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Immunology > L20- Immunology of transplantation > Flashcards

L20- Immunology of transplantation Flashcards

1
Q

What did Sir Peter Mesawar show?

A
  1. If you take skin graft from mouse and give it to same strain of mouse-> graft is tolerated.
  2. Skin graft from yellow mouse to blue mouse with different genetics-> graft rejected at a certain rate.
  3. If repeat step 2, will reject it quicker.
    (We call this 1st and 2nd set rejected kinetics.)
  4. If take (third strain) green mouse graft and put on blue mouse-> rejected at 1st step rate.
    (so shows memory and specificity)
  5. Accelerated rejection could also be transferred by transfer of T cells, not just skin grafts.
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2
Q

What are the ongoing challenges with organ transplant?

A
  • Long-term immune suppression
  • chronic organ rejection
  • organ supply
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3
Q

What kind of transplants are done? And what diseases lead to needing organ transplant?

(examples)

A
  1. Kidney (diabetic complications, nephritis)
  2. Liver (cancer, cirrhosis)
  3. Heart (heart failure)
  4. Haematopoietic stem cells (leukaemia, lymphoma)
  5. Cornea (keratitis, dystophies)
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4
Q

What are the 4 types of grafts described by the relationship between the donor and recipient?

A
  1. Autograft = give to yourself
  2. Isograft = give between identical twins
    (these are both called syngeneic/isogeneic, don’t need immune suppression)
  3. Allograft = most common, to another person.
  4. Xenograft = donation to different species e.g. pig heart
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5
Q

With regards to histocompatibility, what are:

a. Syngeneic grafts
b. Allogenic/xenogeneic grafts

A

a. No immune respons, so Histocompatible

b. Immune response against antigenic differences, so HistoIncompatible

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6
Q

What are the transplantation antigens called that make the stronger and weaker responses?

A

Strongest= MAJOR histocompatibility antigens

Weakest= MINOR histocompatibility antigens

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7
Q

Where is the gene loci responsible for the most vigorous graft rejection?

A

In the MAJOR HISTOCOMPATIBILITY COMPLEX (MHC)

Located on human chromosome 6p21 (called HLA region, Human Leukocyte Antigen region)

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8
Q

Describe the genetic organisation of the Human MHC?

A
  • 3 regions: class I, II, III
  • Class I and II encode the MHC class I and class II so easy
  • Class III codes for other immune proteins e..g complement proteins
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9
Q

What is the MHC class I structure?

A

Single chain. The alpha chain with 3 alpha loops. And a Beta 2 microglobulin which is not MHC encoded!

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10
Q

What is the MHC class II structure?

A

2 chains: the alpha and the beta. 2 loops of each

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11
Q

Describe the MHC class I and II genes?

A 
The genes for MHC I and II are POLYGENIC. (and polymorphic)
So we have 3 genes expressing MHC class I- known as A,B and C.
For class II- they're known as DP, DQ and DR which express an alpha and a beta chain.
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12
Q

What are the most polymorphic molecules in the population? (probably)

A 
MHC class I and II. Many alleles for each gene.
One allele is inherited from each parents at each gene and co- dominantly expressed.
So low chance you have an identical MHC as the person sitting next to you.
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13
Q

Why do siblings make good donors?

A

You inherit the same things from your parents. Tend to inherit them as a Haplotype.

Closely linked genes in the HLA are usually inherited as a set- haplotype. So inherit the genes in MHC and in the densely packed region of HLA are inherited together.

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14
Q

If you have two mice with exactly the same MHCs, are you guaranteed graft survival?

A

No.
They can have same MHC but might have allelic differences somewhere else in the genome.
This slow rejection is due to the MINOR histocompatibility antigens.

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15
Q

What gene loci is responsible for less vigorous allograft rejection?

A

MINOR HISTOCOMPATIBILITY ANTIGENS
(recognises allelic differences in non-MHC encoded genes, leads to presentation of a peptide not previously tolerised against in the host)

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16
Q

Summarise Major histocompatibility antigens

A
  1. Cause strongest response
  2. coded for by highly polymorphic class I and II MHC genes
  3. T cell cross-reactivity
17
Q

Summarise Minor histocompatibility antigens

A
  1. Weaker response
  2. Non-MHC encoded
  3. Due to allelic difference in any gene generating a peptide not previously tolerised against
  4. Happens by Presentation of allopeptide on self-MHC
18
Q

What happens in direct recognition?

A

When you get a transplanted organ, you also carry over some donor APCs because they come over in the organ. These Donor APCs have donor MHC on their surface and are presenting donor peptides.
These can be recognised by recipient’s T cells.
In this process, the T cell receptor is recognising donor MHC and donor peptide.
The donor APCs aren’t being replenished so once these die off, this won’t happen anymore.

19
Q

Summarise direct recognition

A

T cell receptor is recognising donor MHC and donor peptide from a donor APC

20
Q

What happens in indirect recognition?

A

The recipient APC gets into the organ. It picks up antigens from the graft. It processes them and presents donor peptides on the surface on the recipients MHC. It then presents that peptide to the recipient T cell, just as it would with any other antigen.

21
Q

What can the processed donor peptide be in indirect recognition?

A

Processed allelic antigens (minor antigens)

Or processed polymorphic allo-MHC

22
Q

What are the 3 main types of graft rejection?

A
  1. Hyperacute (minutes)
  2. Acute (days to weeks)
  3. Chronic (months to years)
23
Q

How does hyperacute rejection happen?

rare because can screen before

A

Mediated by Pre-formed anti-donor antibodies (usually against MHC I and ABO).
These were caused by sensitising events: e.g. pregnancy, blood transfusion.

Antibodies bind to graft blood vessel endothelium and recruit effector damage;

  1. complement activation-> inflammation-> vascular damage
  2. Platelet aggregation and activation of clotting cascade-> blockage of blood vessels.
24
Q

What are the stages of acute rejection?

A
  1. Sensitisation phase:
    a. Allo-recognition and activation of CD4+ T helper cells
    b. Generation of effector cells (DTH, B cells, CTLs)
  2. Effector phase:
    Attack on graft
25
Q

What is a characteristic of acute immune response?

A

Massive infiltration of T cells and macrophages

26
Q

What happens in the effector phase of acute immune response?

A

Plasma cell-> anti-graft antibody
Tdth-> delayed-type hypersensitivity
Tc-> killing of graft cells

27
Q

Describe chronic rejection

A

Slow progressive loss of graft function (years)
Eventually leads to blockage of vessels
Mechanism not fully understood.
Responds poorly to current immunosuppressive therapy.
(average half life of kidney= 10 years)

28
Q

What is Graft versus Host Disease? (GVHD)

A

A complication of bone marrow and haematopoietic stem cell transplants.
Essentially transplanting their immune system.
Get mature DONOR T cells recognising the host/recipient MHC and recipient peptide and donor cells attack cells and tissues of host.
Very important to get HLA match.

29
Q

What are 3 strategies to prevent graft rejection?

A

Being very careful with:
1. organ retrieval (minimise damage to donated organ)
2. pre-screening and matching
(blood type, HLA-specific antibody screening, cross-matching, HLA typing)
3. immune suppression

30
Q

What is the complement dependent cytotoxicity (CDC) Cross-match reaction?

A

Patient serum mixed with donor lymphocytes.
If there are any anitbodies in patient serum toward donor cells, they will bind
after 1 ohur complement is added and binf to patient antibodies if they are bound to donor cells.
If bound, complement will activate forming MAC complexes, making the donor cell membranes leaky.
The dye can get in to the cell and makes it look red. If this happens the transplant cannot proceed.

31
Q

What are some conventional drugs for immunosuppression?

A
  1. anti-mitotic agents e.f. azathioprine
  2. Cortiosetoids e.g. prednisone=anti-inflammatory
  3. Agents targeting IL-2 e.g. cyclosporin, rapamycin
  4. Targeting lymphocyte trafficking e.g. fingolimod
32
Q

What are some biological agents used for immunosuppresion?

A

rATG (rabbit derived anti-thymoglobulin):
Polyclonal induction agent

Monoclonal Antibodies (humanised): anti-CD52-depletes lymphocytes, anti-IL2R- blocks il2 signalling

33
Q

What is used for immunosuppression?

A

Combinations of biological and conventional drugs used to optimise survival but minimise side effects. Lower doses of any individual agent.

Immunology (21 decks)

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