11 decks)

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