15. Introduction to transplantation immunology

Question 1

Transplantation

Answer 1

the grafting of tissue, usually from one individual to another.

Question 2

Autograft

Answer 2

to another site on the same individual (e.g. after burns)

autologous

Question 3

Isograft

Answer 3

to a genetically identical individual (homozygos twins)

iso/syngeneic

Question 4

Allograft

Answer 4

• to a genetically disparate member of the same species

allogeneic

Question 5

Xenograft

Answer 5

• to a different species (pig o monkey to human)

Question 6

Renal transplantation

Answer 6

Renal Transplantation
(donor may be dead or alive)

• Operation: trauma & ischemia (cold and warm)
• Reperfusion of ischemic organ (reperfusion damage)
• Inflammation/would healing
• Immune response against the graft

Question 7

Warm ischaemic phase vs cold ischaemic phase

Answer 7

warm ischaemic phase: time from interruption of circulation to the donor organ to the time when organ is flushed with hypothermic preservation solution.

cold ischaemic phase: while the organ is preserved in a hypothermic state prior to transplantation into the recipient.

Question 8

Types of graft rejection

Answer 8

Hyperactue rejection - minutes/hours/days

Acute rejection - days-weeks, possibly later (late acute)

Chronic rejection - can be from weeks to months, years

Question 9

What is the difference between a blood transfusion and a solid organ graft

Answer 9

Serum contains antibodies against the ABO antigens which will not be present in the recipient

All stromal cells express ABO antigens.

What about HLA-antigens?

Red blood cells do not express HLA antigens (because do not have nuclei). All nucleated cells do. (HLA is human MHC)

Question 10

How do HLA antibodies cause graft injury?

Answer 10

By inducing phenotypic changes in the donor vasculature which activates endothelial cell (EC) which promotes recruitment of leukocytes and CD4 T cell proliferation in response to alloantigen HLA class II on EC.

Complement-activating antibodies trigger the classical pathway by binding of C1q, resulting in production of anaphylatoxins C3a and C5a, which can directly augment leukocyte recruitment and T cell alloresponses.

FcgammaR binding HLA heavy chains leads to ADCC

Lead to microvascular inflammation characteristic of antibody-mediated rejection.

Question 11

FcgammaR in graft injuries

Answer 11

Monocytes, neutrophils, and natural killer (NK) cells also express Fc receptors (FcγRs), which can interact with the heavy chain of HLA antibodies bound to donor ECs. FcγR functions augment leukocyte recruitment and mediate phagocytosis and antibody-dependent cellular cytotoxicity.

Question 12

What can prevent hyperacute rejection?

Answer 12

Matching donor and recipient HLA and AB0 group antigens

Use PCR - high or low resolution (2 or 4 letter code). Don’t have to match all of the HLA just at the parts where they differ the most, where peptides bind in the binding groove.

Question 13

How can you test for HLA antigens?

Answer 13

Cross-matching.
Incubation of washed donor cells with recipient serum, antibody binding detected by mouse-anti-human Ab stain of recipient cells or cytotoxicity, suitable detection system
e.g. fluorescent conjugated anti-human antibody and luminex system

Question 14

Minor HLA antigens

Answer 14

Polymorphic self proteins that differ in amino acid sequence between individuals give rise to minor H antigen differences between donor and recipient

Donor T cells can respond to these in association with either donor or host H2 type

Question 15

Mechanism behind hyperacute rejection

Answer 15

Preformed antibodies

Question 16

How do TCRs recognise antigens

Answer 16

The TCR recognizes peptide antigen in the ‘context’ of a special presenting molecule, the MHC complex. MHC molecules are found on most cells, however, there are different types. The most important ones are class I and class II MHC. 
Whereas class-I MHC is found on all nucleated cells, class II MHC is only found on a subset.

Question 17

MHC in graft rejection

Answer 17

Reactivity against non-self MHC is high (an estimated 10% of T-cells can recognise non-self MHC) mostly non-self MHC class II

Question 18

What is the mechanism behind acute rejection?

Answer 18

T cells

Question 19

What levels can T cell activation be blocked at?

Answer 19

Level of receptor/ligand interaction
Signal transduction
Gene expression
Cell cycle control

Question 20

Drug therapy in immunosuppression

Answer 20

T-cell inhibition: Cyclosporin A, Tacrolimus
(Calcineurinine inhibitor, inhibition of cytokine synthesis: IL-2, IFNg …)

Anti-proliferative: Azathioprine, MMF (inhibits clonal expansions)

Question 21

Chronic graft rejection complexity

Answer 21

Chronic rejection is a complex process and probably depends to a large extent on the damage done to the graft between removal from the donor and being reperfused in the recipient. Ischemic time, in particular warm ischemic time seems to be a major problem. But minor histocompatibility antigens may also contribute, and other factors, like infection or atherosclerosis. So, it is fair to say that the process is multifactorial and there is no specific therapy to stop it.

Question 22

Corticosteroids

Answer 22

Corticosteroids block NFkB activation
And achive inhibition/reduction of
 Ischaemia/reperfusion injury
 activation of APC
 inhibition of cytokine synthesis (acute inflammation)

Question 23

Immunosuppression can be reduced after a few months why?

Answer 23

‘Passenger leucocytes’ are present in the early phase, sostrong immunosuppression is required.
Donor cells provide non-self MHC

Then after a few months:
Recipient leucocytes (present all of the time). Weaker
suppression required when passenger leukocytes are gone.

Question 24

Conventional view about self and non-self in transplantation

Answer 24

The immune system differentiates between
‘self‘ and ‘non-self‘

But, is non-self enough to trigger an immune response? Why is an embryo not rejected? Or is it?

Question 25

Modern view about self and non-self in transplantation

Answer 25

The immune system discriminates between ‘dangerous‘ and ‘not dangerous‘
(while self and non-self are not important).

There are good arguments on both sides.

Question 26

What activates APCs?

Answer 26

Danger signals

A range of ligand/receptor interactions can be danger signals…

tissue injury
Hypoxia …

Cytokines
TNF, IL-1 …

Microbial products
LPS, LTA, CpG DNA …

Via TLRs and other PRRs, cytokine R

Surgery provides danger signals:
trauma, inflammation, ischemia/reperfusion, etc.
Warm ischemic time is a significant problem