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Year 5 -krish finess > IMMUNO: Transplantation > Flashcards

IMMUNO: Transplantation Flashcards

1
Q

What are the first and second most transplanted organs?

A
  • 1st most common transplanted organs = KIDNEYS (average ½ life of a kidney is 12 years)
  • 2nd most common = LIVER
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2
Q

What proportion of the world population has kidney disease?

5%, 7% or 11%?

A

11%

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3
Q

5years on what are the chances of survival of a patient on CKD starting dialysis?

35, 55 or 85%?

A

35% chance of 5 year survival

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4
Q

What are the phases of T cell immune response to transplanted grafts?

A
  1. Phase 1: recognition of foreign antigens
  2. Phase 2: activation of antigen-specific lymphocytes
  3. Phase 3: effector phase of graft rejection
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5
Q

What are the most relevant protein variations in clinical transplantation? Which one is the most important?

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

What are the two major forms/components of rejection?

A
  1. T cell-mediated rejection
  2. Antibody-mediated rejection
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7
Q

What is the difference between HLA class I and II?

A

MHC (chromosome 6)

  • HLA Class I (A, B and C) – expressed on ALL cells
    • Thought to be the most immunogenic
  • HLA Class II (DR, DQ, DP) – expressed on APCs (also be upregulated on other cells under stress)

Features:

  • polymorphic with hundreds of alleles for each locus
  • high degree of variability lining the peptide-binding groove = allows us to present a wide variety of antigens i
  • number of mismatches is a major determinant of the risk of rejection
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8
Q

Which HLA are most important to match in transplantation?

A

DR>B>A

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9
Q

What happens in phase II of T cell mediated immune activation to transplantation?

A
  • To activated alloreactive T cells, T cellls require:
    • Presentation of foreign HLA antigens in MHC by APCs (both DONOR and HOST APC cells are involved)
    • Co-stimulatory signals
  • This occurs in lymph nodes and causes the effector phase of rejection –> inflammation caused leads to graft dysfunction (i.e. raised Cr).
  • Biopsy can be done to diagnose.
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10
Q

What does 1,0,0 mean in terms of HLA matching?

A

1 mistmatch at HLA-A

0 mismatches at HLA-B

2 mismatches in HLA-DR

Maximum is 2 mismatches in each = 6

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11
Q

How are mismatches counted? Try below.

A

This would be written as 1,1,0.

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12
Q

What happens in the phase 2 of T cell mediated immune reaction to a transplant?

A

Action of activated T cells e.g.

  • Proliferation
  • Production of cytokines (IL2 is important)
  • Providing help to CD8+ cells
  • Providing help for antibody production
  • Recruitment of phagocytic cells
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13
Q

What technique is used for HLA tissue typing?

A

PCR

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14
Q

Where does phase 2 vs phase 3 of immune T cell-mediated reaction to transplantation happen?

A

Phase 2 - lymph nodes

Phase 3 - within graft

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15
Q

How do cytotoxic T cells and macrophages affect the transplanted organ?

A

Cytotoxic T cells:

  • Granzyme B (toxin)
  • Perforin (punch holes)
  • Fas-ligand (apoptosis)

Macrophages:

  • Phagocytosis
  • Proteolytic enzymes
  • Cytokine release
  • O2 and N2 radicals
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16
Q

What is shown?

A

T cell mediated tubulitis.

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

NB: Immunohistotyping can be used to mark which type of cells e.g. T cells, are present.

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17
Q

What is seen here?

A

Infiltration of immune cells and closing of kidney tubules due to T cell mediated graft rejection.

  • N.B. failed graft function may not always be due to rejection… some immunosuppressive drugs given are nephrotoxic –> reduced function
18
Q

What happens in phase 3 of immune T cell-mediated reaction against transplants?

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
19
Q

What happens in the three phases of antibody mediated rejection?

A
  1. Phase 1: exposure to foreign antigen
  2. Phase 2: proliferation and maturation of B cells with antibody production
  3. Phase 3: effector phase – antibodies bind to graft endothelium (capillaries of glomerulus and around tubules)
20
Q

In comparison to T cell mediated rejection, where does antibody-mediated usually occur?

A

Anibody mediated usually –> endothelium damage and capillaritis. This may have procoagulant tendencies so can lead to closure of microcirculation and graft fibrosis

T cell –> interstitial damage and tubulitis

21
Q

What is shown in this antibody mediated rejection?

A
  • Glomerulus with capillary loops
  • Many cells within lumen of these loops
  • This is intravascular primarily
  • Called glomerulonephritis
  • There is also capillaritis
22
Q

Anti-HLA antibodies are not naturally occurring, when are they formed?

A
  1. Pre-formed - transplantation, pregnancy, transfusion
  2. Post-formed/de novo - raised after transplantation

Other antibodies - anti A and B, not HLA antibodies.

23
Q

What happens in phase 3 of antibody-mediated transplant rejection?

A
  1. Antibodies bind to antigens (HLA) on the endothelium of the blood vessels in the transplanted organ
  2. Antibodies fix/activate complement which assembles to:
    • Form MAC –> endothelial cell lysis
    • Recruit inflammatory cells to the microcirculation
  3. Antibodies can crosslink the MHC molecules, thus activating them
  4. The antibodies can also directly recruit mononuclear cells, NK cells and neutrophils –> capillaritis
24
Q

What is the cardinal feature of antibody-mediated rejection?

A

Capillaritis- inflammatory cells in capillaries of kindney

25
What 3 assays are used for screening for anti-HLA antibodies?
1. Cytotoxicity assays 2. Flow cytometry 3. Solid phase assays
26
Describe the use of cytotoxic assays for anti-HLA diagnosis.
* Inspects if recipient's serum will kill the lymphocytes of the donor, in the presence of complement * **Positive** crossmatch suggests that there is cell lysis (i.e. +ve is a bad thing)
27
Describe the use of flow cytometry for anti-HLA Ab detectiion.
* Inspects if recipient's serum binds to the donor's lymphocytes * Detection of bound AB by fluorescently labelled anti-human immunoglobulin * A broad test to look at whether antibodies bind antigen **irrespective** of whether they bind complement
28
Describe the use of solid phase assays for anti-HLA Ab detection.
Uses a series of beads containing all the possible HLA epitopes * Recipient's serum is mixed with beads and fluorescently labelled immunoglobulin is used to determine which HLA epitopes the antibodies bind to (can also give an indication of the strength of the reaction) * Patients that have **antibodies** to lots of different types of **antibodies** are regarded as highly sensitised
29
How can you detect liver/renal transplant dysfunction on bloods?
Raised Cr - renal Deranged LFTs - liver
30
What are some ways of overcoming organ mismatch issues?
* Improve transplantation across tissue barriers * More donors * Organ exchange programmes * **Future**: xenotransplantation (animals), stem cell research
31
What are the three main targets for immunosuppression that prevent T cell activation?
Three signals to activate T-cells – these can ALL be targets for immunosuppression: * APC **_MHC to T-cell TCR_** (main signal) * APC **_CD80/CD86 to T-cell CD28_** - *CD80/86 to CTLA4 suppresses immune reactions* * Cytokine **_IL-2 to T-cell CD25_** - *after T-cell activation, **autocrine IL-2** is released to further activate*
32
What kind of preparation is done for mismatch transplantation?
Plasma exchange and IVIG
33
List 4 drugs used as management in transplantation with T cell-mediated rejection.
* **Steroids** (prevent general T-cell mediated rejection) * **Inhibitors of cell signalling** / Calcineurin inhibitors (i.e. Tacrolimus, Cyclosporine) * **Anti-proliferative agents** (i.e. Mycophenolate mofetil, Azathioprine) * **Inhibitors of cell surface receptors** (i.e. Anti-CD3 antibody (OKT3), ATG / Anti-thymocyte globulin)
34
How does alemtuzumab and basiliximab prevent rejection?
**Alemtuzumab** is an anti-CD52 monoclonal antibody that causes lysis of T cells **Basiliximab** is an anti-CD25 monoclonal antibody which targets the **IL-2-R** à less proliferation
35
What is the most commonly administered drug first after patient develops rejection which is T cell mediated?
Steroids
36
List 4 management drugs used in management of antibody mediated rejection.
1. **Rituximab** (anti-CD20) = B cell depletion 2. **BAFF inhibitors** (target cytokines that promote B cell activation and growth) 3. **Proteasome inhibitors** (i.e. bortezomib) = block production of antibodies by plasma cells 4. **Complement inhibitors** (i.e. eculizumab, anti-C5) = block complement binding to endothelial cells
37
How are episodes of acute rejection treated?
Treatment of episodes of acute rejection: * **Cellular**: steroids, OKT3, ATG * **Antibody-mediated**: IVIG\*, plasmapheresis, anti-C5, anti-CD20
38
Which agents are used for transplant induction and baseline immunosuppression?
* **Induction agent**: e.g. OXT3/ATG, anti-CD52, anti-CD25(anti-IL2R) * Given **at** time of transplantation or **just before** to prepare the patient to receive the foreign organ * **Baseline immunosuppression**: calcineurin inhibitor (tacrolimus) + mycophenolate mofetil(MMF) / azathioprine ± steroids
39
What is the pathogenesis of GvHD in HSCT?
**Pathogenesis**: * Host immune system is eliminated (using total body irradiation and drugs) in preparation * It is then replaced by **own** (autologous) or **HLA-matched donor** (allogeneic) bone marrow * Allogeneic SCT leads to reaction of **donor lymphocytes against host tissues** (related to a degree of HLA-incompatibility) * If there is a malignancy (e.g. leukaemia), the graft can help kill these cells (graft-versus-tumour) * *It is thought that damage to GI tract by irradiation and cytotoxic drugs before the transplant has an important role in liberating antigens which subsequently are presented to the donor’s immune cells*
40
What is the GvHD prophylaxis and treatment in HSCT?
* **GvHD Prophylaxis** = Methotrexate/cyclosporine * **GvHD treatment** = steroids
41
What are the sypmptoms of GvHD?
**Symptoms** – *looks like slow-onset anaphylaxis with jaundice…* * Rash * Nausea and vomiting, abdominal pain, diarrhoea/bloody stool * Jaundice
42
Apart from GvHD, what is there an increased risk of after transplantation?
**Infections** - conventional and opportunistic e.g. CMV, BK virus, PCP **Malignancy** - * Viral associated - Kaposi's (HHV8), lymphoproliferative disease (EBV) * Skin cancer - x20 more common

Year 5 -krish finess (55 decks)

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