W7- Lecture 37- Transplant Immunology

Question 1

what are the two major barriers to transplants ?

Answer 1

Rejection; the response of the host to the donor organ
Tissue availability (a shortage of organs to transplant)

Question 2

describe blood transfusions
how is compatibility determined ?
gene that influences this

Answer 2

Compatibility is determined by genetic diversity and associated immunological response to non-self.
Blood cell antigens:
ABO system, rhesus and >30 others

The ABO system is determined by a single gene encoding a glycosylation enzyme that modifies cell surface antigen H.

Allele A modifies H into A.
Allele B modifies H into B
Allele O encodes a non-functional enzyme, no modification
Humans produce IgM antibodies against these carbohydrate structures, probably due to cross reaction with bacterial antigens etc

Question 3

why are blood transfusions more simple then something like solid organ or bone marrow transplants ?

Answer 3

Blood transfusions are an “acute treatment”, they are not required to be long-lasting

Question 4

what is an autograft?

+ example

Answer 4

a graft of tissue from one anatomical site to another, in the same individual
The cells/tissues are termed autologous (or syngeneic)
e.g. a skin graft

Question 5

what is a syngeneic donor?

Answer 5

Skin can be grafted between genetically identical individuals

Question 6

describe the difference in rejection from allografts and xenografts

Answer 6

Allografts are initially successful (without immunosuppression), but fail after 10-14 days (acute rejection)
With effective immunosuppression, allografts can last months/years, but degrade overtime (chronic rejection)

Xenografts are rejected within hours (hyperacute rejection)

Question 7

what is an allograft ?

+ example

Answer 7

a transplant from an unrelated individual of the same species (sometimes termed homograft)
The cells/tissue are termed allogeneic
e.g. a kidney transplant

Question 8

what is a Xenograft?

+ example

Answer 8

a transplant using the tissue of a different species
The cells/tissue are termed xenogeneic
e.g. use of animal organs in humans (not yet a reality

Question 9

what are the features of an acute rejection ?

Answer 9

normally happens between 10-14 days
repeated exposure happens quicker aka secondary response like an infection

T cells from allografted mouse accelerate the rejection process
Acute rejection is mediated by the MHC and by T cells

allografts put onto nude mice (which lack T cells) are not rejected

Question 10

what are Antigens that differ between members of the same species are known as ?

Answer 10

alloantigens

Question 11

what are the most polymorphic molecules in the human population that produce the effect of rejection in transplantation

Answer 11

MHC molecules

Question 12

how does perfect matching of the MHC molecules effect transplant success ?

Answer 12

rejection is slower / more effective transplant

Question 13

How is donor MHC recognised as an alloantigen?(Direct allorecognition)

Answer 13

Antigen presenting cells (APC, e.g. dendritic cells) present in the grafted tissue migrate out of the graft and into the recipient lymph nodes, where they engage with recipient T cells.

Greater the MHC mismatch, the faster
and more strongly this occurs
Note that this requires recipient TCR
to recognise allo-MHC/peptide

Question 14

How is donor MHC recognised as an alloantigen?(indirect allorecognition)

Answer 14

Allogeneic cells/molecules are processed directly by the recipient APC and presented to recipient T cells.

This means that T cells cannot attack graft directly (different MHC).

Instead, T helper cells activate macrophage which cause inflammation
and tissue damage and may induce anti-graft antibody responses (alloantibodies

The T cell is activated by the macrophage and, in return the
T cell provides signals (e.g. IFN-gamma) that activate the
macrophage to undergo respiratory burst, cytokine production

These activated macrophage damage the donor tissue

Question 15

How is donor MHC recognised as an alloantigen?(semi-direct allorecognition)

Answer 15

involves transfer of donor MHC to recipient APC; mechanistically very similar to indirect.

CD8 cells from direct recognition attack the graft directly

CD4 cells from direct recognition help B cells to make anti-graft antibodies against graft

Antibodies bound to graft lead to destruction via complement and via ADCC (macrophage and NK cells)
and aid further antigen presentation

CD4 T cells from indirect recognition help macrophage to become activated and damage tissue etc etc.

Question 16

Why are T cells reactive to allo-MHC?

Answer 16

thymic education(T cells that bind very strongly to MHC are eliminated )
However, transplanted tissue presents new molecules to T cells post-thymic education

Question 17

what does t cell reactivity depend on ?

Answer 17

allo-MHC + peptide

not TCR and allo-MHC

Question 18

how have in outcomes of transplantation improved ?

negatives of this treatment

Answer 18

Biggest improvements (~post-90s) have come from immunosuppressive drugs

These target;
key steps in T cell activation
Are used to deplete grafts of immune cells (Alemtuzumab=CAMPATH 1, worlds first humanized antibody)

Immunosuppressive drugs enhance susceptibility to
Infection and to cancer

Question 19

descrieb the supply of – in the uk
no. of transplants (live/dead donors)
patients on waiting list
no. died on waiting list last year

Answer 19

~4500 transplants last year (not including corneas) from
1400 deceased donors and 1000 living donors

~6000 patients on the waiting list for a transplant

~500 patients died in the UK last year whilst waiting for a transplant.

Question 20

describe the work being done to make sure pig/xenotranplantaions take place

Answer 20

Much attention has been paid to different carbohydrate structures on pig versus human cells
An α-Gal epitope is added via the action of UDP-Gal: 3Galβ1-4GlcNAc α1-3-galactosyltransferase (α1,3GT)
The gene encoding α1,3GT is a pseudogene in humans
Humans all produce anti-α-Gal antibodies (antigen is carried by gut bacteria); up to 1 % (w/v) of serum Ig
Some primates also lack the enzyme and make anti-α-Gal antibody allowing pig to primate transplant experiments

Pig organs are rapidly coated in anti-α-Gal antibody
leading to complement-mediated destruction

Question 21

Can pigs be genetically modified to minimise hyperacute rejection?

Answer 21

Engineer transgenic pigs to express human complement regulators; CD55, CD59 etc (inhibit complement).
Inactivate α1,3GT gene in pig germline.
Disrupt endogenous MHC class I and class II expression
Add genes for negative regulators of immunity, clotting, inflammation………
Use extensive immunosuppressive drugs, antibodies etc

Question 22

describe how mice pancreatic cells can be inserted into a rat embryo and used later to treat mouse diabetes

Answer 22

Rats deficient in pancreas development can be complemented by injecting mouse pluripotent stem cells into the rat blastocyst.
Rats are born with a mouse pancreas.

Pancreatic islets from “mouse” pancreas in rat can be transplanted into diabetic mice (but rat tissue is also transferred e.g. rat endothelial cells; immunosuppression is still required)

Question 23

what are the problems beyond immunological rejection with Xenotransplantation

Answer 23

The potential to transfer infectious agents from donor species to recipient

Pigs have been engineered with endogenous retroviral sequences inactivated, preventing reactivation in host

2) Ethical considerations
Use of animals as a source of human organs

Generation of human-animal chimaeras for human organ generation

Question 24

Haematopoietic stem cell (HSC) transplantation

used for ?

rejection called ?
how to treat ?

problems/benifits

Answer 24

In HSC transplants (e.g. bone marrow transplantation), the recipient immune system is removed to allow repopulation with donor-derived HSC.

e.g. in haematological malignancies (leukaemia and lymphoma, genetic disease (e.g congenital immunodeficiency

Here rejection is known as graft versus host disease (GVHD).
Like other types of allo-rejection, GVHD is potentially fatal (managed by immunosuppression)

The allo-reaction can be beneficial in graft versus leukemia (GVL) effects.

Question 25

describe how a Foetus and placenta is a allograft

Answer 25

50% of foetal genes encode proteins foreign to father
(including MHC molecules)
(hemi-allograft”)

Mother carries this allograft for nine months and can bear many
children from same allo-father

Question 26

how is foetal maternal tolerance achieved?

Answer 26

The foetal-maternal interface (the trophoblast) does not express MHC class II, has only very low MHC class I, plus a specialised MHC class I called HLA-G (which inhibits NK cells).
This provides limited opportunity for allo-MHC reactions

Placenta is rich in factors that suppress effector T cells and promote inhibitory regulatory T cells (Treg)

Uterine tissue (maternal) has mechanisms to limit T cell attraction via chemokines

Question 27

why does Diversity at MHC provides selective advantage?

Answer 27

pathogens less likely to evade antigen presentation