T1 L15:Cell and Organ Transplantation

Question 1

what are the types of transplantations

Answer 1

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

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

Isograft - to a genetically identical individual (homozygos twins)
(iso/syngeneic)

Allograft - to a genetically disparate member of the same species
(allogeneic)

Xenograft - to a different species (pig o monkey to human)
(xenogeneic)

Question 2

Renal transplant

Answer 2

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

warm ischemic phase: time from interruption of circulation to the donor organ to the time when organ is flushed with hypothermic preservation solution.
cold ischemic phase: while the organ is preserved in a hypothermic state prior to transplantation into the recipient.

Question 3

what happens of the graft is rejected

Answer 3

type:
1-hyperacute rejection -minutes-days

2- acute rejection -days-weeks

3- chronic rejection -months-years

Question 4

what does serum contain

Answer 4

Serum contains antibodies against the ABO antigens not present.

Question 5

what about HLA antigens

Answer 5

Red blood cells do not express HLA antigens. All nucleated cells do.

Question 6

study slide 9

Answer 6

ABO antibodies

Question 7

how do HLA injuries cause graft injuries

Answer 7

Causing endothelial cell (EC) activation, 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 through binding of C1q, resulting in production of the anaphylatoxins C3a and C5a, which have the potential to directly augment leukocyte recruitment and T cell alloresponses.

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 8

Matching donor and recipient for HLA and AB0 blood group antigens generally prevents hyperacute rejection.

Answer 8

PCR :
High or low resolution, e.g. 2 or 4-letter code (HLA-A2, or HLA-A0201) or even higher resolution.

Not all parts of the HLA-molecule are important. The most important parts are those where they differ from one another. This is where peptides are bound in the binding groove.

Question 9

what is cross match

slide 14

Answer 9

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

Question 10

what is the mechanism in hyperacute rejection

Answer 10

-preformed antibodies :
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.  

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

Question 11

T cell activation: acute reaction -what can be done to deactivate this

Answer 11

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

Azathioprine, MMF
antiproliferative (inhibits clonal expansions)

Question 12

what is used for chronic rejection

Answer 12

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

Corticosteroids (e.g. Methyprednisolone)
anti-inflammatory (Inhibition of NFkB, cytokine synthesis and action)

Question 13

how is inflammation reduced in the long term

Answer 13

from :Passenger leucocytes’
These are present in the early phase, strong immunosuppression is required.
Donor cells provide non-self MHC!

to:Recipient leucocytes (present all of the time). Weaker
suppression required when passenger leukocytes are gone.

Question 14

theory of self and non-self

Answer 14

Conventional view:
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?

Modern view :
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 15

what is danger signals

Answer 15

tissue injury-hypoxia

cytokines-TNF, IL-1

microbial products:
LPS,LTA,CpFG,DNA

via TLRs & other PRRs cytokine R

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