Transplantation Flashcards

1
Q

What is an allograft?

A

The transplant of an organ, tissue, or cells from one individual to another individual of the same species who is not an identical twin.

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2
Q

Which parts of the body can be transplanted in an allograft?

A

Solid organs: Kidney, liver, heart, lung, pancreas

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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3
Q

How can transplant outcomes be improved?

A

Patient survival and graft survival

Improved surgical technique

Improved pre- and post-transplant patient management

Drug levels: Infections, cardiovascular disease, diabetes

Better understanding of transplant immunology: Prevention, diagnosis and treatment of graft rejection

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4
Q

What are the different stages of immune response to a transplanted graft?

A

Phase 1: Recognition of foreign antigens.

Phase 2: Activation of antigen-specific lymphocytes.

Phase 3: Effector phase of graft rejection.

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5
Q

What are the relevant protein variations in clinical transplantation?

A

Most relevant protein variations in clinical transplantation:

  • ABO blood group (for ABO-incompatible transplantation).
  • HLA (human leukocyte antigens).

Some other determinants – minor histocompatibility genes.

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6
Q

What is the immunology of transplantation?

A

The immune system recognises someone else’s organ as foreign.

Two major components to rejection:

  • T cell-mediated rejection
  • Antibody-mediated rejection (B cells)
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7
Q

What is HLA?

A

Major Histocompatibility complex (MHC) (chromosome 6). Discovered after first attempts at transplantation (animal models and humans). Cell surface proteins.

  • HLA Class I (A,B,C): Expressed on all cells.
  • HLA Class II (DR, DQ, DP): Expressed on antigenpresenting cells but also can be upregulated on other cells under stress.
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8
Q

What is special about HLA?

A

Highly polymorphic – hundreds of alleles for each locus (for example: A1, A2, A3 – A372 and rising…).

Presentation of foreign antigens on HLA molecules to T cells is central to T cell activation.

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9
Q

How does HLA contribute to infections and neoplasia?

A

To maximise diversity in defense against infections/neoplasia, each individual has a variety of HLA.

Each individual’s HLA are derived from a large pool of population varieties.

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10
Q

How does HLA affect transplantation?

A

The variability in HLA in the population provides a source for immunisation against the transplanted organ.

“Mismatches”

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11
Q

What is the nomenclature for HLA mismatches?

A

Work out number of mismatches based on differences

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12
Q

What is the relationship between HLA mismatches and transplant outcome?

A

Minimising HLA differences between donor and recipient improves transplant outcome.

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13
Q

How is tissue typing (determining HLA in individuals) conducted?

A

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

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14
Q

What is T cell mediated rejection?

A

Phase 1: Presentation of donor HLA by a professional antigen presenting cell (APC), in the context of recipient HLA.

Phase 2: T-cell activation, inflammatory cell recruitment.

Phase 3: Effector phase (organ damage).

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15
Q

Explain T cell activation.

A

Proliferation

Production of cytokines (Il-2)

Help for CD8+ cytotoxic T cell activation

Help for antibody production by B cells

Recruitment of monocyte/macrophage lineage cells

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16
Q

What cells are involved in the effector phase of T cell mediated rejection?

A

“Cytotoxic” T cells:

  • Release of toxins to kill target: Granzyme B
  • Punch holes in target cells: Perforin
  • Apoptotic cell death: Fas -Ligand

Monocyte/macrophages:

  • Phagocytosis
  • Release of proteolytic enzymes
  • Production of cytokines
  • Production of oxygen radicals and nitrogen radicals
17
Q

What can result from T cell mediated rejection?

A

Interstitial inflammation and tubulitis

Arteritis

18
Q

How can T cell mediated rejection be managed?

A

Corticosteroids

Daclizumab: Anti-CD25 monoclonal antibody

Mycophenolate mofetil: MPA inhibitor

Alemtuzumab: Anti-CD52 monoclonal antibody

OKT3, ATG: Anti-CD3 monoclonal antibody

FK506: Cyclosporine, tacrolimus inhibitor

19
Q

What are the phases of antibody mediated rejection?

A

Phase 1: B cells recognise foreign HLA.

Phase 2: Proliferation and maturation of B cells with anti-HLA antibody production.

Phase 3: Effector phase; antibodies bind to graft endothelium: intra-vascular disease.

20
Q

How are anti-HLA antibodies formed?

A

Anti-HLA antibodies are not naturally occurring.

  • Pre-formed: Transplantation, pregnancy, transfusion.
  • Post-formed: Arise after transplantation.

Other antibodies:

  • Anti-A or anti-B antibodies (naturally occurring)
  • Non HLA antibodies
21
Q

What are ABO blood groups?

A

A and B glycoproteins on red blood cells but also endothelial lining of blood vessels in transplanted organ.

Naturally occurring anti-A and anti-B antibodies.

22
Q

When is screening for anti-HLA antibodies conducted?

A

Before transplantation.

At time of transplantation: When a specific deceased donor kidney has been assigned to the patient.

After transplantation, repeat measurements to check for new antibody production.

23
Q

What are three types of assay to test for anti-HLA antibodies?

A

Cytotoxicity assays

Flow cytometry

Solid phase assays

24
Q

What is being tested for in a cytotoxic crossmatch?

A

does the recipient serum kill the donor’s lymphocytes in the presence of complement? – detection of cell death using vital dyes.

25
Q

What is being tested for in flow cytometry?

A

Does the recipient’s serum bind to the donor’s lymphocytes (bound antibody detected by fluorescently-labelled anti-human Ig)?

26
Q

What is being tested for in solid phase assays?

A

Does the recipient’s serum bind to recombinant single HLA molecules attached to a solid support such as beads (bound antibody detected by fluorescently-labelled anti-human Ig)?

27
Q

How can antibody mediated rejection be managed?

A

Remove antibodies with plasma exchange

Intravenous Ig

28
Q

How is rejection detected?

A

Monitor transplant function (creatinine) + screen for antibodies.

If creatinine goes up: take a biopsy to confirm and classify rejection.

29
Q

What does this show?

A

Drug toxicity

Decrease IS drug

30
Q

What does this show?

A

Viral infections

Decrease IS drug

31
Q

What does this show?

A

Vascular disease

BP control + Vascular stent

32
Q

What does this show?

A

Post-transplant Lymphoproliferative Disease

IS drug

Chemotherapy

33
Q

What does this show?

A

Recent glomerulonephritis