L18 - Immunology of Transplantation

Question 1

Transplantation

Answer 1

Involves the artificial transfer of tissue, cells or organs, from one anatomical site to another to replace lost or failing function

Question 2

Does rejection follow general immune trends?

Answer 2

Yes, it’s an Immunological Phenomena Showing Specificity and Memory - second wave is accelerated compared to the first set rejection

Question 3

Transplantation: what ongoing challenges are there?

Answer 3

Managing Organ Rejection:
* Long-term global immune suppression
* Chronic rejection

Organ Supply
* Demand heavily outweighs supply

Question 4

Types of grafts

Answer 4

Described based on the relationship between donor and recipient

• Autograft - self-graft
• Isograft - from a genetically identical donor
• Allograft - from a donor not genetically identical
• Xenograft - from an animal donor

Autografts and isografts are syngenic/isogenic

Question 5

Histocompatibility

Answer 5

No immune response (fully tolerant) - Syngeneic grafts

Graft accepted

Question 6

Histoincompatible

Answer 6

Immune response (against antigenic differences) - Allogeneic/Xenogeneic grafts

Graft rejected

Question 7

Histocompatible antigens

Answer 7

Major histocompatibility antigens - stronger immune response than minor ones

Question 8

What is it that is recognised by the immune system to trigger graft rejection?

Answer 8

Gene loci responsible for the most vigorous graft rejection are located in the Major Histocompatibility Complex (MHC)

Gene loci responsible for less vigorous allograft rejection encode minor histocompatibility antigens

Minor HC antigens explain why fully matched MHC grafts may still result in rejection

Question 9

Major histocompatability antigens

Answer 9

• Strongest response
• Highly polymorphic class I and II MHC molecules
• T cell cross-reactivity

Question 10

Minor histocompatability antigens

Answer 10

• Weaker response
• Allelic difference in a non-MHC encoded gene generating a peptide not previously tolerised against
• Uptake and presentation of graft derived allopeptide

Question 11

Allorecognition by T cells:

Direct and Indirect Recognition

Answer 11

Leccy

Question 12

Types of graft rejection

Answer 12

• Hyperacute minutes
• Acute days to weeks
• Chronic months to years

Question 13

Hyperacute Rejection: what is it, what is it caused by, and what happens?

Answer 13

Rapid rejection - occurs within minutes to hours

Pre-formed antibodies against the donor formed after sensitising events: pregnancy; blood transfusion; previous transplant

• Antibodies bind to graft blood vessel endothelium and recruit effector damage;
• Complement activation → inflammation → vascular damage (haemorrhage)
• Platelet aggregation & activation of clotting cascade → blockage of blood vessels

Question 14

Acute Rejection

Answer 14

Sensitisation phase:

Allo-recognition and activation of CD4+ T helper cells

Generation of effector cells (DTH, B cells, CTLs)

Effector phase:

Attack on graft

Characteristic massive infiltration of T cells and macrophages

Question 15

Chronic Rejection

Answer 15

vSlow progressive loss of graft function (years)

Eventually leads to blockage of vessels

Mechanism not fully understood (vascular & immune features;
cell-mediated and antibody mechanisms potentially involved)

Responds poorly to current immunosuppressive therapy

(half-life of a successful kidney graft remains ~10-15 yrs)

Question 16

Immune Responses in Transplantation:

Graft versus Host Disease (GVHD)

Answer 16

leccy plus lowkey interesting

Question 17

Strategies to Avoid/Prevent Graft Rejection

Answer 17

Avoidance (pre-transplant; avoid sensitisation)
* Organ retrieval
* Pre-screening & Matching

Prevention (during & following transplantation; supress/prevent effector responses)
* Immune suppression

Minimise damage to donated organs during procurement
* Consideration of the health of the graft begins immediately a potential donor is identified
* Optimal donor management - physiological optimisation, such as regulating chemical balances of brain-dead donor prior to organ removal
* Organ preservation - optimise surgical removal, perfusion, speed of delivery

Screening & matching:
* HLA typing
* Blood typing
* HLA-specific antibody screening
* Cross-matching (serum from recipient) - a functional assay that tests for anti-donor abs in a patient’s serum based on their ability to bind a sample of donor cells and mediate complement lysis.

Immunosuppression:
* Global immunosuppressive drugs - long-term global immune suppression may lead to increased risk of infections, malignancy, and drug associated toxicities (eg Nephrotoxicity by CsA)
* Specific immunosuppressive drugs - Cortiosteroids:

Prednisone - anti-inflammatory

Anti-mitotic agents:

Azathioprine

Agents targeting IL-2:

Cyclosporin → inhibits IL-2 synthesis

Rapamycin → inhibits IL-2 receptor signalling

Targeting lymphocyte trafficking:

Fingolimod → blocks exit from lymphoid tissue
* Biological agents as immunosuppressive - enable more specific targeting of immune suppression, rATG (rabbit derived anti-thymoglobulin):

Polyclonal induction agent → lymphocyte depletion, plus..

Monoclonal Antibodies (humanised):

Anti-CD52 → depletes lymphocytes

Anti IL2R → blocks IL2 signalling

Engineered CTLA4-Ig (Belatacept) → co-stimulation blockade → energy

• Induction Therapy

Drugs given at high dose before or at the time of the transplant to prevent sensitisation and inhibit initiation of alloresponses

• Maintenance Therapy

Lower dose of drugs to enable continued graft survival

Question 18

Ideal immunosuppressive treatment

Answer 18

Combinations of drugs (biological and conventional) are optimised to maximise survival, but minimise harmful side effects (such as infections, malignancy and toxicity) by using lower doses of any individual agent

Question 19

Different donor types and how quickly they can be done

Answer 19

Cadaveric - damage to organ may occur within minutes so extraction must be done quickly

Braindead - can take a few hours for surgery to be completed

Living donor -

leccy

Question 20

Most ideal method to prevent transplant rejection

Answer 20

The ‘Holy Grail’ of Transplantation is Tolerance

‘Short-term therapy for long-term benefit’

→ re-educate for unresponsiveness to transplant antigens, leaving the remainder of the immune system intact and responsive to other antigens.