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76 Cards in this Set

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Define Autograft?
Autologous Transplantation. One's own tissue grafted from one site to another. This is typical for burn victims. There is no rejection phenomenon.
Define isograft?
Syngeneic transplantation. Tissue transferred between genetically identical individuals (monozygotic twins, isogenic strains of animals, or clones)
Define Allograft?
Allogeneic transplantation. Tissue transferred between genetically different members of the same species.
Define Xenograft?
Xenogeneic transplantation. Tissue transferred between different species.
List two Key Determinants of engraftment versus rejection?
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)
Briefly describe autograft acceptance.
1. Grafted epidermis

2. Days 3-7: Revascularization

3. Days 7-10: Healing

4. Days 12-14: Resolution
Briefly describe first-set rejection.
1. Grafted epidermis

2. Days 3-7: Revascularization

3. Days 7-10: Cellular infiltration

4. Days 10-14: Thrombosis and necrosis
Briefly describe second-set rejection?
1. Grafted epidermis

2. Cellular infiltration

3. Thrombosis and necrosis

(never revascularizes)
In adoptive tranfer studies ? mice accept transplants.
Irradiated mice accept transplants.
? cells transfer immunity.
T-cells transfer immunity.
"nude" mice are aka what?
Athymic mice
If there is no ?, there are no T-cells.
No thymus, no T-cells.
Nude mice studies show that allograft rejection involves ? (?) and ? (?) T-cells.
Allograft rejection involves CD4+ (helper) and CD8+ (cytotoxic) T cells.
In nude mice studies if you eliminate ? cells there is no change in the rate (15d).
If you eliminate CD8+ cells.
In nude mice studies if you eliminate ? cells there is a delayed rejection (30d).
If you eliminate CD4+ cells.
In nude mice studies if you eliminate ? = significantly delayed rejection (60d).
If you eliminate both (CD4+ and CD8+) cells.
In allograft rejection what do dendritic cells do?
Dendritic cells aid rejection process by presenting antigen with Class I MHC (professional antigen presenting cells).
In nude mice studies of allograft rejection what does an inhibition of dendritic cell function cause?
It will promote tolerance and prolong graft acceptance.
If you transfer spleenic T-cells from a mouse displaying first set skin graft rejection into another mouse given a skin graft what happens?
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)
In MHC what determines histocompatibility?
40+ genetic loci determine histocompatibility.
MHC loci are closely linked and usually inherited as what?
Usually inherited as a unit called a haplotype.
MHC called H-2 in mice and ? in humans.
HLA in humans.
Inbred strains ? at MHC.
Homozygous at MHC.
MHC is highly ? at each loci (?).
MHC is highly polymorphic at each loci (heterozygosity).
What does heterozygosity explain?
It explains the 25% chance of MHC identity between siblings. (mendelian genetics)
Parent-child grafts share ? but are most ? ? at the other.
Parent-child grafts share 1 haplotype but are most always different at the other.
Blood donor and recipient are screened for ? blood-group compatibility
ABO blood group compatibility.
ABO blood group compatibility is expressed on ?, ?, and ?.
ABO blood group compatibility is expressed on RBCs, epithelial cells and endothelial cells.
Recipient antibodies against donor ABO antigens induces what?
Recipient antibodies against donor ABO antigens induce complement-mediated lysis.
HLA typing is by ? testing.
HLA typing is microtoxicity testing.
In HLA typing by microtoxicity testing involves MHC class 1 and 2 alleles that do what?
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.
A mixed lymphocyte rxn test what?
It test class 2 mhc compatibility.
Survival of kidney transplants is dependent on ?, matching at ? is less important.
Survival of kidney transplants is dependent on Class 2 antigens, matching at Class 1 is less important.
HLA matching is most important to ? and ?. What about heart and liver transplants?
HLA matching is most important to kidney and bone marrow. Heart and liver transplants survive with greater mismatching.
There are ? stages of cell-mediated rejection.
There are 2 stages of cell-mediated rejection.

1. Sensitization stage

2. Effector stage
What are the three components of the sensitization stage of cell-mediated rejection?
1. Presentation
2. Recognition/Activation
3. Proliferation
What are the three components of the effector stage of cell-mediated rejection?
1. DTH - cytokines (delayed type hypersensitivity)

2. Cytotox - CD8+

3. ADCC (production of Ab leading to cytolytic events)(least common)
The clinical aspects of graft rejection are distinguished by what?
Time course, tissue grafted, and immune response engaged.
What are the 3 basic types of rejection?
1. Hyperacute

2. Acute

3. Chronic
What are the characteristics of a hyperacute rejection?
1. Rapid: minutes to hours

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

3. Activates complement and platelet coagulation
What are the aspects of acute rejection?
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
What are some aspects of chronic rejection?
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
Hyperacute rejection requires ? to be present.
Require a high concentration of antibodies.
List 4 general steps of hyperacute rejection. (in kidney)
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.
What are some of the multiple disadvantages of immunosuppressive therapy?
1. Nonspecific (general immunosuppresion); antiproliferative drugs impact non-immune tissues

2. Increased risks of infection and lymphoid cancer

3. Often lead to serious complications
What are some of the serious complications that result from immunosuppresive therapy?
Poor digestive function, hematopoietic stem cell insufficiency, hypertension, and metabolic bond disease.
A study by Schwartz and Damchek ('59) illustrated what?
6-mercaptopurine (6MP)(azathioprine) suppresses immune response in animals.

(mitotic inhibitor)
What do combinations of 6MP and corticosteroids do?
Prolong graft survival.

(mitotic inh)
Azathiorine blocks what?
Azathioprine blocks synthesis of nucleoside precursor (inosinic acid) and therefore T-cell numbers.

(mitotic inhibitor)
What is cyclophosphamide?
A mitotic inhibitor. An alkylating agent that binds DNA. (so interferes with DNA synthesis)
What is Mycophenolate Mofetil?
A mitotic inhibitor that blocks purine synthesis (interferes with DNA synthesis)
What is Methotrexate?
A mitotic inhibitor that is a folic acid antagonist which blocks purine synthesis (thus interfering with DNA)
Why are corticosteroids used in transplantation immunology?
1. Potent anti-inflammatory drugs

2. General utility
Name 2 potent anti-inflammatory drugs.
1. Prednisone

2. Dexamethasone
List 4 diseases that corticosteroids may be used for?
1. Asthma

2. Allergy

3. Osteoarthritis

4. Auto-immune induced inflammation
Antifungals are ? ?.
Specific immunosuppressants.
Why are antifungals a mainstay of allograft transplantation pt care?
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.
List 3 antifungal agents that act as specific immunosuppressants.
1. Cyclosporin A (CsA)

2. FK506 (tacrolimus)

3. Rapamycin (sirolimus)
Cyclosporin A (CsA) may cause this serious side effect.
Acute nephrotoxicity.
FK506 (tacrolimus) is 10-100x more potent than what?
Cyclosporin A (CsA), so you can deliver less because it is very specific.
Rapamycin is as potent as what?
Rapamycin (sirolimus) is as potent as FK506 (tacrolimus) so it can also be used in lower doses with fewer side effects.
CsA and FK506 use a ? ?. Explain.
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.
Rapamycin works ? than CsA and FK506. Explain.
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.
Lymphocytes are exquisitely sensitive to ?.
Lymphocytes are exquisitely sensitive to x-irradiation.
Transplanted bone marrow stem cells repopulates lymphoid tissue and marrow. Transplanted lymphocytes are more tolerant to what.
More tolerant to foreign antigens in graft.
Animal studies indicate that that this therapy is a possibility?
Specific immunosuppressive therapy but (this is the ultimate goal) but there is no clinical success yet.
Specific immunosuppressive therapy has Ag-specific targets (monoclonal antibodies) against ?, ?, and ?.
Against CD3, CD40L, and CD25.
Other than CD3, CD40L, and CD25 list some other potential targets of specific immunosuppressive therapy?
1. Co-stimulatory molecules

2. Cell surface adhesion molecules

3. Cytokines

4. JAK/STAT signal transduction pathway
How is T-cell anergy induced?
Block co-stimulatory signal with soluble CTLA-4. So you are blocking B7 to CD28 by CTLA-4.
Allograft tolerance is graft acceptance without ?.
without immunosuppresion.
What tissues lack alloantigens?
1. Cartilage

2. Heart valves

(so from pigs this tissue is not rejected)
List 6 sites involved with allograft tolerance that are sequestered from immune surveillance.
(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)
2 components for the induction of tolerance?
1. Create a privileged site

2. Early exposure to alloantigens
The transplantation option is influenced by what?
1. Pt health

2. Availability of tissue or organs

3. Technical difficulty

4. Ancillary factors
The standard of care is known as ?.
AUTOGRAFT
If you do not have a living donor, your chance of getting a transplant is only ?.
50%