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Immunology Y5 > Immunology 3 - Transplantation > Flashcards

Immunology 3 - Transplantation Flashcards

1
Q

Recall the 3 phases of immune response to a transplanted graft

A
  1. Recognition of foreign antigens
  2. Activation of antigen-specific lymphocytes
  3. Effector phase of grant rejection: where the immune system mounts a response against the organ, causing damage
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2
Q

What are the 2 most variant protein variants in clinical transplantation?

A

ABO blood group
HLA antigens

**these are the proteins against which immune responses are mounted

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3
Q

On which type of cell is HLA class I expressed?

A

All cells

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4
Q

On which type of cell is HLA class II expressed?

A

Antigen-presenting cells

**but can be upregulated on other cells in time of stress

eg transplanted organs

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5
Q

Which part of the HLA molecule is highly variable?

A

Peptide binding groove

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6
Q

In T cell-mediated transplant reaction, how are alloreactive T cells activated?

A
  1. Both donor and host APCs present foreign HLA in their own MHCs
  2. Costimulatory signals
  3. Cytokines (feedback loop between APC and T cells)\

**NB DONOR APC are presenting self antigen to recipient immune system…almost like self sabotage….**

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7
Q

Which types of HLA fall into each class?

which ones are the most important in the context of transplant

A 
HLA-A, B, C = class 1
HLA-DR, DQ, DP =class 2

Importance: DR > B > A

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8
Q

What are the actions of activated T cells in T cell-mediated transplant rejection?

A
  1. Proliferation
  2. Produce cytokines (especially IL2)
  3. ‘Help’ CD8+ cells
  4. ‘Help’ antibody production
  5. Recruit phagocytic cells
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9
Q

How can you identify graft dysfunction?

A
  1. abnormal renal function tests
  2. abnormal liver function tests
  3. biopsy - determines if rejection is happening or not
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10
Q

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

What are the key immunohistochemical features of T-cell mediated transplant rejection?

A

biopsy:

Lymphocytic interstitial infiltration
Ruptured tubular basement membrane
Tubulitis (inflammatory cells within the tubular epithelium)
Macrophages, recruited by the T cells

immunohistochemistry:

  • mainly T cells: CD3+ cells

**main thing is that inflammation is interstitial

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11
Q

Recall the 3 phases of antibody mediated rejection

A
  1. B cells recognise foreign HLA
  2. Proliferation and maturation of B cells with anti-HLA antibody production
  3. Effector phase: antibodies bind to graft ENDOTHELIUM
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12
Q

Recall the process of antibody-mediated rejection phase 3

A

This is where the antibodies against HLA exert damage. This can be:

a) Compelment dependent
- complement binds to immunoglobulin on endothleium
a) activates MAC –> lysis
b) Complement independent
- antibody directly binds to HLA antigens present on the graft endothelium and neurtalise HLA antigens

(in both cases, the antibody is still binding to the endothelium)

–> Overall this lead sto cogaulatio, compromise to blood supply and organ dysfunction

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13
Q

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

A
  1. Inflammatory cell infiltrate
  2. Capillaritis
  3. Immunohistochemistry shows fixation or complement fragments on endothelial cell surfaces - in cases of complement mediated effector damage
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14
Q

Describe the effector phase of T cell-mediated transplant rejection

A

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 is done to prevent graft rejection?

A
  • Tissue typing : to check compatibility between donor and recipient
  • Screening for anti-HLA antibodies in the recipient
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16
Q

What test is used to do HLA typing before a transplant?

A

PCR-DNA sequencing

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17
Q

What at the 3 methods of screening for anti-HLA antibodies?

A
  1. Cytotoxicity assays - inspects if recipient’s serum binds to the donor lymphocytes by looking for LYSIS
  2. Flow cytometry - inspects if recipient’s serum binds to the donor lymphocytes by looking for BOUND FLUORESCENTLY-LABELLED ANTIBODY
  3. Solid phase assays, ‘Luminex’ (uses a series of beads that contain all the possible HLA phenotypes) - fluorescently labelled immunoglobulin used to determine which HLA epitopes the antibodies bind to
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18
Q

What is the most reliable HLA test nowadays?

A

Solid phase assays - uses beads that have different HLA epitopes and fluorescent colour

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19
Q

Recall 2 treatments that all transplant recipients receive to prevent rejection?

A

Induction agent
Base-line immunosuppression
Baseline immunosuppression is important to learn (has been in PPQ) =
Mycophenalate mofetil
Tacrolimus (calcineurin inhibitor)
Prednisolone
(Pre-Transplant Meds = acronym)

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20
Q

A pt has an episode of acute T cell-mediated rejection 2 months post-transplantation. What would be the most common drug administered?

A

Corticosteroid (prednisolone)

*can also give anti CD3 antibody

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21
Q

Recall 3 pathologies that immunosuppresion increases risk of

A

Infection, malignancy and drug toxicity

22
Q

Recall some drugs used to manage T cell vs antibody-mediated transplant rejection

A

T cell rejection management:

  • Steroids (prevent general T cell activation)
  • Calcineurin inhibitors (prevent cell signalling)
  • Anti-proliferative agents (mycophenalate, azothioprine)
  • receptor inhibitors (eg anti-CD3)

Antibody rejection management:

  • Rutiximab (anti-CD20)
  • BAFF inhibitors
  • proteasome inhibitors (block antibody production by plasma cells)
  • complement inhibitors (block complement binding to endothelium)
23
Q

What is the main complication of HSCT?

A

GvHD

24
Q

What is the pathogenesis of GvHD?

A
  1. During SCT, the host immune system is eliminated (total body irradiation and drugs)
  2. Bone marrow then replaced (allogenic/autologous)
  3. Allogenic SCT leads to reaction of donor lymphocytes against host tissues (related to a degree of HLA-incompatibility)
  4. If there is a malignancy, the graft can help kill these cells (graft-versus-tumour)

**NB - THIS IS DIFF FROM TRANSPLANT REJECTION WHERE HOST MOUNTS A RESPONSE AGAINST THE DONOR CELLS

25
Q

What are the 2 options for GvHD prophylaxis before HSCT?

A

Methotrexate
Cyclosporine

26
Q

How should GvHD following HSCT be treated?

A

Steroids

27
Q

What are the symptoms of GvHD following HSCT?

A

A bit like a slow anaphylaxis with jaundice:

  • Rash
  • Nausea and vomiting
  • Abdominal pain
  • Diarrhoea/bloody stool
  • Jaundice
28
Q

What is the post-transplant risk of malignancy?

A

Viral-associated malignancies are much more common, such as:
- Kaposi sarcoma (HHV8)
- Lymphoproliferative disease (EBV)
Skin cancer is 20x more common

29
Q

What is the most commonly transplanted organ?

A

Kidney

Avergae life of a kidney: 12 years

30
Q

Which are the most polymorphic HLA molecules?

A

HLA A, B, DR

31
Q

What is used to determine the risk of rejection prior to transplantation?

A

Number of mismatches in HLA alleles - important ones like A, B, DR

32
Q

What is an atypical feature of T-cell mediated rejection?

A

Arteritis

*T cells attack the endothelium

33
Q

What is the purpose of doing a graft biopsy?

A

To test whether graft failure is actually due to rejection or due to other things like drug reaction or infection

34
Q

What is the difference between antibodies against HLA and antibodies against AB antigens?

A

Anti- HLA antibodes are not naturally occurring. Either pre-formed (from previous transplantation or pregnancy) or post-formed in this current transplantation

Anti- AB antibodies are present from birth.

35
Q

Difference in target between T cel and B cell mediated rejection

A

T cell mediated rejection: target is the interstitium (or atypical -artertitis)

B cell mediated rejection: antibodies target the endothelium

36
Q

What are the different stages of rejection?

A

Hyper acute rejection requires sensitsation prior to this.

37
Q

How do ABO antigens cause transplant rejection?

A

AB glycoproteins are expressed on the surface of the endothelium of the transplanted graft\so an immune response cna be mounted against them.

You have pre-formed anti-A or anti-B antibodies from birth dpeneidng on your blood group

38
Q

Clinically how are ABO incompatible transplants achieved?

A

Antibodies are removed from the recipient prior to transplant soan ABO incompatible transplant can be acocmplished

39
Q

What methods are used in clinical practice to prevent B cell mediated rejection?

A
  • Plasma exchange
  • IVIG
  • Rituximab - anti CD20
  • BAFF inhibitors - target cytokines that drive B cell activation and growth
  • Proteasome inhibitors - bortezomib- blocks production of antibodies by plasma cells
  • Complement inhibitors - eculizumab
40
Q

Which drugs target the interaction between T and B cells?

A
  • anti CD40
  • CD28/B7 blockade
41
Q

Examples of induction agents given prior to transplant

A

T cell suppression

  • anti CD3
  • anti CD52 (TCR aka CD52)

others:

  • anti CD25- daclizumab (targets IL-2 signalling)
  • anti- IL2 R
42
Q

Drugs used to treat T cell mediated rejection acutely

A
  1. corticosteroids
  2. anti CD3
43
Q

Drugs used to treat B cell mediated rejection (acutely)

A
  • IVIG
  • plasma exchange
  • anti-CD20
  • anti-CD5
44
Q

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

A

T cells and macrophages

45
Q

Isograft vs allograft vs xenograt vs split graft

A
46
Q

Deceased donor vs living donor transplants

A
47
Q
A
48
Q

Direct vs indirect transplant rejection

A

direct

donor antigen presenting cell presents antigen to recipient T-cells. mainly involved in acute rejection

***D for Direct, D for donor***

indirect

recipient APC presents donor antigen to recipient T cells - i.e. immune system working normally as it would for an infection. mainly in chronic rejection

49
Q

summarise t cell vs antibody mediated rejection

A
50
Q

Sumamry of preventative and treatment measures during different phases of transplant

A
51
Q

what are some post transplant complications?

A
52
Q

what cuases lymphoproliferative disease (post transplant)?

A

ebv

Immunology Y5 (11 decks)

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