L12 - K Okkenhaug - transplantation

Question 1

2 situations where allogenic cells come into contact are…

Answer 1

Iatrogenic (effects of medical treatment), such as blood transfusion, or

Natural, such as pregnancy in placental mammals.

Question 2

D: Transplantation

Answer 2

introduction of biological material - organs, tissue, cells or fluids - into an organism.

Question 3

The main problem with transplanting tissue is that most cells express _____ surface antigens encoded by the ___

Answer 3

The main problem with transplanting tissue is that most cells express polymorphic surface antigens encoded by the MHC

Question 4

is there such thing as a universal donor?

Answer 4

no

(except in blood transfusiosn)

Question 5

four possible relationships between transplanted donor material and the recipient,

Answer 5

Question 6

which scenario of transplantation is the most common clinically?

Answer 6

Question 7

Allogeneic, the most common type of transplants, display immunological memory.

what is meant by this?

Answer 7

When a recipient that has previously rejected a skin graft is regrafted with skin from the same donor the graft is rejected more rapidly, in a second-set reaction.

Question 8

describe the role T cells play in tissue rejection

Answer 8

T cell recognition may be through

1. direct recognition of the donor MHC or
2. indirect recognition, of an antigen presented by self MHC molecules.

Question 9

3 types of rejection?

Answer 9

1) Hyperacute rejection
2) Acute rejection
3) Chronic rejection

Question 10

describe hyperacute rejection

Answer 10

Very fast

Hyper acute rejection occurs if there are pre-existing antibodies

eg: rejection of ABO mis-matched red cells (Blood transfusion)➔type II hypersensitivity! Anti-A and anti-B antibodies can also bind other tissues.

Question 11

T or F:

Hyperacute rejection also takes place in Xenotransplants

Answer 11

T - Natural antibodies recognise differentially glycosylated proteins.

Question 12

Antibodies can also form against MHC molecules:

give 3 circumstances

Answer 12

1. From previous organ transplants (e.g. children who have multiple transplants)
2. From pregnancy – at childbirth foetal cells enter maternal circulation and stimulate adaptive response to paternal HLA
3. From blood transfusion matched for ABO but not HLA (transplant must include nucleated cells, not just erythrocytes which lack MHC)

Question 13

why are pig grafts bad news complement wise?

Answer 13

complement does not function well across species. Normally complement is disabled on self tissues by the action of regulatory proteins such as decay accelerating factor (DAF). This does not work on pig tissue and the graft is attacked by the human complement.

Question 14

does rejection produce a memory response?

Answer 14

yep - cant use the same person again after 1st transplat - rejection second time will be faster

Question 15

describe acute graft rejection

Answer 15

caused by T cell recognition of the transplanted tissue

involves the response of CD8 T cells to HLA class I differences and CD4 T cells to HLA class II differences.

T cells us direct and indirect recognition modes

Question 16

Acute rejection can be thought of as a type of Type __ hypersensitivity reaction

Answer 16

Acute rejection can be thought of as a type of Type IV hypersensitivity reaction

Question 17

This is the main immunological barrier to allotransplantation. It is caused by T cell recognition of the transplanted tissue. Note it is not an issue in blood transfusion – why?

Answer 17

Note it is not an issue in blood transfusion as red blood cells do not carry MHC antigens.

Question 18

describe the direct recognition of allogenic MHC

Answer 18

allogenic MHc molecules itself is recognised as bad - even if it presents self peptides.

Both CD8+ T cells and CD4+ T cells mediate graft rejection.

Question 19

why do MHC products cause such reproducible and rapid graft rejection

Answer 19

• individuals inadvertently have a high frequency of T cell receptors reactive with allo-MHC products, irrespective of the loaded peptide
• receptors may not need to bind with a particularly high affinity to result in activation of the T cell
• abundant on cell surface , therefore readily activated

Question 20

describe indirect recognition

Answer 20

uptake of allogeneic proteins by the
recipient’s own antigen presenting cells
(APC’s) and their presentation to T cells by
self MHC molecules.

Question 21

male vs female regarding indirect rejction?

Answer 21

Female recipients of a male organs may

generate immune responses against peptides

encoded by genes on the Y chromosome.

Question 22

can MHc matching be bad sometimes>

Answer 22

for indirect recognition rejection yep

Counter-intuitively, MHC sharing between donor and recipient in indirect recognition may increase reactivity as donor, as well as recipient, dendritic cells can prime recipient T cells for minor peptides

Question 23

describe chronic rejection

Answer 23

several years

poorly understood

may relate to immune response against blood vessels. The blood supply to the organ is compromised, resulting in ischemia and loss of function.

Question 24

privileged sites?

Answer 24

Transplants at certain sites may be occur with little or no immune rejection. The most important of these is the cornea.

The absence of lymphatic drainage is probably the critical common factor but some sites also lack vascularisation.

Question 25

describe the big problem with healthy HLA matched allogenic transplants

Answer 25

• The recipient’s immune system is destroyed by irradiation and drugs.
• Problems arise as donor T cells respond to the recipient’s HLA molecules in a graft versus host (GvH) reaction.
• This is essentially a systemic type IV hypersensitivity reaction.
• T cells from the donor access recipient lymphoid tissue, interacting with host dendritic cells divide and proliferate.
• These T cells attack epithelial tissues inflamed by irradiation and chemotherapy.
• External signs include rash and raised or discoloured areas of the skin and eyes but internal organs may also be damaged.

Question 26

advantages of Haploidentical transplants

(haematopoietic transplants)

Answer 26

A close relative sharing one HLA haplotype (parent or sibling) is selected as the donor.

T cells are depleted to prevent a strong reaction.

In spite of the incompatibility of HLA on one haplotype, this strategy has some tangible advantages:

there is little GvH yet at the same time potent graft versus leukaemia (GvL) takes place, probably due to alloreactive NK cells.

Another advantage is speed and convenience as a local willing donor, generally a close relative, can be used.

Haloidentical transplants are particularly effective for AML (acute myelogenous leukaemia) but not ALL (acute lymphoblastic leukaemia).

Question 27

Haloidentical transplants are particularly effective for …..

but no….

Answer 27

Haloidentical transplants are particularly effective for AML (acute myelogenous leukaemia) but not ALL (acute lymphoblastic leukaemia).

Question 28

Answer 28

Question 29

Is HLA matching important in kidney transplants?

Answer 29

data collected over decades shows that there is a precise relationship between the number of mis-matches and transplant survival.

Question 30

do you know how HLA inheritance works?

Answer 30

Question 31

whats GvL in relation to haematopoietic transplants

Answer 31

Related to GvHD is graft versus leukaemia (GvL). This takes place in infused donor CD8 T cells and NK cells kill remaining host leukaemic cells.

Question 32

what does a positive cross match show?

Answer 32

A positive cross-match indicates that the recipient has antibodies against HLA proteins carried by the donor. The most common method is to screen the recipient serum against panels of microbeads, each coupled with a specific HLA protein

Question 33

how is immunosuppression used in transplants?

Answer 33

essential for clinical transplantation of organs such as kidneys (excluding privileged sites or autologous transplants). Some drugs may be given before the transplant, to condition the immune response in the patient.

Question 34

what drugs are given for transplant to condition the immune system of the recipient

Answer 34

before:

Steroids such as prednisone- given for systemic immunosuppressive effects

Humanised antibody to CD52 on the surface of leukocytes results in long-lasting lymphopenia due to activation of complement.

after:

Other drugs may be given after the transplant. These include:
Cytotoxic drugs such as azathioprine lead to death of rapidly dividing cells such as T cells Anti-CD25 (Il-2 receptor) antibodies. These are also highly T cell-specific.

Immunosuppressive drugs that target cell signalling pathways in lymphocytes e.g. cyclosporine, FK506, rapamycin. Many of these drugs were isolated from soil organisms. They block signal transduction for activation of T cells. The immunosuppressive drug needs to be maintained indefinitely.

Question 35

The most commonly used drugs to prevent transplant rejection are ….

Answer 35

The most commonly used drugs to prevent transplant rejection are cyclosporine and rapamycin.

Question 36

how do rapamycin and cyclosporin work?

Answer 36

Both of these interfere with signals generated by the TCR.

Rapamycin also blocks IL-2 signalling.

Question 37

Pictre of drugs used in transplants

Answer 37

Question 38

Haematopoietic transplants can both be rejected and conversely, cause ___ _ ___ disease.

Answer 38

§Haematopoietic transplants can both be rejected and conversely, cause graft-versus host disease.

Question 39

fat

Answer 39

mamba