Immunology: Chapter 17: Transplantation Immunology

Front 1

Define Autograft?

Back 1

Autologous Transplantation. One's own tissue grafted from one site to another. This is typical for burn victims. There is no rejection phenomenon.

Front 2

Define isograft?

Back 2

Syngeneic transplantation. Tissue transferred between genetically identical individuals (monozygotic twins, isogenic strains of animals, or clones)

Front 3

Define Allograft?

Back 3

Allogeneic transplantation. Tissue transferred between genetically different members of the same species.

Front 4

Define Xenograft?

Back 4

Xenogeneic transplantation. Tissue transferred between different species.

Front 5

List two Key Determinants of engraftment versus rejection?

Back 5

1. Genetic differences between the donor (graft) and recipient (host)
-Major Histocompatibility Complex
-Minor Histocompatibility Loci (40+)
-1000s proteins between xenografts

2. Immune recognition of those differences.
- Antibody-mediated (humoral response)
- T and B-lymphocytes (cell-mediated)

Front 6

Briefly describe autograft acceptance.

Back 6

1. Grafted epidermis

2. Days 3-7: Revascularization

3. Days 7-10: Healing

4. Days 12-14: Resolution

Front 7

Briefly describe first-set rejection.

Back 7

1. Grafted epidermis

2. Days 3-7: Revascularization

3. Days 7-10: Cellular infiltration

4. Days 10-14: Thrombosis and necrosis

Front 8

Briefly describe second-set rejection?

Back 8

1. Grafted epidermis

2. Cellular infiltration

3. Thrombosis and necrosis

(never revascularizes)

Front 9

In adoptive tranfer studies ? mice accept transplants.

Back 9

Irradiated mice accept transplants.

Front 10

? cells transfer immunity.

Back 10

T-cells transfer immunity.

Front 11

"nude" mice are aka what?

Back 11

Athymic mice

Front 12

If there is no ?, there are no T-cells.

Back 12

No thymus, no T-cells.

Front 13

Nude mice studies show that allograft rejection involves ? (?) and ? (?) T-cells.

Back 13

Allograft rejection involves CD4+ (helper) and CD8+ (cytotoxic) T cells.

Front 14

In nude mice studies if you eliminate ? cells there is no change in the rate (15d).

Back 14

If you eliminate CD8+ cells.

Front 15

In nude mice studies if you eliminate ? cells there is a delayed rejection (30d).

Back 15

If you eliminate CD4+ cells.

Front 16

In nude mice studies if you eliminate ? = significantly delayed rejection (60d).

Back 16

If you eliminate both (CD4+ and CD8+) cells.

Front 17

In allograft rejection what do dendritic cells do?

Back 17

Dendritic cells aid rejection process by presenting antigen with Class I MHC (professional antigen presenting cells).

Front 18

In nude mice studies of allograft rejection what does an inhibition of dendritic cell function cause?

Back 18

It will promote tolerance and prolong graft acceptance.

Front 19

If you transfer spleenic T-cells from a mouse displaying first set skin graft rejection into another mouse given a skin graft what happens?

Back 19

The first mouses first-set rejection takes about 14 days and the second-set rejection would only take about 6 days because of rejection specificity and memory. In the second mouse the response would be much quicker because they would have the injected memory cells (response time would be only 6 days)

Front 20

In MHC what determines histocompatibility?

Back 20

40+ genetic loci determine histocompatibility.

Front 21

MHC loci are closely linked and usually inherited as what?

Back 21

Usually inherited as a unit called a haplotype.

Front 22

MHC called H-2 in mice and ? in humans.

Back 22

HLA in humans.

Front 23

Inbred strains ? at MHC.

Back 23

Homozygous at MHC.

Front 24

MHC is highly ? at each loci (?).

Back 24

MHC is highly polymorphic at each loci (heterozygosity).

Front 25

What does heterozygosity explain?

Back 25

It explains the 25% chance of MHC identity between siblings. (mendelian genetics)

Front 26

Parent-child grafts share ? but are most ? ? at the other.

Back 26

Parent-child grafts share 1 haplotype but are most always different at the other.

Front 27

Blood donor and recipient are screened for ? blood-group compatibility

Back 27

ABO blood group compatibility.

Front 28

ABO blood group compatibility is expressed on ?, ?, and ?.

Back 28

ABO blood group compatibility is expressed on RBCs, epithelial cells and endothelial cells.

Front 29

Recipient antibodies against donor ABO antigens induces what?

Back 29

Recipient antibodies against donor ABO antigens induce complement-mediated lysis.

Front 30

HLA typing is by ? testing.

Back 30

HLA typing is microtoxicity testing.

Front 31

In HLA typing by microtoxicity testing involves MHC class 1 and 2 alleles that do what?

Back 31

In HLA typing by microtoxicity testing MHC class 1 and 2 alleles either bind specific antibodies or not, and complement-mediated lysis allows dye to enter dead cells.

Front 32

A mixed lymphocyte rxn test what?

Back 32

It test class 2 mhc compatibility.

Front 33

Survival of kidney transplants is dependent on ?, matching at ? is less important.

Back 33

Survival of kidney transplants is dependent on Class 2 antigens, matching at Class 1 is less important.

Front 34

HLA matching is most important to ? and ?. What about heart and liver transplants?

Back 34

HLA matching is most important to kidney and bone marrow. Heart and liver transplants survive with greater mismatching.

Front 35

There are ? stages of cell-mediated rejection.

Back 35

There are 2 stages of cell-mediated rejection.

1. Sensitization stage

2. Effector stage

Front 36

What are the three components of the sensitization stage of cell-mediated rejection?

Back 36

1. Presentation
2. Recognition/Activation
3. Proliferation

Front 37

What are the three components of the effector stage of cell-mediated rejection?

Back 37

1. DTH - cytokines (delayed type hypersensitivity)

2. Cytotox - CD8+

3. ADCC (production of Ab leading to cytolytic events)(least common)

Front 38

The clinical aspects of graft rejection are distinguished by what?

Back 38

Time course, tissue grafted, and immune response engaged.

Front 39

What are the 3 basic types of rejection?

Back 39

1. Hyperacute

2. Acute

3. Chronic

Front 40

What are the characteristics of a hyperacute rejection?

Back 40

1. Rapid: minutes to hours

2. Requires pre-existing host antibodies (ex, ABO transfusion)

3. Activates complement and platelet coagulation

Front 41

What are the aspects of acute rejection?

Back 41

1. Slower than hyperacute: days to weeks

2. Main barrier to allograft transplantation

3. Host T-cells directly recognize donor MHC as foreign

4. Massive infusion of macrophages and T-cells

Front 42

What are some aspects of chronic rejection?

Back 42

1. Slowest: months to years later

2. Mediated by humoral and cellular responses

3. Least well understood; difficult to manage

4. Requires long-term immunotherapy

Front 43

Hyperacute rejection requires ? to be present.

Back 43

Require a high concentration of antibodies.

Front 44

List 4 general steps of hyperacute rejection. (in kidney)

Back 44

1. Preexisting host abs are carried to kidney by graft.

2. Abs bind to ags of renal capillaries and activate complement

3. Complement split products attract neutrophils, which release lytic enzymes

4. Neutrophil lytic enzymes destroy endothelial cells; platelets adhere to injured tissue, causing vascular blockage.

Front 45

What are some of the multiple disadvantages of immunosuppressive therapy?

Back 45

1. Nonspecific (general immunosuppresion); antiproliferative drugs impact non-immune tissues

2. Increased risks of infection and lymphoid cancer

3. Often lead to serious complications

Front 46

What are some of the serious complications that result from immunosuppresive therapy?

Back 46

Poor digestive function, hematopoietic stem cell insufficiency, hypertension, and metabolic bond disease.

Front 47

A study by Schwartz and Damchek ('59) illustrated what?

Back 47

6-mercaptopurine (6MP)(azathioprine) suppresses immune response in animals.

(mitotic inhibitor)

Front 48

What do combinations of 6MP and corticosteroids do?

Back 48

Prolong graft survival.

(mitotic inh)

Front 49

Azathiorine blocks what?

Back 49

Azathioprine blocks synthesis of nucleoside precursor (inosinic acid) and therefore T-cell numbers.

(mitotic inhibitor)

Front 50

What is cyclophosphamide?

Back 50

A mitotic inhibitor. An alkylating agent that binds DNA. (so interferes with DNA synthesis)

Front 51

What is Mycophenolate Mofetil?

Back 51

A mitotic inhibitor that blocks purine synthesis (interferes with DNA synthesis)

Front 52

What is Methotrexate?

Back 52

A mitotic inhibitor that is a folic acid antagonist which blocks purine synthesis (thus interfering with DNA)

Front 53

Why are corticosteroids used in transplantation immunology?

Back 53

1. Potent anti-inflammatory drugs

2. General utility

Front 54

Name 2 potent anti-inflammatory drugs.

Back 54

1. Prednisone

2. Dexamethasone

Front 55

List 4 diseases that corticosteroids may be used for?

Back 55

1. Asthma

2. Allergy

3. Osteoarthritis

4. Auto-immune induced inflammation

Front 56

Antifungals are ? ?.

Back 56

Specific immunosuppressants.

Front 57

Why are antifungals a mainstay of allograft transplantation pt care?

Back 57

1. Block Th-cell proliferation, cytokine expression, and activation of other immune effectors.

2. Used most for kidney, liver, heart, heart-lung, and bone-marrow transplants.

Front 58

List 3 antifungal agents that act as specific immunosuppressants.

Back 58

1. Cyclosporin A (CsA)

2. FK506 (tacrolimus)

3. Rapamycin (sirolimus)

Front 59

Cyclosporin A (CsA) may cause this serious side effect.

Back 59

Acute nephrotoxicity.

Front 60

FK506 (tacrolimus) is 10-100x more potent than what?

Back 60

Cyclosporin A (CsA), so you can deliver less because it is very specific.

Front 61

Rapamycin is as potent as what?

Back 61

Rapamycin (sirolimus) is as potent as FK506 (tacrolimus) so it can also be used in lower doses with fewer side effects.

Front 62

CsA and FK506 use a ? ?. Explain.

Back 62

CsA and FK506 use a common mechanism. They bind immunophilin to inhibit phosphatase-activation of calcineurin, nuclear translocation of NFATc, formation of DNA binding complex and gene transcription of T-cell genes including IL-2 ad IL-2R-alpha.

Front 63

Rapamycin works ? than CsA and FK506. Explain.

Back 63

Rapamycin works differently than CsA and FK506. It binds immunophilin but does not block activation of calcineurin. It blocks the proliferation and differentiation of activated Th cells in the G1 phase of the cell cycle.

Front 64

Lymphocytes are exquisitely sensitive to ?.

Back 64

Lymphocytes are exquisitely sensitive to x-irradiation.

Front 65

Transplanted bone marrow stem cells repopulates lymphoid tissue and marrow. Transplanted lymphocytes are more tolerant to what.

Back 65

More tolerant to foreign antigens in graft.

Front 66

Animal studies indicate that that this therapy is a possibility?

Back 66

Specific immunosuppressive therapy but (this is the ultimate goal) but there is no clinical success yet.

Front 67

Specific immunosuppressive therapy has Ag-specific targets (monoclonal antibodies) against ?, ?, and ?.

Back 67

Against CD3, CD40L, and CD25.

Front 68

Other than CD3, CD40L, and CD25 list some other potential targets of specific immunosuppressive therapy?

Back 68

1. Co-stimulatory molecules

2. Cell surface adhesion molecules

3. Cytokines

4. JAK/STAT signal transduction pathway

Front 69

How is T-cell anergy induced?

Back 69

Block co-stimulatory signal with soluble CTLA-4. So you are blocking B7 to CD28 by CTLA-4.

Front 70

Allograft tolerance is graft acceptance without ?.

Back 70

without immunosuppresion.

Front 71

What tissues lack alloantigens?

Back 71

1. Cartilage

2. Heart valves

(so from pigs this tissue is not rejected)

Front 72

List 6 sites involved with allograft tolerance that are sequestered from immune surveillance.

Back 72

(the immune system cannot seem to 'attack' these so transplantation in these areas works well)

1. Anterior chamber of eye

2. Cornea

3. Uterus

4. Testes

5. Brain

6. Cheek pouch (Syrian hamster)

Front 73

2 components for the induction of tolerance?

Back 73

1. Create a privileged site

2. Early exposure to alloantigens

Front 74

The transplantation option is influenced by what?

Back 74

1. Pt health

2. Availability of tissue or organs

3. Technical difficulty

4. Ancillary factors

Front 75

The standard of care is known as ?.

Back 75

AUTOGRAFT

Front 76

If you do not have a living donor, your chance of getting a transplant is only ?.

Back 76

50%