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PathY5 > Transplantation > Flashcards

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

What can you transplant?

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

Where do organs come from?

A

Live donor

Deceased donor

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4
Q

What are the most common transplants?

A 
Kidney
Pancreas
Cardiothoracic
Liver
Intestinal
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5
Q

How do improve transplant outcomes?

A

Improved surgical technique

Improved pre- and post-transplant patient management and monitoring

Better understanding of transplant immunology
(Immunosuppression, graft rejection)

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6
Q

What are the 3 phases of graft rejection?

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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7
Q

What are the important immunological considerations in transplant?

A

Foreign object!

Mostly ABO and HLA (Chr6MHC)

Other: Minor histocompatibility genes

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8
Q

What are the two major components to rejection?

A

T cell-mediated rejection

Antibody-mediated rejection (B cells)

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9
Q

What is HLA?

A

Discovered after first failed attempts at human transplantation

Cell surface proteins

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

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10
Q

How are HLA variable?

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

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

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11
Q

How are HLA antigens connected to infections and neoplasia?

A

To maximise diversity in defense against infections, each individual has a variety of HLA proteins

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

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12
Q

What is the relevance of HLA in transplantation?

A

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

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13
Q

What may help improve transplant outcomes regarding HLA?

A

Minimising HLA differences between donor and recipient improves transplant outcome

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14
Q

What is T cell mediated rejection?

A

T cells require presentation of the foreign HLA antigens by a professional antigen presenting cell (APC), in the context of HLA, to initiate activation of alloreactive T-cells

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15
Q

What do T cells do?

A 
Proliferate
 Produce cytokines
 Provide help to activate CD8+ cells
 Provide help for antibody production
 Recruit phagocytic cells
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16
Q

What is graft infiltration?

A

Graft infiltration by alloreactive CD4+ cells

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17
Q

What is the role of Cytotoxic T cells?

A 
Release of toxins to kill target
Granzyme B
Punch holes in target cells
Perforin
Apoptotic cell death
Fas -Ligand
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18
Q

What do macrophages do?

A

Phagocytosis
Release of proteolytic enzymes
Production of cytokines
Production of oxygen radicals and nitrogen radicals

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19
Q

What is the histology of acute cellular rejection?

A

Interstitial inflammation and tubulitis

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20
Q

What are the 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, arterial)

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21
Q

What are the naturally occurring antibodies?

A

Anti-A or anti-B antibodies are naturally occurring

Other Anti bodies may be wither naturally or non naturally occurring

anti-HLA antibodies are not naturally occurring
Pre-formed – previous exposure to epitopes (previous transplantation, pregnancy, transfusion)
Post-formed - arise after transplantation

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22
Q

How do cells come to the graft?

A

Endothelial cell activation and inflammatory cell recruitment and injury

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23
Q

What are the ABO 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

24
Q

What is rejection?

A

T-cell mediated, antibody-mediated or combined
Both cause graft dysfunction (e.g. raised creatinine, raised LFT)
Graft biopsy: management and outcome are different

25
Q

How do you manage graft rejection?

A

Preventing rejection:
A. AB/HLA matching
B. Screening for anti-HLA antibodies
C. Immunosuppression: dampen the immune system of the recipient

Treating rejection:
More immunosuppression

Always balance the need for immunosuppression with the risk of infection/malignancy/drug toxicity

26
Q

How do we control AB/HLA typing?

A

Part of the organ allocation procedure

Encourage living donation from “blood” relatives

27
Q

How do we do HLA matching in organ transplantation?

A 
HLA matching is an important part of organ allocation procedure
Bone marrow
Kidney
HLA matching not as important
Heart
Lung 
Liver - ?
28
Q

How can we determine HLA type?

A

PCR-based DNA sequence analysis determines the individuals genotype

29
Q

When should we screen for antibodies?

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

30
Q

How do we screen for anti HLA antibodies?

A

Cytotoxicity assays
Flow cytometry
Solid phase assays

31
Q

What is a cytotoxic assay?

A

does the recipient serum kill the donor’s lymphocytes

in the presence of complement? – detection of cell death using vital dyes

32
Q

What is flow cytometry?

A

does the recipient’s serum bind to the donor’s lymphocytes

bound antibody detected by fluorescently-labelled anti-human Ig

33
Q

What are 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)

34
Q

What do we need to increase organs?

A

Transplantation across tissue barriers (ABOi, positive cross match transplantation) – esp. if blood group O, rare HLA genotypes, sensitised; improved immunosuppression

More donors
Encourage registration for organ donation
Marginal donors – donation after cardiac death, elderly, sick

Organ exchange programmes

35
Q

What is the future of transplant?

A

Xenotransplantation

Stem cell research

36
Q

How do we target T cells?

A 
FK506
OKT3ATG
Daclizumab
Mycophenolate mofetil
Alemtuzumab
37
Q

What are modern transplant immunosuppression?

A

Induction agent ex. OKT3/ATG, anti-CD52, anti-CD25 (anti-IL2R)

Base-line immunosuppression: CNI inhibitor + MMF or Aza, with or without steroids

Treatment of episodes of acute rejection:
Cellular: steroids (MethylPrednisolone IV 3x 60mg/kg then oral), ATG/OKT3

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

38
Q

What is a haematopoeitic stem cell transplantation?

A

Haematological and lymphoid cancers

Acquired (autoimmune) or inherited deficiencies in marrow cells such as errors of metabolism or immunodeficiencies

39
Q

Why does GVHD occur in haematopoeitic stem cell transplants?

A

Eliminate hosts immune system (total body irradiation; cyclophophamide; other drugs)
Replace with own (autologous) or HLA-matched donor (allogeneic) bone marrow
Allogeneic HSCT leads to reaction of donor lymphocytes against host tissues
Related to degree of HLA-incompatibility
Also graft-versus-tumour effect
GVHD prophylaxis: Methotrexate/Cyclosporine

40
Q

How does GVHD present?

A

Injury induced by
preparative regime
before HSCT –
GI tract

41
Q

What does GVHD present with?

A

Skin: rash
Gut: nausea, vomiting, abdominal pain, diarrheoa, bloody stool
Liver: jaundice

Treat with corticosteroids

42
Q

What infections may you get post transplant?

A

Increased risk for conventional infections

Bacterial, viral, fungal

Opportunistic infections – normally relatively harmless infectious agents give severe infections because of immune compromise

Cytomegalovirus
BK virus
Pneumocytis carinii (jirovecii)

43
Q

What malignancies are linked to post transplant?

A 
Viral associated (x 100)
Kaposi’s sarcoma (HHV8)
Lymphoproliferative disease (EBV)
Skin Cancer (x20)
Risk of other cancers eg lung, colon also increased (x 2-3)
44
Q

How does HLA mismatch predict prognosis?

A

More mismatches has a higher chance of rejection

45
Q

Where does T cell and Antibody rejection occur?

A

Antibody mediated = intra vascular (endothelial injury)

T cell = Extra vascular damage

46
Q

How do we treat latent infection re activation post transplant?

A

Reduce immunosuppression

47
Q

How do you manage vascular disease post transplant?

A

Better BP control

48
Q

What do you do for post transplant lymphoproliferation?

A

Reduce immunosuppression

Start chemo

49
Q

How do you treat post transplant recurrent Glomerulonephritis?

A

Kidney pathway

50
Q

What is the most important antigenic determinant of rejection in current clinical practice for kidney transplantation?

A

HLA/ MHC

51
Q

A potential donor is described as being 1:1:0 MM. What does this mean?

A

1MM at A
1MM at B
0MM at DR

52
Q

What are the main effector cells in T-cell mediated rejection?

A

T cells and monocyte/macrophages

53
Q

A patient has an episode of acute T cell-mediated rejection 2 months post transplantation. What additional drug would most commonly be administered?

A

IV Methylprednisolone (steroids)

54
Q

Which cell is injured in the effector phase of antibody-mediated rejection?

A

Endothelium

55
Q

Recipient: A2 A24 B75 B61 Cw8 Cw15 DR 11 DR12 DQ7
Potential donor: A11 A24 B61 B18 Cw15 Cw7 DR1 DR11 DQ5 DQ7
Recipient anti-HLA serology: anti-DR1 (MFI 2,800), DQ5 (2600 MFI)

You are given the HLA genotype of a potential live donor and a recipient, and the recipient’s anti-HLA serology. Do you agree?

The live donor could be the recipient’s son.

A

50% mismatch- could be related

56
Q

Recipient: A2 A24 B75 B61 Cw8 Cw15 DR 11 DR12 DQ7
Potential donor: A11 A24 B61 B18 Cw15 Cw7 DR1 DR11 DQ5 DQ7
Recipient anti-HLA serology: anti-DR1 (MFI 2,800), DQ5 (2600 MFI)

You are given the HLA genotype of a potential live donor and a recipient, and the recipient’s anti-HLA serology. Do you agree?

A standard transplant procedure is likely to go smoothly

A

Disagree- anti HLA found

57
Q

You are given the HLA genotype of a potential live donor and a recipient, and the recipient’s anti-HLA serology. Do you agree?

The recipient would benefit from treatment to remove the anti-DR1 and DQ5 before transplantation

Recipient: A2 A24 B75 B61 Cw8 Cw15 DR 11 DR12 DQ7
Potential donor: A11 A24 B61 B18 Cw15 Cw7 DR1 DR11 DQ5 DQ7
Recipient anti-HLA serology: anti-DR1 (MFI 2,800), DQ5 (2600 MFI)

A

Agree- can still find use

PathY5 (98 decks)

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