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4 - Y5 a Path lectures 2021/22 > Immuno 5: Transplantation > Flashcards

Immuno 5: Transplantation Flashcards

1
Q

What are some allografts that can be done? Which of these are most common?

A
  • • Solid organs (kidney, liver, heart, lung, pancreas) → MOST COMMON
  • • Small bowel
  • • Free cells (bone marrow stem cells, pancreas islets)
  • • Temporary: blood, skin (burns)
  • • Privileged sites: cornea
  • • Framework: bone, cartilage, tendons, nerves
  • • Composite: hands, face
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2
Q

Which organ is the most commonly transplanted? What is its half life?

A

o 1st most common transplanted organs = KIDNEYS (average 1⁄2 life of a kidney is 12 years)

o 2nd most common = LIVER

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3
Q

What are the phases of Immune Response to Transplanted Graft?

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

What are the most relevant protein variations in clinical transplantation?

A
  • ABO blood group
  • HLA (on chromosome 6 by MHC; n.b. HLA can mean the proteins OR the genes)
  • other minor histocompatibility genes
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5
Q

What are the 2 major forms/components of graft rejection?

A
  • T cell-mediated rejection
  • Antibody-mediated rejection
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6
Q

What is the difference between HLA Class I And HLA class II?

A
  • HLA Class I (A,B,C)– expressed on all cells
  • HLA Class II (DR, DQ, DP) – expressed on antigen- presenting cells but also can be upregulated on other cells under stress
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7
Q

Describe HLA

A
  • They are highly polymorphic with hundreds of alleles for each locus
  • High degree of variability from the areas of protein lining the peptide-binding groove which allows us to present a wide variety of antigens in that peptide-binding groove to the cells of the immune system
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8
Q

Which HLA class subtypes are most important to match? What does the number of mistmatches relate to?

A

Most important to match = DR > B > A

  • most immunogenic of A, B, C, DR, DQ
  • The number of mismatches is a major determinant of the risk of rejection and graft survival
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9
Q

How many mismatches are there here? What is the max number of mismatches

A
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10
Q

How many alleles are matched in parent to child donations? What about sibling to sibling?

A
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11
Q

How is donor and recipient HLA type determined?

A

tissue typing

PCR-based DNA sequence analysis for HLA alleles determines the individuals genotype

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12
Q

Summarise phase 1 of T cell mediated rejection of a graft

A
  • To activate alloreactive T cells, the T cells require:
    • Presentation of foreign HLA antigens in MHC by APCs (both DONOR and HOST APC cells are involved)
    • Co-stimulatory signals
  • These actions occur in the lymph nodes – APCs pick up antigens from donor MHC and activate T cells in nodes
  • This leads to effector phase of rejection → inflammation caused leads to graft dysfunction (i.e. raised creat)
  • A biopsy can serve to determine if rejection is occurring
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13
Q

Summarise phase 2 of T cell mediated rejection of a graft

A
  • Proliferation
  • Product cytokines (IL2 is important)
  • Provide help to CD8+ cells
  • Provide help for antibody production
  • Recruit phagocytic cells

Effects cells have inside the transplanted organ:

o Cytotoxic T cells:

§ Granzyme B (toxin)
§ Perforin (punch holes)

§ Fas-ligand (apoptosis)

o Macrophages:
§ Phagocytosis

§ Proteolytic enzymes production

§ Cytokine release
§ O2 and N2 radicals production

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14
Q

Summarise phase 3 of T cell mediated rejection of a graft

A

• Effector phase:

  • The T cells will tether, roll and arrest on the endothelial cell surface
  • They will then crawl through into the interstitium and start attacking the tubular epithelium
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15
Q

What are the Histological Features of T cell-mediated Rejection?

A
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16
Q

What is another cause of failed graft function, other than rejection?

A

failed graft function may not always be due to rejection… some immunosuppressive drugs given are nephrotoxic → reduced function

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17
Q

What are the 3 phases of antibody-mediated rejection?

A
  • 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)
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18
Q

Can antibodies against ABO occur without exposure? What about anti-HLA antibodies?

A

Whilst anti-ABO blood group ABs naturally occur, anti-HLA antibodies are not naturally occurring

  • Can be pre-formed due to previous exposure to epitopes (e.g. previous transplantation, pregnancy, transfusion)
  • Can be post-formed (after transplantation)
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19
Q

Where are ABO antigens found?

A

A and B glycoproteins on RBCs but also endothelial lining of blood vessels in transplanted organ

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20
Q

What are the monosaccharides found on on A, B, AB, O antigens?

A
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21
Q

What are the antigens in blood and antibodies in plasma for A, B, AB, O blood groups?

A
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22
Q

Explain phase 3 of antibody-mediated graft rejection

A

Phase 3 (antibodies in transplantation):

  • Antibodies bind to antigens (HLA) on the endothelium of the blood vessels in the transplanted organ
  • Antibodies fix/activate complement which assembles to:
    • Form MAC → endothelial cell lysis
    • Recruit inflammatory cells to the microcirculation
  • Antibodies can crosslink the MHC molecules, thus activating them
  • The antibodies can also directly recruit mononuclear cells, NK cells and neutrophils → capillaritis
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23
Q

What are the actions of antibodies in transplant rejection?

A

Action of Antibodies in Infection – the same mechanisms occur in transplant rejection:

  • Neutralise toxins
  • Opsonise (aid phagocytosis)
  • Antibody-dependant cellular cytotoxicity
  • Complement activation (which leads to):
    • MAC lysis
    • Opsonise (aid phagocytosis)
    • Inflammation

in image, top box = complement independent, bottom = complement dependent

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24
Q

What is a Cardinal feature of antibody-mediated rejection?

A

Cardinal feature of antibody-mediated rejection = capillaritis = inflammatory cells in capillaries of the kidney → injury

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25
Q

What can antibody-mediated rejection of a graft cause?

A

procoagulant tendencies and closure of the microcirculation → graft fibrosis

26
Q

Summarise the role of lymph nodes in stages 1 and 2 of antibody-mediated graft rejection

A
27
Q

What does this show? What type of graft rejection is this?

A

acute T cell mediated rejection

28
Q

What are the histological features of antibody-mediated graft rejection?

A

o Inflammatory cell infiltrate

o Capillaritis (inflammatory cells in the microcirculation – a cardinal feature of antibody mediated rejection)

o Immunohistochemistry can see fixation of complement fragments on endothelial cell surfaces

29
Q

What type of damage is caused by T cell-mediated and antibody-mediated graft rejection?

Why is a graft biopsy useful?

A
30
Q

What are the 3 signals involved in T cell-mediated graft rejection?

A
  • signal 1: MHC and T cell receptor
  • signal 2: costimulatory molecules and CD38
  • signal 3: self-stimulation of the IL2 receptor
31
Q

What does this show? What type of graft rejection is this?

A

acute T cell mediated rejection

32
Q

What does this show?

A

left - capillaritis

right - glomerulitis

33
Q

What does this show?

A

Complement fragmentation in antibody-mediated graft rejection

34
Q

What does this show?

A

Complement fragmentation in antibody-mediated graft rejection

35
Q

What are the main methods of Graft Rejection Prevention?

A
  • HLA Typing
  • Screening for anti-HLA antibodies
  • Immunosuppression (targeting T cells):
  • Immunosuppression (targeting antibody-mediated rejection):
36
Q

Summarise HLA typing

A
  • BEFORE TRANSPLANT – via PCR DNA sequencing:
  • Particularly important for BM and kidney transplantation
  • Less important in heart and lung transplants
37
Q

Summarise screening for anti-HLA antibodies and name the 3 types of assays used

A

Screening for anti-HLA antibodies – BEFORE, AT TIME (at organ assignment) and AFTER TRANSPLANT – 3 assays used:

  1. Cytotoxicity assays
  2. Flow cytometry
  3. Solid phase assays (uses a series of beads containing all the possible HLA epitopes)
38
Q

Explain Cytotoxicity assays used in anti-HLA antibody screening

A
39
Q

Explain flow cytometry used in anti-HLA antibody screening

A
40
Q

Explain Solid phase assays used in anti-HLA antibody screening

A
41
Q

Can mismatch positive transplantation take place?

A

mismatch positive transplantation CAN take place, but requires a lot of preparation (plasma exchange and IVIG)

42
Q

How are organ mismatch issues overcome?

A

Overcoming Organ Mismatch Issues:
o Improve transplantation across tissue barriers
o More donors
o Organ exchange programmes
o Future: xenotransplantation (animals), stem cell research

43
Q

Summarise immunosuppression of T cells to prevent graft rejection

A
44
Q

Summarise immunosuppression of T cells to prevent graft rejection

A
45
Q

Name some immunosuppressive drugs targeting T cell activation and their targets.

A
46
Q

Name some management drugs used in immunosuppression of T cells to prevent graft rejection

A
47
Q

Summarise immunosuppression of antibodies to prevent graft rejection. Name some drugs and their targets.

A
48
Q

Summarise Prevention and treatment of graft rejection

A
49
Q

What is the modern transplant immunosuppression regime?

A
50
Q

What is a complication of Haematopoietic Stem Cell Transplantation (for haematological and lymphoid cancers)

A

complication GvHD

51
Q

What are the symptoms of GvHD?

A

Symptoms – looks like slow-onset anaphylaxis with jaundice…

§ Rash
§ Nausea and vomiting
§ Abdominal pain
§ Diarrhoea/bloody stool

§ Jaundice

52
Q

What is the pathogenesis of GvHD?

A
53
Q

What is given for GvHD prophylaxis and its Tx?

A

GvHD Prophylaxis = Methotrexate/cyclosporine

GvHD treatment = steroids

54
Q

Which organisms pose a risk of infection post-transplant?

A

o Increased risk of conventional infections
o Also increased risk of opportunistic infections → CMV, BK virus, PCP

55
Q

What is another risk of transplant?

A
  • Viral-associated malignancies are much more common, such as:
    • Kaposi sarcoma(HHV8)
    • Lymphoproliferative disease(EBV)
  • Skin cancer is 20x more common
  • Risk of other cancers is also increased
56
Q

What does this image show? What is the Tx?

A

Calcineurin inhibitor toxicity

Reduce immunosuppressive drugs

57
Q

What does this image show?

A

BK nephropathy

Reduce immunosuppresive drugs

58
Q

What does this image show? What is the Tx?

A

vascular disease (small lumen → HTN)

BP control, possibly stent

59
Q

What does this image show? What is the Tx?

A

Post transplant lymphoproliferative disease

Reduce immunosuppresants, possibly chemotherapy

60
Q

What does this image show? What is the Tx?

A

Recurrent glomerulonephritis (disease that was indication for transplant)

Tx depends on glomerulonephritis

4 - Y5 a Path lectures 2021/22 (37 decks)

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