Transplantation And Manipulation Of The Immune Response

Front 1

Graft rejection is an immunological response mediated primarily by...

Back 1

T cells

Front 2

Name 7 tissues commonly transplanted.

Back 2

1. Kidney
2. Liver
3. Heart
4. Pancreas
5. Lung
6. Cornea
7. Bone marrow

Front 3

What is an autograft?

Back 3

Tissue transplanted to self

Front 4

What is a syngeneic graft?

Back 4

Tissue transplanted between genetically identical individuals.

Front 5

What is an allograft?

Back 5

Tissue transplanted between unrelated individuals.

Front 6

What is skin graft rejection the result of?

Back 6

Skin graft rejection is the result of a T cell-mediated anti-graft response.

Front 7

Skin graft to syngeneic recipient...

Back 7

Graft is tolerated

Front 8

Skin graft to allogeneic recipient...

Back 8

graft is rejected rapidly (10-13 days)
1st set rejection

Front 9

Second skin graft from same donor to same recipient...

Back 9

graft shows accelerated rejection
2nd set rejection

Front 10

T cells transfer accelerated rejection from a sensitized donor to a naive recipient...

Back 10

graft shows accelerated rejection
2nd set rejection

Front 11

Naive mice that are given T cells from a sensitized donor behave as if...

Back 11

they had already been grafted

Front 12

What accounts for the accelerated response and rejection to a 2nd skin graft?

Back 12

The accelerated response is MHC specific; skin from a 2nd donor of the same MHC type is rejected equally fast, whereas skin from an MHC different donor is rejected in a 1st set pattern.

Front 13

Skin graft to syngeneic recipient...

Back 13

graft tolerated

Front 14

Skin graft to allogeneic recipient...

Back 14

graft rejected rapidly

Front 15

Skin graft to minor H Ag incompatible recipient...

Back 15

graft rejected slowly

Front 16

What are the two ways the recipient's T cells are sensitized to alloantigens from the donor?

Back 16

Direct and Indirect Recognition

Front 17

MOA of Direct Recognition...

Back 17

Donor APCs migrate to a local lymph node and stimulate alloreactive recipient T cells.

Front 18

MOA of Indirect Recognition...

Back 18

Recipient APCs process and present peptides derived from the graft.

Front 19

The initiation of graft rejection normally involves...

Back 19

migration of the donor APCs from the graft to the local lymph node.

Front 20

The initiation of graft rejection normally involves migration of the donor APCs from the graft to the local lymph node. Describe the process w/ Langerhans' cells.

Back 20

1. Skin graft w/ Langerhans' cells.
2. Langerhans' cells migrate to local lymph node where they activate effector cells.
3. Effector cells migrate to graft via blood.
4. Graft destroyed by effector cells.

Front 21

If the grafted tissue is depleted of APCs by treatment with Abs or by prolonged incubation...

Back 21

rejection occurs only after a much longer time.

Front 22

What is the converse of graft rejection?

Back 22

Graft-versus-host disease (GVHD)

Front 23

Give an example of GVHD.

Back 23

In leukemic patients who have their bone marrow destroyed and then receive a bone marrow transplant, mature T cells in the bone marrow recognize tissue of the recipient as foreign. The inflammatory response begins (rash, diarrhea, and pneumonitis)

Front 24

How is it possible to predict if there are alloreactive T cells in a potential donor?

Back 24

Mixed lymphocyte reaction

Front 25

Describe the mixed lymphocyte reaction.

Back 25

1. Mix MHCa T cells and irradiated MHCb non-T cells as APCs.
2a. Measure proliferation of T cells by incorporation of 3H-thymidine.
3a. T cell proliferation depends largely on differences in MHC class II alleles.
2b. Measure killing of 51Cr-labeled target cells to detect activated cytotoxic T cells.
3b. Generation of cytotoxic T cells depends largely on differences in MHC class I alleles.

Front 26

What causes chronic organ rejection?

Back 26

Chronic organ rejection is caused by inflammatory vascular injury to the graft.

Front 27

Tolerance to allogeneic skin can be established...

Back 27

in bone marrow chimeras.

Front 28

Allogeneic skin tolerance w/ bone marrow chimeras... describe process.

Back 28

1. Neonatal mouse injected with allogeneic bone marrow cells.
2. Both donor and recipient T cells are selected in the recipient thymus. T cells are negatively selected on both donor and recipient APC.
3. Chimeric animals accept a donor-type skin graft but reject an unrelated graft.

Front 29

Immunomodulatory drugs can be divided into three categories...

Back 29

1. Anti-inflammatory
2. Cytotoxic drugs
3. Fungal and bacterial derivatives

Front 30

What are anti-inflammatory drugs?

Back 30

steroids (ex. cortisol, prednisone)

Front 31

MOA of steroids (4 steps)

Back 31

1. Steroid receptors are found in the cytoplasm complexed with a heat-shock protein Hsp90.
2. Steroids cross the cell membrane and bind to the steroid receptor complex, releasing Hsp90
3. The steroid:receptor complex can now cross the nuclear membrane.
4. In the nucleus the steroid receptor binds to specific gene regulatory sequences and activates transcription.

Front 32

What are adverse effects of corticosteroid therapy? (5)

Back 32

1. Bone mineral loss
2. Diabetes
3. Fluid retention
4. Skin thinning
5. Weight gain

Front 33

There are many beneficial effects of corticosteroid therapy. What are the physiological effects of decreased IL-1, IL-3, IL-4, IL-5, TNF-a, GM-CSF, and CXCL8

Back 33

Decreased inflammation caused by cytokines

Front 34

There are many beneficial effects of corticosteroid therapy. What are the physiological effects of decreased NOS?

Back 34

Decreased NO

Front 35

There are many beneficial effects of corticosteroid therapy. What are the physiological effects of decreased phospholipase A2 and COX 2 and increased lipocortin-1?

Back 35

Decreased prostaglandins and leukotrienes

Front 36

There are many beneficial effects of corticosteroid therapy. What are the physiological effects of decreased adhesion molecules?

Back 36

Reduced emigration of leukocytes from vessels

Front 37

There are many beneficial effects of corticosteroid therapy. What are the physiological effects of increased endonucleases?

Back 37

Induction of apoptosis in lymphocytes and eosinophils.

Front 38

What are two examples of cytotoxic drugs?

Back 38

1. Azathioprine
2. Cyclophospamide

Front 39

Azathioprine MOA...

Back 39

Azathioprine converted in vivo to 6-Mercaptopurine-->6-Thioinosinic acid-->inhibits purine synthesis

Front 40

Cyclophosphamide MOA...

Back 40

Cyclophosphamide-->Phosporamide mustard-->DNA alkylating agent

Front 41

What are two examples of fungal and bacterial derivatives?

Back 41

1. Cyclosporin A
2. FK506 (tacrolimus)

Front 42

How do the fungal and bacterial derivatives cyclosporin A and tacrolimus function?

Back 42

They interfere with T cell signaling.

ian says: technically interfering with the proliferation of tcells due to decreased IL-2

Front 43

What is the Normal Signaling pathway that leads to clonal expansion of the activated T cell? (4)

Back 43

1. Signaling via the TCR induces AP-1 activation and increases intracellular [Ca2+].
2. Raised intracellular Ca2+ activates calcineurin, a phosphatase that activates NFATc family members.
3. Activated NFATc family members migrate to the nucleus and bind to AP-1 and other partner proteins to form active transcription factors.
4. Activation of specific genes including IL-2 gene (leading to clonal expansion of the activated T cell).

Front 44

What is the pathway of "Inhibition of T cell activation" by cyclosporin A and tacrolimus? (4)

Back 44

1. The immunosuppressive drugs cyclosporin A (CsA) and tacrolimus act in the cytoplasm.
2. CsA and tacrolimus bind to distinct targets, the intracellular proteins cyclophilin (CyP) and FK-binding protein (FKBP).
3. Both CsA:CyP and the tacrolimus:FKBP complex bind to calcineurin, preventing its activation by calcium and blocking activation of NFATc.
4. No activation of transcription.