Transplantation

Question 1

What are the 5 types of transplant?

Answer 1

Autologous transplant
-tissue returning to the same individual after a period outside the body, usually in a frozen state

Syngeneic transplant/isograft
-transplant between identical twins; there is usually no problem with graft rejection

Allogeneic transplant
-takes place between genetically nonidentical members of the same species; there is always a risk of rejection

Cadaveric transplantation
-uses organs from a dead donor

Xenogeneic transplant
-takes place between different species and carries the highest risk of rejection

Question 2

What criteria must be met before solid organ transplant?

Answer 2

There must be good evidence that the damage is irreversible

That alternative treatments are not applicable

The disease must not recur

Question 3

How can changes of solid organ rejection be reduced?

Answer 3

1) The donor and recipient must be ABO compatible
2) The recipient must not have anti-donor human leukocyte antigen (HLA) antibodies
3) The donor should be selected with as close as possible HLA match to the recipient
4) The patient must take immunosuppressive treatment

Question 4

How can stem cells be donated?

Answer 4

Only live

Question 5

What is a hyperactive rejection?

Answer 5

TYPE II, due to ABO or HLA mismatch

Within hours of transplantation

Preformed antibodies binding to either ABO blood group or HLA class I antigens on the graft

Antibody binding triggers a type II hypersensitivity reaction, and the graft is destroyed by vascular thrombosis

Hyperacute rejection can be prevented through careful ABO and HLA cross-matching and is now rare

Question 6

What is an acute rejection?

Answer 6

Type IV (cell-mediated) delayed hypersensitivity reaction, HLA incompatibility is main cause

Takes place within days or weeks of transplantation

Donor dendritic cells stimulate an allogeneic response in a local lymph node and T cells proliferate and migrate into the donor kidney

Shortage of donor kidneys leads to using a partially mismatched kidney

The survival of the kidney is related to the degree of mismatching, especially at the HLA-DR loci

Could be antibody mediated rejection

Question 7

What are the 2 immunological phases of graft rejection?

Answer 7

Afferent and effector phases

Question 8

Describe the afferent and effector phases

Answer 8

Afferent phase:
-Donor MHC molecules on ‘passenger leucocytes’ (dendritic cells) within the graft are recognised by the recipient’s CD4+ T cells (allorecognition)

Effector phase:
-CD4+ T cells recruit effector cells responsible for the tissue damage of rejection; macrophages, CD8+ T cells, NK cells and B lymphocytes

Question 9

What is chronic rejection?

Answer 9

Chronic rejection takes place months or years after transplant

An element of allogeneic reaction is often mediated by T cells, which can result in repeated acute rejection

Chronic rejection may be caused by recurrence of pre-existing autoimmune disease

Question 10

How may tolerance of graft be aided and what are the issues with this?

Answer 10

Immunosuppressive drugs prevent rejection if given at the time of transplantation, but once the drugs are stopped, rejection still takes place

Immunosuppressive drugs also lack the specificity of true tolerance and thus prevent immune responses to infectious agents

Opportunist infections are a major limit to the use of potent immunosuppressive drugs

Question 11

How is rejection prevented?

Answer 11

ABO typing
HLA typing
HLA cross-typing

Question 12

What is HLA cross-typing?

Answer 12

After typing (as a final check) the B cells from the donor blood are mixed with recipient serum to find out if the recipient will produce antibodies against donor cells

Question 13

Which HLA loci are most important when finding a match?

Answer 13

D

Question 14

What is stem cell transplantation and what is it used for?

Answer 14

Haematopoietic stem cells are used to restore myeloid and lymphoid cells

Question 15

When is autologous stem cell transplant carried out?

Answer 15

Marrow is removed, frozen, and reinfused after potent chemotherapy has been given

Autologous transplants carry minimal immunologic risk

Question 16

How does allogenic stem cell transplantation compare with solid organ transplantation?

Answer 16

It is a much riskier procedure than most solid organ transplants
Even with well-matched donors and in the best of circumstances, the mortality rate can be as high as 20%

Question 17

When is alleged SCT carried out?

Answer 17

Haematologic malignancy with no alternative treatment options

Cases when myeloid cell production is reduced or notably abnormal, such as in aplastic anaemia

Primary immunodeficiencies such as severe combined immunodeficiency (SCID)

Question 18

Where are the sources of stem cells in the body?

Answer 18

Bone marrow
-Aspiration of a considerable amount of donor marrow under general aesthetic

Peripheral blood
-Harvested after treating the donor with colony-stimulating factors to increase the numbers of circulating stem cells

Umbilical cord blood

• Contains a large number of stem cells, which can be frozen before use
• Immature lymphocytes are less likely to cause GVHD

Question 19

How can and a recipient be condition before an SCT and what is the purpose of this?

Answer 19

High dose chemotherapy
High dose radiotherapy

Destroy the recipient’s stem cells and allows the engraftment of donor cells

Do this even in autologous transplantation

Question 20

What is the cause for high rates of allogenic SCT failure?

Answer 20

Graft vs. host disease

Question 21

What is graft vs. host disease?

Answer 21

GVHD occurs when donor T cells respond to allogeneic recipient antigens

Mismatches in major or minor histocompatibility antigens

All patients who receive SCT are given immunosuppressive drugs to prevent GVHD, even if the donor and the recipient are HLA identical

Acute GVHD occurs up to 4 weeks after SCT

• Involvement of skin, gut, liver, and lungs is widespread
• When severe, acute GVHD carries a 70% mortality risk

Chronic GVHD occurs later and affects the skin and liver

Question 22

What are some examples of immunosuppressive drugs?

Answer 22

Corticosteroids

T-cell signalling blockade e.g. cyclosporin

IL-2 blockade e.g. monoclonal antibodies, rapamycin

Anti-proliferatives e.g. azathioprine

Question 23

How do low and high dose steroids work?

Answer 23

Low doses
-Act on antigen-presenting cells, preventing some of the early stages of graft rejection

Higher doses
-Effects on T cells and are used to treat episodes of rejection

Question 24

How do T-cell signalling blockade immunosuppressants work?

Answer 24

E.g. Cyclosporine and tacrolimus

Work by interacting with proteins in the intracellular T-cell signalling cascade

Question 25

How monoclonal antibodies against the IL-2 receptor work?

Answer 25

Completely block IL-2 and have potent immunosuppressive effects

Only used to treat episodes of acute graft rejection

E.g. basiliximab and daclizumab

Question 26

How does rapamycin work (IL-2 blockade)?

Answer 26

Can be given orally and interacts with signalling events downstream of the IL-2 receptor

Rapamycin is less potent and easier to take than the monoclonal antibodies, so it is used to prevent graft rejection

Question 27

How do anti-proliferatives work?

Answer 27

Inhibit DNA production

E.g. azathioprine, mycophenolate mofetil, and methotrexate

These drugs prevent lymphocyte proliferation, but they are not specific for T cells and can cause myelotoxicity (bone marrow suppression)

Question 28

What are the side effects of cyclosporin?

Answer 28

Viral, fungal and bacterial infections
Increased risk of getting certain cancers
Nephrotoxic properties
Diabetes
Hypertension

The side effects of cyclosporin are thought to be largely due to its mode of action in inhibiting calcineurin

Question 29

What are the side effects of rapamycin?

Answer 29

• Raised lipid and cholesterol levels
• Hypertension
• Anaemia
• Diarrhoea
• Rash
• Acne
• Thrombocytopenia
• Decreases in platelets and haemoglobin

Question 30

What are the issues with xenograft?

Answer 30

Primates assemble different sugar side chains from other species

• Galactose-α1,3-galactose (gal-α1,3-gal) is a sugar present on the cells of most non-primate species
• The immune system can recognize gal-α1,3-gal, and all humans possess antibodies against it following exposure to gut bacteria
• Antibodies against gal-α1,3-gal bind onto xenotransplanted organs, activate complement, and trigger hyperacute rejection

Complement inhibitors from other species do not inhibit human complement. As a result of this molecular incompatibility, xenotransplanted organs activate complement

Question 31

How are the issues with xenograft tackled?

Answer 31

Transgenic pigs are being developed with reduced gal-α1,3-gal expression to prevent natural antibody binding and with human complement inhibitors to bypass molecular incompatibility

Pigs are used because they are a similar size to humans and are easy to rear in captivity

Question 32

Even with amendments, why might xenografts be rejected?

Answer 32

Acute rejection may occur because pig proteins elicit T-cell responses

Even pigs reared in microbe-free conditions are infected with endogenous retroviruses; these have never been known to infect humans, but there is a risk as pig viruses are more likely to infect recipients taking immunosuppressive drugs