L10 - Transplantation

Question 1

What are the 2 important barriers against transplants?

Answer 1

Rejection

tissue availability (shortage)

Question 2

What is the most simple transplant used in clinical practice?

Answer 2

blood transfusion - ABO system

Question 3

What does allele A of the blood do?

Answer 3

modifies H into A

Question 4

What does allele B of the blood do?

Answer 4

modifies H into B

Question 5

What does Allele O of the blood do?

Answer 5

NON-FUNCTIONAL enzyme

Question 6

What do humans produce IgM against blood of?

Answer 6

IgM against blood group carbohydrate YOU LACK!

Question 7

What is an autograft?

Answer 7

graft of tissue from one site to another - SAME INDIVIDUAL

Question 8

What is an allograft?

Answer 8

transplant from unrelated individual of same species

Question 9

What is a Xenograft?

Answer 9

transplant using tissue of different species

Question 10

What is acute rejection?

Answer 10

initial success
NO immunosuppression
fail after 10-14 days

Question 11

What is chronic rejection?

Answer 11

effective immunosuppression
last months/years
degraded

Question 12

What is hyperacute rejection?

Answer 12

Xenographs

rejected within HOURS

Question 13

What molecule is a major barrier to transplantation?

Answer 13

MHC

Question 14

Why do animals given a 2nd allograft reject it quicker than 1st?

Answer 14

primed rejection

memory-type response

Question 15

What is acute rejection mediated by?

Answer 15

MHC and T cells

Question 16

Are Allografts put onto nude mice, lacking T cells, rejected?

Answer 16

NO

Question 17

What are alloantigens?

Answer 17

antigens that differ between members of same species

Question 18

What are the most polymorphic proteins in the human pop?

Answer 18

MHC - diversity between donor and recip

Question 19

What is polymorphism for MHC?

Answer 19

for single gene

e.g. allele from father and mother - codominant

LOOK AT SLIDES IF CONFUSED

Question 20

What is polygeny for MHC?

Answer 20

for (3) different genes

COMBINED WITH 2 ALLELES FROM POLYMORPHISM = 6 DIFF MHC CLASS I

LOOK AT SLIDES

Question 21

What is the other loci that contributes to graft rejection?

Answer 21

Minor Histocompatibility antigens

Y-chromosome encoded, any polymorphic protein

Question 22

How was the other loci than MHC found?

Answer 22

mice with identical MHC but different strains had a longer rejection

Question 23

What are the 2 main pathways for how donor MHC is recognised as an alloantigen?

Answer 23

DIRECT ALLORECOGNITION - APCs, T-cells,

INDIRECT ALLORECOGNITION - T-helper cells activate macrophages

Question 24

What is the 3rd mechanism of allorecognition?

Answer 24

Semi-direct - similar to indirect

transfer of donor MHC to recipient APC

Question 25

What occurs during direct allorecognition?

Answer 25

APC migrate out of graft into lymph nodes engage with T-cells TCR recognises allo-MHC/peptide host effector T-cells attack graft donor DC die

Question 26

What is another way to get rejection of graft?

Answer 26

if you deplete donor DC from the graft

Question 27

What occurs during indirect allorecognition?

Answer 27

Allogenic molecules processed by recipient DCs presented to T cells T-helper cells activate macrophage (presenting graft peptides) inflammation, tissue damage - induce ALLOANTIBODIES

Question 28

What signals to T-cells provide to macrophages?

Answer 28

IFN-y respiratory burst cytokine production

Question 29

How do CD8 cells cause tissue damage?

Answer 29

attack graft directly

Question 30

How do CD4 cells cause tissue damage?

Answer 30

help B-cells make anti-graft antibodies against graft

Question 31

How do antibodies bound to the graft lead to destruction?

Answer 31

via complement via ADCC = antigen presentation

Question 32

What is thymic education?

Answer 32

T-cells learn self from non-self

Question 33

How can Allo-MHC-peptide complex bind efficiently to some TCRs?

Answer 33

similar net contacts between TCR and MHC-peptide activation

Question 34

What are the initial and current focuses for transplantation?

Answer 34

initial - MHC matching, HLA-typing current: immunosuppressive drugs

Question 35

What do immunosuppressive drugs target?

Answer 35

T-cell activation steps deplete grafts of immune cells

Question 36

Downside of immunosuppressive drugs?

Answer 36

ALL transplants will still have some degree of chronic rejection susceptible to infection

Question 37

What is the 'future' of transplantation?

Answer 37

xenotransplantation

Question 38

What are immunological problems with pig xenotransplantation

Answer 38

Hyperacute rejection different carb structures a-Gal epitope added via UDP--Gal : a1,3GT PSEUDOGENE IN HUMANS anti-a-Gal antibodies pig organs rapidly coated = complement-mediated destruction

Question 39

Why do humans produce anti-a-Gal antibodies?

Answer 39

antigen carried by gut bacteria

Question 40

can pigs be gen mod to minimise hyperacute rejection?

Answer 40

try to express human complement regulators inactivate a1,3GT disrupt endogenous MHC I/II expression add genes for negative regulators of immunity extensive immunosuppressants

Question 41

What is another aspect to consider when using pig organs?

Answer 41

has to function correctly too genome engineering tools - CRISPR-Cas9

Question 42

What is an animal chimera?

Answer 42

single organisms composed of two or more different populations of genetically distinct cells

Question 43

How can a diabetic mouse be treated (animal chimera)?

Answer 43

mouse stem cells into rat embryo mouse pancreas inside rat pancreatic islets transferred to mouse - also includes rat tissue = immunosuppressants required after a while - mouse-derived vessels go through pancreas

Question 44

What are issues with xenotransplantation beyond immunological rejection?

Answer 44

transfer infectious agents from donor ethical considerations

Question 45

What is HSC transplantation?

Answer 45

recipient immune system remove to allow repopulation with donor-derived HSC recipient is allogenic to donor HSC and donor-derived immune system

Question 46

What disease occurs from HSC transplantation?

Answer 46

graft v host disease (GVHD)

Question 47

how can the allo-reaction in HSC transplantation be beneficial?

Answer 47

Graft v leukemia (GVL)

Question 48

What is the most common allograft?

Answer 48

foetus is half mother, half father 50% genes have MHC from father HEMI-ALLOGRAFT REPEATED exposure if have more children

Question 49

How is fetomaternal tolerance ahcieved?

Answer 49

does NOT express MHC II very low MHC I specialised MHC I = HLA-G : INHIBITS NK CELLS factors suppress effector T-cells promote inhibtory Treg uterine tissue - chemokine limit T-cell attraction

Question 50

How can fetomaternal tolerance help transplants?

Answer 50

understand tolerance mechanisms - apply to solid organs