Immunology - Graft Rejection

Front 1

Graft rejection is mediated by..

Back 1

T-cells

Front 2

The basis of the "graft rejection" concept is

Back 2

cross-reactive MHC molecules that are recognized by the host TCR's

Front 3

"Autograft"

Back 3

a graft from, and to, yourself

Front 4

"Syngeneic graft"

Back 4

a graft between genetically identical individuals, eg. twins

Front 5

"Allograft"

Back 5

a graft between unrelated people, same species

Front 6

"Xenograft"

Back 6

a graft between members of different species

Front 7

"non-self" MHC is recognized by what percent of TCR's

Back 7

1-10%

Front 8

Why aren't blood 'transplants' (transfusions) mediated by T-cells?

Back 8

RBC's and platelets do not express MHC!

Front 9

What does complete MHC matching between donor and recipient do for the survival of the graft?

Back 9

it improves, but does not guarantee, survival

Front 10

Minor Histocompatibility Antigens

Back 10

when a different "version" (allele) of a self-protein is expressed by the cells of the donor tissue, it can be digested by those cells, presented on their surface, and recognized as "foreign" by recipient T-cells

Front 11

explain: H-Y antigen

Back 11

male-specific proteins coded in the Y-chromosome can be expressed in females that receive a male tissue graft, and seen as foreign.

An example of a response caused by "minor histocompatibility antigen"

Front 12

The FIRST target of chronic graft rejection is usually:

and leads to:

Back 12

first target: graft blood vessels

leads to: hemorrhage, clotting, necrosis

Front 13

what are "passenger leukocytes"

Back 13

APC's of donor origin that are transplanted along with the graft

Front 14

What 2 ways are donor alloantigens presented to recipient T-cells?

Back 14

1. Direct allorecognition
2. Indirect allorecognition

Front 15

what is "Direct allorecognition"

Back 15

*donor APC's bearing foreign MHC leave the graft tissue and migrate to lymph node.
*recipient T-cells recognize donor MHC I or II as foreign and migrate to graft site to initiate rejection

Front 16

what is "Indirect allorecognition"

Back 16

recipient's APC's process and present donor peptides, activating recipient T-cells

Front 17

describe "Hyperacute rejection"

Back 17

*complete rejection and graft death within minutes
*when recipient happens to have pre-existing Abs against donor Ags

Front 18

what color is donor tissue that has undergone "hyperacute rejection"

Back 18

purple, from the presence of deoxygenated blood (after vascular hemorrhage)

Front 19

the most common examples of "hyperacute rejection" stem from:

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*blood group mismatching
*anti-MHC Abs that the host has from:
--previous grafts
--multiple pregnancies

Front 20

Xenografts are complicated by: (2 things)

Back 20

1. anti-carbohydrate Abs
2. foreign (donor) complement regulatory proteins on the surface of graft tissue

Front 21

How can we avoid the complications presented by xenografts? eg. pig --> human

Back 21

genetically engineer pigs with human-like carbohydrates and human complement regulatory proteins

Front 22

What are "acellular grafts"

Back 22

grafts that are depopulated of donor cells, then seeded with host stem cells to generate new host tissue

Front 23

explain "Graft Versus Host Disease"

Back 23

GVHD occurs when Tc cells in the graft (usually bone marrow-BM) react to all cells of the host

Front 24

how can GVHD be minimized?

Back 24

by treating the BM with Ab to destroy mature donor lymphocytes
by transferring only BM stem cells

Front 25

all BM transplants require...

Back 25

elimination or suppression of host immunity

Front 26

BM stem cells used for transplantation are harvested from the donor's ____ by _____

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*blood
*treating the donor with cytokines that induce excess stem cell production

Front 27

3 common symptoms of GVHD are:

Back 27

1. rash
2. diarrhea
3. liver disease

Front 28

Why don't maternal lymphocytes attack the fetus?

Back 28

fetus is protected by placenta

Front 29

Why don't maternal Tc-cells attack the placenta?

Back 29

the placental "trophoblasts" don't express classical MHC

Front 30

Why don't maternal NK-cells attack the fetus?

Back 30

placental cells express HLA-G

(HLA-G binds the inhibitory NK-receptors and prevents killing)

Front 31

how does the environment of the placenta help protect the fetus from maternal t-cells?

Back 31

the placenta creates a nutrient-poor environment that starves t-cells

Front 32

What are "congenic strains"

Back 32

strains (of mice) differing from parent by ONLY 1 locus
or
differing by ALL BUT 1 locus

Front 33

"congenic strains" allow us to:

Back 33

observe the effect of a single gene

Front 34

what is the procedure for creating transgenic mice

Back 34

1. female injected with FSH and gonadotropin to induce ovulation, then mated
2. fertilized eggs removed
3. DNA containing gene of interest is injected into 'male pronucleus' of egg
4. injected eggs transferred into uterus of female
5. some offspring will have the 'transgene'

Front 35

what is the purpose of the "Mixed Lymphocyte Reaction (MLR)"

Back 35

to predict the likelihood of MHC compatibility PRIOR to grafting

Front 36

for the "mixed lymphocyte reaction", explain the:
-procedure
-results

Back 36

procedure: mix host T-cells with donor APC's

results:
- if host T-cells proliferate, it means there is a difference between donor and recipient MHC-I
- if host T-cells differentiate into Tc-cells, it means there is a difference between donor and recipient MHC-II

Front 37

What is the "chromium release assay" used for?

Back 37

it tests for pre-existing CTL immunity

Front 38

What is the "chromium release assay" most useful for clinically?

Back 38

for predicting if a recipient who has already rejected one graft, will accept or reject another one.

Front 39

What is the basic scheme for the "chromium release assay"

Back 39

1. label donor tissue cells with sodium-chromate
2. add recipient CTL's to the labeled tissue cells
3. if CTL's react with and kill the donor tissue cells, they will release the radioactive chromium

Front 40

Which organ had the most transplants in 2009? second most?

Back 40

cornea, kidney

Front 41

how many kidney transplants in 2009?
what is the 5-year graft survival percentage?

Back 41

17,750 transplants
81% survival

Front 42

how many lung transplants in 2009?
what is the 5-year graft survival percentage?

Back 42

1,700 transplants
51% survival

Front 43

what 2 steroids are commonly used for "immunosuppression"

Back 43

1. cortisol
2. prednisone

Front 44

what is the mechanism of steroid action?

Back 44

1. steroid diffuses into cell
2. steroid binds to steroid receptor in cytoplasm
3. steroid binding causes Hsp90 (heat-shock protein) to dissociate, exposing DNA binding site of the steroid receptor
4. steroid:receptor crosses into nucleus and activates/inhibits transcription of immune system genes

Front 45

what are the side effects of corticosteroids?

Back 45

*fluid retention
*weight gain
*bone thinning
*skin thinning
*retarded wound healing
*adrenal atrophy (leading to dependency)

Front 46

what is "cyclosporin A"

Back 46

a "fungal ring protein" that is an immunosuppressive

Front 47

what is "tacrolimus"

Back 47

a "bacterial product" that is an immunosuppressive

Front 48

How do "cyclosporin A" and "tacrolimus" suppress the immune system?

Back 48

they bind to intracellular proteins called "immunophilins", interfering with intracellular signaling

Front 49

what is "anti-lymphocyte globulin"

Back 49

horse IgG against human lymphocytes

Front 50

"anti-lymphocyte globulin" is an example of what type of immunosuppressive agent?

Back 50

immunosuppressive Abs

Front 51

Give a few examples of engineered immunosuppressive Abs

Back 51

Anti-CD3
Anti-CD40L
Anti-CD4
Anti-B7

Front 52

is anti-CD4 Ab used as a short-term or long-term prevention of graft rejection?

Back 52

short-term