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Cellular and Molecular pathology > 20. HLA and Transplantation > Flashcards

20. HLA and Transplantation Flashcards

1. Transplantation from a historical perspective 2. Barriers to successful transplantation 3. Human leukocyte antigen matching 4. Mechanisms of organ rejection 5. difficulties with obtaining sufficient organs

1
Q

What is transplantation?

A
  1. The transfer of living cells from one part of the body to another
  2. The transfer of living cells from one body to another
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2
Q

When was the idea of transplant first thought of?

A
  1. Early skin grafts in 600BC
  2. autologous transplantation in 1597 for nose reconstruction.
  3. Allogeneic transplantation in 1650
  4. determined that xenografts were impossible
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3
Q

The idea of transplantation from an immunological perspective

A
  1. Snell discovered MHC locus in mice in the 1930s.
  2. concept of self and non-self in 1937 while observing destruction of grafts.
  3. lots of experimentation during 1940s on rejection and skin grafts
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4
Q

What can be transplanted today?

A
  1. Kidneys
  2. Liver
  3. Heart
  4. Lungs
  5. pancreas
  6. intestines
  7. cornea
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5
Q

When was the first full face transplant?

A

2010

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6
Q

When was the first hand transplant?

A

2012
It was complicated to get full used of. the hand.

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7
Q

What is one of the most common transplants?

A

Haematopoietic stem cell transplants from the bone marrow, peripheral blood HSC and cord blood

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8
Q

Why are transplant now regularly possible?

A

Due to the availability of immunosuppressant drugs like cyclosporin A, tacrolimus and corticosteroids.

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9
Q

What are the barriers to successful transplantation?

A
  1. Availability of organs from living and deceased donors.
  2. responses to alloantigens.
  3. The donor organ is seen as foreign and being rejected.
  4. HLA are highly polymorphic making it hard to find a match.
  5. donors needs to be matched for ABO and HLA.
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10
Q

What would be the ideal donor?

A

An identical twin

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11
Q

What is the ideal donor for most people?

A

A sibling with an identical HLA haplotype.

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12
Q

What haplotypes can siblings have in common?

A
  1. No match
  2. A 50% match
  3. A 100% match (still have minor differences in the body)
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13
Q

What makes finding a HLA match more likely?

A

If the patient and donor are the same ethnicity

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14
Q

Is there difference in the distribution of the HLA alleles?

A

Yes
1. Some alleles are very commonly expressed throughout the world.
2. Other alleles are more distinct and specific to different races.

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15
Q

How were most HLA alleles defined?

A

by genotyping and NGS

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16
Q

What are the types of immune rejection of transplanted organs?

A
  1. Hyperacute
  2. Acute
  3. Chronic
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17
Q

What is hyperacute rejection?

A
  1. Happens very fast within mins or hours.
  2. Due to mistakes in ABO matching.
  3. Antibody and complement mediated due to circulating in the blood.
  4. Not very common anymore as you would not intentionally do a mistmatch.
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18
Q

What is acute rejection?

A
  1. Happens in days to weeks.
  2. CD4 or CD8 T cell mediated with antibody deposition.
  3. Adaptive immunity so takes longer to develop.
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19
Q

What is chronic rejection?

A
  1. Takes months or years
  2. Due to macrophage infiltration and fibrosis, antibodies and T cells.
  3. Don’t really know what causes it
20
Q

Why does hyperacute rejection occur?

A
  1. ABO antigens are expressed on all tissues including vascular endothelium.
  2. When organs are transplanted they undergo reperfusion injuries. This can cause the upregulation of HLA1 on the endothelium.
  3. Very stressed endothelial cells can express HLA2.
  4. The recipient needs to be checked for antibodies for blood group antigens and HLA alloantigens which can lead to rapid rejection.
21
Q

What can cause pre-existing antibodies to blood group antigens?

A
  1. Pregnancy
  2. Previous transplant
  3. Blood transfusion
22
Q

What causes the hyperacute rejection and loss of function of the graft?

A
  1. As soon as the blood vessels are joined antibodies can bind to donor antigens and recruit immune cells.
  2. This kills or blocks the blood vessels.
  3. This kills the death of the graft.
23
Q

How is hyperacture rejection treated?

A

There is no treatment available.

24
Q

How is hyperacute rejection prevented?

A
  1. Correct ABO matching
  2. Correct HLA typing
  3. Cross matching
25
Q

What is cross-matching?

A
  1. Takes the blood from the recipient and testing it for reactive antibodies to the donor cells.
  2. Use leukocytes as they express HLA1 and HLA2.
  3. This determines whether the transplant recipient has pre-existing antibodies to the donor leukocytes.
26
Q

What causes acute rejection?

A
  1. about 10% of T cells are alloreactive against HLA.
  2. These T cells respond to donor HLA differences causing acute rejection.
  3. This is a big problem for kidneys.
  4. CD8 T cells recognise HLA1 alloantigens.
  5. CD4 T cells recognise HLA2 alloantigens.
27
Q

What do acutely rejected graft blood vessels look like?

A
  1. Blocked up with lots of monocytes and lymphocytes.
  2. Thicked vessel walls.
  3. Fatty macrophages
  4. Cell deposits
28
Q

What does a rejected kidney look like?

A
  1. swollen
  2. Haemorrhage
  3. necrosis
29
Q

What can prevent acute rejection?

A
  1. Immunosuppressive drugs. This reduces T cell activation.
  2. Closer matches lowers need for suppression and lowers other risks.
30
Q

What are the 3 ways alloreactive T cells are activated in acute rejection?

A
  1. Direct
  2. Indirect
  3. Semi-direct
31
Q

What is direct activation of alloreactive T cells in acute rejection?

A
  1. Donor dendritic cells in the donor organs expresses the donor HLA1/2.
  2. These cells can enter the recipient’s body after transplantation.
  3. This activates the T cells.
  4. If these T cells migrate to the graft they can destroy the graft.
32
Q

What is indirect activation of alloreactive T cells in acute rejection?

A
  1. Dying donor dendritic cells shead bits of membrane containing the HLA peptides.
  2. These can be taken up by the recipient’s dendritic cells into the proteasome and are degraded. Then fuses with the late endosome where the HLA2 are.
  3. The dendritic cells then present peptide fragments of the donor HLA.
  4. T cells recognise these as foreign and mount an immune response.
33
Q

What is semidirect activation of alloreactive T cells in acute rejection?

A
  1. More recently discovered and less well researched.
  2. Donor dendritic cells shed their membrane with the HLA part of it.
  3. These parts of the membrane become contiguous with the recipient dendritic cell.
  4. The recipient dendritic cell presents donor peptides on donor HLA complexes.
  5. This is recognised by T cells.
34
Q

How does the indirect pathway of activation of alloreactive T cells cause the production of alloantibodies?

A
  1. An indirectly activated T cell recognises a peptide fragment of the donor HLA.
  2. If these are CD4 T cells when they are activated, they can stimulate B cells to produce antibodies.
  3. B cells recognising the same HLA peptide fragment take up the donor HLA.
  4. The B cells can also present this donor HLA peptide.
  5. The B cell produces alloantibodies to the donor HLA peptide.
35
Q

How do we think chronic graft rejection is caused?

A
  1. We don’t know why it takes so long.
  2. Alloantibodies and T cells recruit inflammatory cells to the blood vessels of the graft.
  3. This causing increasing damage to the graft tissue.
36
Q

What is a patient reason for chronic graft rejection?

A

They stop taking their immunosuppressives.

37
Q

What is the half life of renal transplants?

A

About 8 years

38
Q

What contributes to chronic graft rejection?

A
  1. Presense of alloantibodies.
  2. macrophage infiltration and scaring.
  3. reperfusion injury at the time of the graft appearing later.
  4. Show slow loss of graft function.
39
Q

What are the problems associated with organ transplantation?

A
  1. Rejection
  2. Immunosuppressive drugs are needed but increase risk of infection or cancer.
  3. Problems with toxicity of long term medication use.
  4. Disease that destroyed the original organ might damage the graft.
  5. Infection from the donor organ.
  6. Difficulty obtaining sufficient organs.
40
Q

How do the immunosuppressive drugs cyclosporin A and tacrolimus work?

A
  1. They bind to binding proteins that prevent calcineurin’s function.
  2. This means it cannot dephosphorylate a transcription factor.
  3. This prevents IL-2 production.
  4. This Prevents T cell proliferation.
41
Q

What are some anti-proliferative immunosuppressive drugs?

A
  1. Mycophenolate Mofetil
  2. Mycophenolate sodium
  3. Azathioprine
42
Q
A
43
Q

How do anti-proliferative immunosuppressive drugs work?

A

They suppress nucleotide synthesis and prevent proliferation.

44
Q

What do mTOR inhibitors do?

A

Prevents IL-2 receptor signalling

45
Q

What do steroids like prednisone do?

A

Decrease leukocyte migration to decrease the chance of recipient cells entering the graft.

46
Q

Why was the opt out system introduced?

A

It was hoped it would result in a significant increase in the availability of donated organs from deceased donors.

47
Q

Why did the COVID-19 pandemic reduce organ transplantation?

A
  1. Lots of transplantation staff were redeployed.
  2. Less accidental deaths to be donors.
  3. Essential/urgent transplants still went ahead.

Cellular and Molecular pathology (25 decks)

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