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Microbiology and Immunology - SGUL (Sem 4) > Transplantation and Immunosuppressive Drugs > Flashcards

Transplantation and Immunosuppressive Drugs Flashcards

1
Q

What does transplantation mean

A

Transplantation is the introduction of biological material (eg organs, tissue, cells) into an organism

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2
Q

What are the types of donor relationships

A
  • Autologous and syngeinic donations
  • genetically identical
  • no immune reactions
  • donation to and from same part of body
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3
Q

What is an example of an autologous transplant

A

Skin grafts from one part to another part of the body

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4
Q

What is an example of an syngeneic transplant

A

From one identical twin to another twin

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5
Q

What is allogenic transplantation

A

Same species but genetically different

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6
Q

What is xenogeneic transplantation

A

Transplantation between different species entirely

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7
Q

What is the cause of transplantation rejection

A
  • Immune responses to transplant are caused by genetic differences between the donor and the recipient
  • The most important are differences between the antigens forming the major histocompatibility complex (MHC)
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8
Q

What is the importance of epitopes on donor MHC

A
  • B-cell epitopes on donor MHC
  • T-cell epitopes derived from donor MHC
  • 1000’s of HLA alleles but perhaps only 100’s of epitopes
  • Next-generation sequencing is required to assassin the difference between the HLA of the recipient and donor
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9
Q

How is MHC recognised in a transplant

A

Both the MHC protein and the peptide in its binding groove may be foreign

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10
Q

What is Indirect allo-recognition

A
  • Where a self HLA and non-self peptide is present there is T cell activation
  • Cause lysis of cell
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11
Q

What is direct allo-recognition

A
  • Where a unmatched HLA and peptide causes T cell activation
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12
Q

How do we ensure transplant survival

A
  • try to match 4/6 MHC class 2 loci
  • Reduces likelihood of future transplants and problems with future transplant
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13
Q

Describe the possibility of using Live vs Dead donors

A
  • Recipients will have a history of disease which will have
    resulted in a degree of inflammation
  • Organs from deceased donors are also likely to be in
    inflamed condition due to ischemia
  • Transplant success is less sensitive to MHC mismatch
    for live donors
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14
Q

What are the types of graft rejections

A
  • Hyperacute rejection
  • Acute rejection
  • Chronic rejection
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15
Q

What is hyper-acute rejection

A
  • Within a few hours of transplant
  • Most commonly seen for highly vascularised organs
    (e.g. kidney)
  • Requires pre-existing antibodies, usually to ABO
    blood group antigens or MHC-I proteins
  • (ABO antigens are expressed on endothelial cells of
    blood vessels)
  • Antibodies to MHC can arise from pregnancy, blood
    transfusion or previous transplants
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16
Q

How does antibodies cause damage to transplanted tissue

A
  • Recognition of Fc region leading to
  • Complement activation
  • Antibody-dependent cellular cytotoxicity
    (Fc Receptors on NK cells)
  • Phagocytosis
    (Fc Receptors on macrophages)
17
Q

How does antibodies cause damage in hyper acute rejection

A
  • Antibodies bind to endothelial cells
  • complement fixation
  • accumulation of innate immune cells
  • Endothelial damage, platelets accumulate, thrombi develop
18
Q

Describe acute reaction

A
  • Inflammation results in activation of organ’s resident dendritic cells
  • T cell response develops as a result of MHC mismatch
19
Q

Describe the direct allorecognition response in acute rejection

A
  • Inflammation results in activation of organ’s resident dendritic cells
  • DC migrate to secondary lymphoid tissue where they encounter circulating effector T cells
  • Macrophages and CTL increase inflammation and destroy transplant
20
Q

Describe chronic rejection

A
  • Can occur months or
    years after transplant
  • Blood vessel walls thickened, lumina narrowed – loss of blood supply
  • Correlates with presence of antibodies to MHC-I
21
Q

Describe the indirect allorecognition response in chronic rejection

A
  • Donor-derived cells die
  • Membrane fragments containing donor MHC are taken up by host DC
  • Donor MHC is processed into peptides which are presented by host MHC
  • T cell and antibody responses is generated to the peptide derived from processed donor MHC
22
Q

What is Haematopoetic stem cell transfer

A
  • Previously called bone marrow transplant, now
    renamed as source is often blood
  • Often autologous
  • Until 1980 only HLA identical siblings could be used as donors due to the risk of rejection or graft versus host disease
23
Q

What is meant by Graft vs Host disease

A
  • When transplanted tissue is immune cells themselves, there is the risk of
    donor immune cells attacking the host – GVHD
  • Can be lethal – best approach is prevention
  • Removing T cells from transplant or suppressing their function reduces
    GVHD
24
Q

Describe the graft vs leukemia response

A
  • Sometimes mismatch and donor leukocytes can be
    beneficial - removing original leukaemia
  • Graft versus leukaemia response
  • Development of GVL may prevent disease relapse
25
Q

Why is immunosuppression important

A
  • essential to maintain non-autologous transplants
26
Q

What are the 3 phases of immunosuppression treatment

A
  • Induction
  • Maintenance
  • Rescue
27
Q

What are some types of immunosuppressants used

A
  • General immune inhibitors (e.g. corticosteroids)
  • Cytotoxic – kill proliferating lymphocytes (e.g. mycophenolic
    acid, cyclophosphamide, methotrexate)
  • Inhibit T-cell activation (cyclosporin, tacrolimus, rapamycin)
28
Q

Describe the use of cyclosporin

A
  • Blocks T cell proliferation and differentiation
  • improved patient and graft survival rates dramatically from 30%-50% to 80% at 1 year.
  • Next generation therapies less toxic and effective at lower doses
29
Q

Describe the use of combination immunosuppressive regimes

A
  • (1) Steroids – e.g. prednisolone
  • (2) Cytotoxic – e.g. mycophenolate motefil
  • (3) Immunosuppressive specific for T cells
    – e.g. cyclosporin A, FK506,
30
Q

Describe the Induction phase of immunosuppressive regimes

A

Antibody induction therapy:

  • Lymphocyte depleting rabbit Anti-thymocyte globulins (ATG) is the most
    commonly used antibody for induction therapy, followed by basiliximab and
    alemtuzumab.

Triple drug regimen:

  • a calcineurin inhibitor, an antiproliferative agent, and corticosteroid.
  • Tacrolimus, mycophenolate mofetil, and prednisone is the most common regimen.
31
Q

Describe the maintenance phase of immunosuppressive regimes

A

Use of triple drug regimen at lower doses

32
Q

Describe the Rescue phase of immunosuppressive regimes

A
  • T-cell mediated rejection (TCMR) is treated with ATG and steroids (eg,
    methylprednisolone 250-1000 mg per dose).
  • B-cell mediated rejection (BCMR) may be treated with Intravenous
    immunoglobulin or anti-CD20 antibody and steroids.
33
Q

How do we monitor immunosuppressive therapy

A
  • There is currently no immunosuppressive that will prevent
    transplant rejection whilst maintaining other immune responses
  • Transplant patients more susceptible to infection and malignancy
    – Immediate risk e.g. CMV
  • Immunosuppressive drug toxicity can lead to organ failure eg
    cyclosporin nephrotoxicity in kidney transplant.
34
Q

How does intestinal microbiome affect transplants and immunosuppressed patients

A
  • The microbiome, particularly of the intestine, is involved
    in regulating adaptive immune responses
  • Immunosuppressed patients (e.g. cancer patients) can
    take FMT – faecal material transplant – in order to
    promote effective anti-cancer immune responses
  • May be implicated in transplantation outcomes

Microbiology and Immunology - SGUL (Sem 4) (30 decks)

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