WK 6- TRANSPLANTATION IMMUNOLOGY

Question 1

What does auto… mean

Answer 1

The donor is the recipient

Question 2

What does allo… mean

Answer 2

The donor and the recipient are genetically different but belong to the same species

Question 3

What does xeno… mean

Answer 3

The donor is another species

Question 4

What is the graft versus leukemia effect

Answer 4

Allogeneic preparations of haematopoietic stem cells contain donor T cells that recognize minor histocompatibility antigens or tumor-specific antigens expressed by the host leukemic cells→ leading the donor cells killing the leukemic cell (therapeutic)

Question 5

What is graft versus host disease

Answer 5

condition that occurs after an allogenic transplant and is due to donor bone marrow or stem cells (such as T cells) viewing the recipients antigens as foreign and attacking the recipient’s cells

• causes severe inflammatory disease characterised by rashes, diarrhea, and pneumonitis
• Symptoms generally begin developing after 7-10 post-surgery.

Question 6

What are the 3 requirements for a transplant

Answer 6

1. ABO compatibility
2. Tissue typing (HLA typing)→ involves 6 antigen matching→ 2x HLA- A, -B, -DR. If 6 HLA’s are different then MHC won’t match
3. Cross matching → presence of antibodies to HLA. HLA antibody levels can change following events such as blood transfusions, previous transplants, pregnancies/miscarriages and even surgeries

Question 7

Why is immunosuppression important in preparing a patient who is going to receive a transplant

Answer 7

stops T cell function and prevents T cells from attacking the graft→ stops rejection)

Question 8

What are examples of immunosuppressive agents

Answer 8

irradiation, cyclosporine, antibodies, corticosteroids, cytotoxic agents

Question 9

What is the method by which cross matching is conducted

Answer 9

1. combining recipient serum (potentially containing donor-specific anti-HLA antibodies) with donor lymphocytes (B and T cells) and complements
2. if there are donor specific anti-HLA antibodies present in serum they will bind to the lymphocytes and activate complement
3. Binding of complement causes cell lysis and indicates a positive cross match result

Question 10

When would a syngeneic transplant occur

Answer 10

Syngeneic= graft between individuals with identical MHC

-occurs in identical twins

Question 11

What is a first set rejection

Answer 11

Grafts differing at the MHC are rejected around 10–13 days after grafting

Question 12

What is a second set rejection

Answer 12

due to memory cells being present from the original presentation- occurs faster with an MHC specific response

Question 13

What is a hyperacute rejection

Answer 13

Occurs from min-hours

-occurs due to recipient already have Ab to donor antigens, which are often blood group antigens or HLA Ag

Question 14

What happens to the graft following a hyperacute rejection

Answer 14

When the donor organ is grafted into recipients, Ab bind to vascular endothelium in the graft→ initiating the complement cascade (causing inflammatory cell recruitment and MAC development on endothelial cells (causing endothelial damage and exposing VWF))→ damage initiates the clotting cascade→ causes blood vessels in the graft to become obstructed by clots and leak, causing hemorrhage of blood into the graft→ causes death of graft

Question 15

What is an accelerated rejection

Answer 15

AKA 2nd set rejection

• Reactivation of sensitised T cells followed by cell and humoral immune responses
• takes 2-5 days

Question 16

What is an acute rejection

Answer 16

Most common- occurs from days-weeks after transplant
-Activation of naive T cells
= 1st set skin graft rejection
-naive T cells are primed against donor antigens, proliferate and then attack donated graft

Question 17

What is a chronic rejection

Answer 17

Takes months-years

-Multifactoral: Ab, immune complexes T cell activation, immunosuppressants, original disease process

Question 18

What is allorecognition

Answer 18

Ability of an individual organism to distinguish its own tissues from those of another. It manifests itself in the recognition of antigens expressed on the surface of cells of non-self origin.

Question 19

How do dendritic cells contribute to the alloimmune response (attack graft)

Answer 19

1. DCs migrating from the graft display peptides from the graft on their surface (via MHC)→
2. after travelling to lymph node, these APCs encounter naive T cells specific for graft antigens, and the DC stimulate these T cells to divide→ 3. the resulting activated effector T cells migrate via the thoracic duct to blood and move to grafted tissue, which they rapidly destroy.

Question 20

What are the two ways of presenting alloantigens to recipient cells

Answer 20

Direct and Indirect

Question 21

What is the direct method of presenting alloantigens

Answer 21

involves presentation of donor peptide directly to T cells by donor APC/MHC

Question 22

What is the indirect method of presenting alloantigens

Answer 22

involves presentation of peptides from the graft organ by self APC (dendritic cells) directly to T cells

Question 23

What does the effector stage encompass

Answer 23

Response of the immune system towards the presentation of foreign antigens

Question 24

What is the function of T cells during the effector stage

Answer 24

-CD8 promotes cytotoxicity (apoptosis) by acting on MHC1
-CD4 promotes release of cytotoxic and regulatory cytokines through acting on MHC2
→ cytokines promote macrophage infiltration, endothelial cell activation, more T cells→ amplification of response

Question 25

What is the function of other APC/sensor cells during the effector stage

Answer 25

Macrophages, Natural killer cells and B cells→act to cause cytotoxicity by perforin, granzymes, ADCC, cytokines and complements
-NK cells distinguish allogenic cells from self > potent cytolytic effector mechanisms

Question 26

What is the function of other APC/sensor cells during the effector stage

Answer 26

Macrophages, Natural killer cells and B cells→act to cause cytotoxicity by perforin, granzymes, ADCC, cytokines and complements
-NK cells distinguish allogenic cells from self > potent cytolytic effector mechanisms

Question 27

If the graft is MHC-identical, why can rejection still occur?

Answer 27

There can be other alloantigens bound to graft MHC molecules→ Even though MHC genotype might be matched exactly, there might be polymorphism–> these are minor histocompatibility antigens-> trigger T cell responses

Question 28

What is an example of a minor histocompatibility antigen- eg. what would be present in a set of fraternal twins boy/girls that would cause the identical MHC to be rejected

Answer 28

As females do not have genes that have a loci on the Y chromosome the female will view it as foreign→Female anti-male minor H responses occur

Question 29

What are some of the absolute requirements for kidney transplants (4)

Answer 29

• ABO identity or compatibility
• Negative T cell cross match
• No previous Ab against donor HLA Ag
• No shared incompatibilities with previous donor(s)

Question 30

How many MHC molecules/HLA have to be matched in order for the transplant to go ahead

Answer 30

6 matches- HLA-A, HLA-B, HLA-DR

Question 31

When are bone marrow transplants done

Answer 31

be used to correct immunodeficiencies caused by defects in lymphocyte maturation-> leukemia

Question 32

What are the 3 requirements for a BMT

Answer 32

1. HLA Matching: Matching of MHC class I & II genes between donor and recipient
2. Cross Matching: Used to determine whether Antibodies are present in the recipient’s serum that may cross-react with the donor cell surface Antigens
3. Mixed lymphocyte culture (MLC): Involves mixing lymphocytes from two individuals→different histocompatibility antigens on the surface of donor lymphocytes will activate the recipient lymphocytes and vice versa

Question 33

What are the 3 steps of the immunosuppresive protocol

Answer 33

1. Immunosuppression of recipient & histocompatibility matching (make T cell non-responsive will mean T cell will not attack the graft)
2. Induction of specific tolerance
3. Pretreatment of allograft prior to transplant (removing certain types of cells/blocking APC coming from graft)

Question 34

What is serological HLA typing

Answer 34

1. leucocytes from potential donors and recipient are distributed into series of wells on microtiter plate→ 2. Ab specific for various class I and class II MHC alleles are added to different wells→ 3. After incubation, complement is added to the wells→ 4. if antibody is bound and complement is added it will cause the cells to leak (from MAC) and take up dyes→
2. cytotoxicity is assessed by the uptake or exclusion of various dyes (e.g., trypan blue or eosin Y) by the cells

Question 35

What is an induction regimen in regard to immunosuppression

Answer 35

Brief use of potent immunosuppressive agents in immediate post-transplant period to reduce the immune response of T cells to the transplanted organ. Individual agents either deplete T cells, or interrupt T cell activation and proliferation