Transplantation and Immunosuppressive Drugs Flashcards

1
Q

What is autologous, syngeneic, allogeneic and xenogeneic transplantation?

A

In both, donors and recipients are genetically identical, do not usually generate any immunological problems.

Autologous- transplantation of biological material between one part of an organism to another part of the same organism eg skin graft

Syngeneic- transplantation of biological material between a donor to its recipient- different organisms but genetically identical eg identical twins

Allogeneic- Donors and recipients are from the same species but genetically different eg between a brother and a sister

Xenogeneic- Donor and recipient are different species eg between pigs/cows and humans eg porcine or bovine valves used in the transplantation of heart valves

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2
Q

What is the link between major histocompatibility antigens and transplantation tissue compatibility?

A

Histocompatibility = tissue compatibility

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)

Human transplants largely unsuccessful until identification of human MHC in 1967

In 1968 WHO nomenclature committee designated that human MHC proteins be named HLA (Human Leukocyte Antigen)

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3
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 required

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4
Q

What do T cells need to be able to recognise? What is their link to MHC?

A

T cells need to be able to recognise foreign peptides that are bound to self-MHC

T cells recognise short peptide fragments that are presented to them by major histocompatibility (MHC) proteins

CD8 cells interact with an MHC Class I and the epitope it is expressing
CD4 cells interact with an MHC Class II

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5
Q

What is the difference between MHC Class I and MHC Class II loading?

A

MHC Class I:

Protein (eg viral protein) is degraded by proteasome into peptides. These peptides are transferred by the endoplasmic reticulum to MHC Class I molecule. This MHC Class I molecule makes its way to the cell surface and can be identified by the TCR of antigen specific T cells

MHC Class II

The antigen is usually internalised by a phagolysosome. Protein is lysed into peptides which are then transferred to MHC Class II molecules, which is then presented on the surface of the cell.

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6
Q

As a summary, what does MHC Class I bind and what is it seen by?

A

MHC Class I binds fragments of intracellular proteins and it is seen by a T cell receptor on Cytotoxic T cells, with assistance from CD8.

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7
Q

As a summary, what does MHC Class II bind and what is it seen by?

A

MHC Class II binds fragments of proteins which have been taken up by endocytosis and it is seen by a T cell receptor on helper T cells, with assistance from CD4

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8
Q

How can T cell activation occur directly and indirectly?

A

In transplants, both the MHC protein and the peptide in its binding groove may be foreign
The Peptide presented by an HLA allele may be derived from an HLA molecule. Both the peptide and the HLA allele may be defined as foreign/non self

known as allo-recognition:

Recipient cell:
Self HLA + self peptide = no T-cell activation
Self HLA + non self peptide = T-cell activation

Donor cell:
Matched HLA + peptide = no T-cell activation
Unmatched HLA + peptide = T-cell activation

If no HLA matches between donor and recipient, survival is very short

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9
Q

What are the 3 types of graft rejection?

A

Hyperacute rejection

Acute rejection

Chronic rejection

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10
Q

What is hyperacute rejection? What occurs?

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

How it occurs:
Antibodies bind to endothelial cells

complement fixation

accumulation of innate immune cells

Endothelial damage, platelets accumulate, thrombi develop

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11
Q

How can antibodies cause damage to transplanted tissue?

A

Recognition of Fc region leading to :

1.Complement activation

2.Antibody dependent cellular cytotoxicity
(Fc Receptors on NK cells)

3.Phagocytosis
(Fc Receptors on macrophages)

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12
Q

What is acute rejection?

What usually occurs?

A

Inflammation results in activation of organ’s resident dendritic cells

T cell response develops as a result of MHC mismatch

In transplants, both the MHC protein and the peptide in its binding groove may be foreign

How it occurs:

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

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13
Q

What is chronic rejection?

What takes place when this happens?

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

Chronic rejection results from indirect allorecognition of foreign MHC/HLA

How it occurs?

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

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14
Q

What is haematopoietic stem cell transfer? (HSCT)

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

HSCs can find their way to bone marrow after infusion and regenerate there
They can be cryopreserved with little damage

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15
Q

What is 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

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16
Q

What is the Graft versus Leukaemia response?

A

But sometimes mismatch and donor leukocytes can be beneficial - removing original leukaemia
Graft versus leukaemia response
Development of GVL may prevent disease relapse

This is because the graft sees the Leukaemia as non self whereas the recipients original immune response would partially see leukaemia as self so its immune response against the tumour cells is weaker

17
Q

What does immunosuppression involve? What are the 3 stages?

A

Essential to maintain non-autologous transplant

3 stages of immunosuppression are:
Induction, maintenance and rescue phases of treatment

Immunosuppressants for transplant can be -
General immune inhibitors (e.g. corticosteroids)
Cytotoxic – kill proliferating lymphocytes (e.g. mycophenolic acid, cyclophosphamide, methotrexate)
Inhibit T-cell activation (cyclosporin, tacrolimus, rapamycin)

Immunosuppressive may need to be maintained indefinitely

18
Q

What does Cyclosporin do?

A

Breakthrough drug for transplant

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

19
Q

What will immunosuppressive drugs used to prevent transplant rejection depend on? Expand using examples

A

immunosuppressive drugs used to prevent transplant rejection depends on the phase of treatment during the induction phase

Induction:
Antibody induction therapy
Lymphocyte depleting rabbit Anti-thymocyte globulins (ATG) is the most commonly used antibody for induction therapy, followed by basiliximab and alemtuzumab. (bind to T cells preventing proliferation)

Triple drug regimen
a calcineurin inhibitor, an antiproliferative agent, and corticosteroid. Tacrolimus, mycophenolate mofetil, and prednisone is the most common regimen.

Maintenance:
Triple drug regimen at lower doses

Rescue: (if transplant rejection does occur drugs can be used to try ‘rescue’ this)
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.