Transplantation and Immunosuppressive

Question 1

What is transplantation?

Answer 1

Transplantation is the introduction of biological material (e.g. organs, tissue, cells) into an organism
The immune system has evolved to remove anything it regards as non-self

Question 2

What is the difference between autologous and syngeneic transplantation?

Answer 2

In this case donors and recipients are genetically identical, do not usually generate any immunological problems
Autologous is the transplantation from one part of an individual to another part of that same individual
Syngeneic is the transplantation between genetically identical organisms

Question 3

What is the difference between allogenic and xenogeneic?

Answer 3

Donor/recipient relationships- allogenic
- Donors and recipients are from the same species but genetically different
Donor/recipient relationships- xenogeneic
- Donor and recipient are different species

Question 4

What role does MHC play in transplantation?

Answer 4

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)

Question 5

What is the importance of epitopes on donor MHC?

Answer 5

There are B-cell epitopes on donor MHC
There are T-cell epitopes derived from donor MHC
There are 1000’s of HLA alleles but perhaps only 100’s of epitopes
Next generation sequencing required to ascertain the differences between the HLA between the donor and recipient

Question 6

How do T cells react to transplanted material?

Answer 6

When T cells are activated to respond to transplanted material this is called allo-recognition
This can be direct or indirect
Recipient cell
- Self HLA + self peptide = no T-cell activation
- Self HLA + non self peptide = T-cell activation- indirect allo-recognition
- This can occur if there is partial matching between the donor and recipient HLA
- So one of the HLAs which does match presents peptide form a HLA which does not match
Donor cell
- Matched HLA + peptide = no T-cell activation
- Unmatched HLA + peptide = T-cell activation- direct allo-recognition

Question 7

What is the difference between dead vs. live doners?

Answer 7

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

Question 8

What are the types of graft rejection?

Answer 8

Hyperacute rejection
Acute rejection
Chronic rejection

Question 9

What is hyperacute rejection?

Answer 9

Occurs within a few hours of transplant
Most commonly seen for highly vascularised organs (e.g. kidney) so they are more accessible to immune system
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

Question 10

How can antibodies cause damage to transplanted tissue?

Answer 10

Recognition of Fc region leading to - 
Complement activation
Antibody dependent cellular cytotoxicity 
	- (Fc Receptors on NK cells)
Phagocytosis
	- (Fc Receptors on macrophages)

Question 11

What happens during hyperacute rejection?

Answer 11

Antibodies bind to endothelial cells
Complement fixation occurs
There is accumulation of innate immune cells
This leads to endothelial damage, platelets accumulate, thrombi develops

Question 12

What is acute rejection?

Answer 12

Inflammation results in activation of organ’s resident dendritic cells
T cell response develops as a result of MHC mismatch

Question 13

What happens during direct allorecognition of foreign MHC?

Answer 13

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

Question 14

What is chronic rejection?

Answer 14

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

Question 15

What happens during chronic rejection?

Answer 15

Chronic rejection results from indirect allorecognition of foreign MHC/HLA
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

Question 16

What is HSCT?

Answer 16

Haematopoietic Stem cell transfer (HSCT)
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

Question 17

What is graft versus host disease? How can it be beneficial?

Answer 17

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

But sometimes mismatch and donor leukocytes can be beneficial - removing original leukemia
This is called graft versus leukaemia response
Development of GVL may prevent disease relapse

Question 18

What are immunosuppressant like for transplantation?

Answer 18

Essential to maintain non-autologous transplant
There is the 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)
Immunosuppressives may need to be maintained indefinitely

Question 19

What is cyclosporin?

Answer 19

Breakthrough drug for transplant
Blocks T cell proliferation and differentiation
But is quite cytotoxic
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

Question 20

What are the typical immunosuppressive regimes?

Answer 20

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.
- 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
- 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.

Question 21

What is the purpose of immunosuppressive therapy monitoring?

Answer 21

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.

Question 22

How is the intestinal microbiome involved in transplantation?

Answer 22

The microbiome, particularly of the intestine, is involved in regulating adaptive immune responses
Immunosuppressed patients (e.g. cancer patients) can take FMT – faecal material transplant – in order to promote effective anti-cancer immune responses
May be implicated in transplantation outcomes