Transplantation

Question 1

What criteria must be met for a transplant?

Answer 1

• Tissue/organ undergone an Irreversible Pathological Process which either Threatens Patient’s Life or Significantly Hampers QoL
• Alternative treatment is not available
• Disease must not recurre

Question 2

What are the 4 major types of graft?

Answer 2

Xenograft - From an animal
Allograft - From another person
Isograft - From someone genetically identical
Autograft - From yourself

Question 3

Define Histocompatibility?

Answer 3

State in which the donor and recipient share the same (or sufficiently similar) alleles of HLA genes that they express the same MHC proteins and so would not attack the graft

Question 4

Where are HLA alleles found?

Answer 4

on chromosome 6

Each person has 2 sets of alleles and they are co-dominantly expressed

Question 5

How are HLA alleles inherited

Answer 5

As Haplotypes (meaning 2 half sets, one from each parent)

Hence each person is 1/2 identical to each parent and so has a 1/4 chance of being identical to a sibling

Question 6

What are the major requirements for tissue typing?

Answer 6

HLA match, particularly:

• HLA-A
• HLA-B
• HLA-DR

And ABO blood group

Question 7

What do HLA-A & HLA-B code for?

Answer 7

MHC 1

Found on all nucleated cells, present intracellular antigens and recognised by CD8+ T cells

Question 8

What does HLA-DR code for?

Answer 8

MHC 2

Found on APCs, presents extracellular antigens and recognised by CD4+ T cells

Question 9

What are privileged sites?

Answer 9

Places with little to no blood flow and so no immunity. They don’t require tissue matching or immunosuppression

E.g. Cornea

Question 10

What are the major causes of rejection?

Answer 10

• HLA/ABO incompatible
• Pre-formed immunity (sensitized to donor antigen)
• Failed Immunosuppression (incl non-compliance)
• Infections or environmental triggers

Question 11

How do we categorize rejection?

Answer 11

Immediate
Acute
Chronic

Question 12

how do you prevent someone rejecting an organ?

Answer 12

ABO matching
Tissue Typing (HLA)
Prophylactic Immunosuppresants

Question 13

Other than rejection what else can go wrong in a transplant?

Answer 13

Infection
Neoplasia
Drug SEs
Recurrence of disease
Surgical/ ethical complications
Graft vs host disease

Question 14

What are the types of immunosuppresants used in organ transplant?

Answer 14

• CCS
• T-cell blockade: cyclosporin and tacrolimus
• IL-2 blockade: monoclonal antibodies and rapamycin
• Antiproliferatives

Question 15

What’s the difference between graft rejection and Graftvshost disease?

Answer 15

In rejection the host attacks the graft

In GvH, white cells in the donated tissue attack the host’s body

Question 16

So what is required for GvH disease?

Answer 16

Graft must contain immunocompetent cells

Recipient must have defective immunity (pretty likely since you’re smacking them with immunosuppresants)

HLA mismatch

Question 17

What can we do to prevent GvH?

Answer 17

Tissue Typing (HLA)

Can do Donor Marrow T cell Depletion

Question 18

What kind of donors are associated with the longest life, least rejection and best health?

Answer 18

1) Living Donors (Related or unrelated)
2) Living donors altruistic
3) Brain Death Donors (DBD)
4) Cadaveric Death Donors (DCD)

So 4 are the least healthy transplants and 1 the most

Question 19

what are privileged transplantation sites?

Answer 19

Tissues which do not receive much blood supply and therefore require less mismatching

Question 20

What are the types of graft rejection

Answer 20

• Hyperacute : within minutes
• Accelerated: 2-5 days
• Acute : 7-21 days
• Chronic: months to years

Question 21

What are hyper acute graft rejection due to?

Answer 21

Hyperacute:

• Preformed antibodies binding to ABO or HLA antigens on graft.
• Triggers a type 2 hypersensitivity

Question 22

what is accelerate graft rejection due to?

Answer 22

presence of T-cells which are presensitised to the donor

Question 23

what is acute graft rejection due to?

Answer 23

newly sensitised T cells to donor

Question 24

what is chronic rejectoion due to?

Answer 24

Multifactorial

usually related to T cells

Question 25

Classification of GVHD?

Answer 25

Acute: can last up to 4 weeks post transplant - affects skin, gut, liver and lungs Chronic: occurs later and can affect skin and liver

Question 26

Immunopathology of graft rejection?

Answer 26

1- Afferent phase: donor MHC molecules on “passenger leucocytes” within the graft are recognized by recipients CD4+ T Cells (ALLORECOGNITION) 2- Efferent phase : CD4+ cells recruit effector cells responsible for tissue damage of rejection e.g. macrophages, CD8+ cells, NK cells, B lymphocytes

Question 27

What are the two mechanisms of graft rejection?

Answer 27

Direct: T cell recognises unprocessed allogenic MHC on graft APC Indirect: presentation of a processed peptide of allogenic MHC bound to self MHC

Question 28

Types of stem cell presentation?

Answer 28

Autologous: self stem cells which have been frozen, conditioned and rein fused Allogenic: much riskier

Question 29

when are allogenic stem cells preferred?

Answer 29

- Hamatological malignancy - Aplastic anaemia - primary immunodeficiency

Question 30

Sources of stem cells?

Answer 30

- Bone marrow - Peripheral blood - Cord blood

Question 31

How can stem cells be conditioned?

Answer 31

- high dose chemo - high dose RT - Destroy recipients stem cells and allow engraftment of donor cells

Question 32

How does CCS work?

Answer 32

* At low doses they predominantly act on antigen-presenting cells, preventing some of the early stages of graft rejection. * Higher doses of corticosteroids have direct effects on T cells and are used to treat episodes of rejection.

Question 33

What are the two types of IL-2 blockade?

Answer 33

1- Monoclonal antibodies against IL-2 receptor : •used to treat ACUTE episodes of graft rejection • completely blocks IL-2 •vey potent immunosuppressive drug •e.g. basiliximab, daclizumab.. 2- Rapamycin •Less potent than monoclonal antibodies and easier to take •Used to prevet graft rejection •Blocks pathway further down

Question 34

Main problem with xenotransplantation?

Answer 34

* 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.