Transplantation And Immunosupressive Drugs Flashcards

1
Q

what is transplantation?

A

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

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2
Q

what has the immune system evolved to do?

A

the immune system has evolved to remove anything it regards as non-self

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3
Q

why was the eye transplant so successful and done so early on?

A

because it’s an immunologically privileged site

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4
Q

Donor/recipient relationships - diff types?

A

Autologous
Syngeneic

Allogenic
Xenogenic

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5
Q

Autologous vs Syngeneic

A

for both of these, you wouldn’t expect an immune response

Autologous: Transplantation of tissue from 1 part of the organism into another part of the same organism. May be inflammatory responses, but no immune response as it is “self transplanting into self”

Syngeneic: Donor material transplanted into a recipient - donor and recipient are genetically identical.

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6
Q

Allogenic vs Xenogenic

A

both are genetically different, immune response may be generated

Allogenic: Donors and recipients are from the same species but genetically different

Xenogenic: Donor and recipient are different species

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7
Q

what are Immune responses to transplant caused by?

A

genetic differences between the donor and the recipient

  • most important are differences between the antigens forming the major histocompatibility complex (MHC)
  • MHC = biggest site of variability in human genome, which is why immune responses are raised against it
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8
Q

what is the human antigen called?

A

HLA (human leukocyte antigen)

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9
Q

HLA diversity

A

can be split into class I and class II:

Class I has 3 alleles
Class II are dimers and there are 6 alleles

Almost all mutated cells express HLA class I
Only WBC’s/professional APC's express HLA class I and HLA class II – important for rejection
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10
Q

Importance of epitopes on donor MHC

A

there are 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 - this means that even if people have different HLA’s, they may still have the same epitopes, therefore rejection won’t occur.

So, we are moving from matching recipient and donor HLA’s to matching recipient and donor alleles on the HLA, but NGS is too expensive for this to become a regular thing right now

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11
Q

what do T cells need to recognise?

A

foreign peptides bound to self-MHC

  • peptide is bound into the binding groove
  • TCR detects the combination of peptide and MHC
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12
Q

T cells and MHC class I

A

CD8 T cells recognise short peptide fragments from intracellular proteins that are presented to them by major histocompatibility (MHC) proteins

eg. a cell infected by a virus, viral proteins are processed by the proteasome into peptides

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13
Q

T cells and MHC class II

A

MHC class II only on WBC’s and professional APC’s

Good at taking up external material into a phagolysosome and breaking it down into peptides

Peptides interact with vesicle containing MHC

CLIP maintains the shape of HLA until the peptides are ready to bind.

MHC/peptide —-> APC surface, activates CD4 T cells

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14
Q

types of T cells?

A

Cytotoxic T cells – highly specific killer cells

Helper T cells – information and support for other immune cells via cytokine production

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15
Q

in transplants, what may be foreign?

A

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

so, donor HLA could be detected as foreign by the recipient immune system, or the peptide, OR both!

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16
Q

Direct and indirect T-cell activation

A

Direct allo recognition = recipient TCRs detecting donor/non-self HLA

Indirect allo recognition = recipient TCRs detecting donor/non self peptides

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

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

17
Q

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

18
Q

Types of graft rejection

A

Hyperacute rejection

Acute rejection

Chronic rejection

19
Q

Hyperacute rejection

A

Within a few hours of transplant

Most commonly seen for highly vascularised organs (e.g. kidney) because it is easier for an immune response to target highly vascularised tissue

Requires pre-existing antibodies, usually to ABO blood group antigens expressed on blood vessel endothelial cells, or to MHC class I - Antibodies to MHC can arise from pregnancy, blood transfusion or previous transplants

Antibodies bind to endothelial cells, complement fixation. Accumulation of innate immune cells, endothelial damage, platelets accumulate, thrombi develop

20
Q

How can antibodies cause damage to transplanted tissue?

A

The pre existing antibodies detect their antigen on the donor tissue, bind via the Fab-like fragment (variable)

The Fc region on antibodies can bind to Fc receptors on immune cells, initiating a quick innate immune response.

Recognition of Fc region leads to complement activation:

  1. Antibody dependent cellular cytotoxicity
    (Fc Receptors on NK cells)
  2. Phagocytosis
    (Fc Receptors on macrophages)
21
Q

Acute rejection

A

Inflammation results in activation of organ’s resident dendritic cells (donor DC’s, NOT recipient)

T cell response develops as a result of MHC mismatch

22
Q

Direct allorecognition of foreign MHC

A

eg. kidney transplant

inflammation activates recipient DC’s (in this case, they are in the kidney)

DC’s migrate to secondary lymphoid tissue. They are professional APC’s so they have MHC class I/II. Activate effector CD4 and CD8 T cells, which proliferate and migrate to the donor organ.

CD4’s and CD8’s target every cell that expresses the “foreign” HLA in the tissue and destroy the kidney transplant.

23
Q

Chronic rejection

A

results from indirect allorecognition of foreign MHC/HLA

Donor-derived cells die, and cells taken up and broken down by host DC’s and presented as peptides on host MHC. DC’s activate T cells in the lymph node, which are sensitive to the foreign peptide and kill any cell presenting it.

Can occur months or years after transplant - this MHC mismatch effect is less pronounced so takes longer to develop.

Blood vessel walls thickened, lumina narrowed – loss of blood supply

24
Q

Haematopoietic Stem cell transfer (HSCT)

A

The donor immune response is removed, and the stem cell transfer provides a new immune system

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

25
Q

Graft Versus 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

26
Q

Graft versus Leukemia

A

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

Typically happens with radiation therapy with leukaemia, where the patients immune system is destroyed, so they need a transplant of immune cells
There could be residual tumerogenic cells – but the new immune cells can target it in a way that the host immune system cannot – why? It’s because the cancer cells are self, so the immune system struggles to recognise it, so adding in these donor immune cells and creating a whole new immune system is a benefit.

27
Q

Immunosuppression

A

Essential to maintain non-autologous transplant, even if there’s good HLA matching

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)

Immunosuppressives may need to be maintained indefinitely

28
Q

autologous transplant

A

uses a person’s own stem cells

29
Q

Cyclosporin

A

Breakthrough drug for transplant

Blocks T cell proliferation and differentiation, Inhibit production of IL-2

Next generation therapies less toxic and effective at lower doses

30
Q

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,

Combination is typically more effective than single drugs, and it may also allow you to lower the dose of them and reduce side effects

31
Q

Immunosuppressive therapy monitoring

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.

Needs to be monitored as an immune response against the transplant may happen quietly in the background

32
Q

Intestinal microbiome

A

The microbiome, particularly of the intestine, is involved in regulating adaptive immune responses
-releases metabolites that reduce or increase the functioning of the immune system in a general way

Immunosuppressed/cancer patients who don’t respond to immunotherapy can take FMT (faecal material transplant) and it allows them to start responding – positive treatment effect.

May be implicated in transplantation outcomes