Immune Dysfunction - Transplant Immuno/autoimmune Disease

Front 1

2 things that must be matched for a successful graft transplant:

Back 1

-ABO
-HLA as much as possible

Front 2

Which is more important?

Back 2

ABO

Front 3

3 ways to get around rejection:

Back 3

-Immunosuppressive drugs
-Radiation
-Recipient Tcell depletion

Front 4

Downside to preventing rejection:

Back 4

Clinically significant immunosuppression - susceptible to disease!

Front 5

2 types of Allograft Recognition:

Back 5

-Direct
-Indirect

Front 6

What is Direct allograft recognition?

Back 6

Donor MHC presented in DONOR APC to host Tcell

Front 7

How can a host Tcell recognize donor peptide in donor APC, if host Tcells are RESTRICTED to self?

Back 7

Donor MHC molecules RESEMBLE self

Front 8

What is the Indirect pathway of allorecognition?

Back 8

Donor MHC/antigen presented in HOST APC to HOST TCell

Front 9

3 basic patterns of graft rejection:

Back 9

-Hyperacute
-Acute
-Chronic

Front 10

Cause of hyperacute rejection:

Back 10

Pre-formed antibody

Front 11

Example of hyperacute rejection:

Back 11

ABO Mismatch

Front 12

How soon does hyperacute rejection manifest?

Back 12

In minutes

Front 13

Main manifestation of Hyperacute rejection:

Back 13

Vascular thrombosis

Front 14

What type of hypersensitivity reaction is illustrated by Hyperacute rejection?

Back 14

Type III - Arthus reaction (local, acute, fibrinoid necrosis and vascular thrombosis)

Front 15

What is Acute rejection mediated by?

Back 15

Tcells

Front 16

When does acute rejection occur?

Back 16

Within days to weeks after transplant

Front 17

What are the predominant histologic findings in Acute rejection?

Back 17

-Interstitial infiltration of lymphs and monos
-Vasculitis if Ab mechanisms are prominent

Front 18

What is Chronic rejection primarily caused by?

Back 18

Antibody mediated vascular damage

Front 19

When does Chronic rejection of a tissue graft become apparent?

Back 19

Over 4-6 months and up to years later!

Front 20

What is the main manifestation of chronic rejection?

Back 20

Vascular fibrosis

Front 21

So the main finding in each:
-Hyperacute rejection
-Acute rejection
-Chronic rejection

Back 21

Hyper = Vascular THROMBOSIS
Acute = Lymphocyte infiltrn
Chronic = Vascular FIBROSIS

Front 22

What is the main goal in current immunosuppressive therapy?

Back 22

Prevention of ACUTE rejections (in days-weeks after the transplant)

Front 23

Why don't we care as much about Hyperacute?

Back 23

Because we crossmatch to prevent it

Front 24

What is becoming more common now that we are better and have more immunosuppressive drugs?

Back 24

Chronic rejection

Front 25

What is a non-antibody mediated mechanism of Chronic rejection?

Back 25

Chronic DTH where Tcells secrete cytokines that stimulate Fibroblasts and Vascular sm musc proliferation in vessels

Front 26

What effect does the fibrosis and smooth muscle proliferatn in vessels have in chronic rejection?

Back 26

Causes vessel occlusion leading to loss of blood supply!

Front 27

So what is the end result of what the kidney looks like in chronic rejection?

Back 27

Small and scarred

Front 28

In what type of tissue transplantation is Acute/chronic rejection a concern?

Back 28

Solid tissue organ transplant

Front 29

In what type of tissue transplantation is GVHD rejection a concern?

Back 29

Hematopoietic stem cell transplant!

Front 30

What is HSCT done for?

Back 30

Hematologic cancers

Front 31

Why does GVHD develop only in bone marrow transplants rather than STO transplants?

Back 31

Because it is in cell transplants that immunocompetent cells are transplanted

Front 32

What is a scenario other than BMT in which GVHD can develop?

Back 32

Whole blood transfusions in patients with SCID

Front 33

What is the reaction that occurs in GVHD?

Back 33

-Donor Tcells react to
-Tissue in the Host

Front 34

What are the 3 principal target organs of GVHD? Why?

Back 34

-Skin
-Liver
-Gut
This is where the most rapid cell turnover is occuring

Front 35

What are the 4 main clinical symptoms of GVHD?

Back 35

-Fever
-Rash
-Diarrhea
-Hepatosplenomegaly

Front 36

What are the 3 criteria for diagnosing GVHD?

Back 36

-Apoptotic keratinocytes
-Bile duct damage
-Apoptotic bodies in GI crypts

Front 37

What is Autoimmunity caused by?

Back 37

Failure of the immune system to tolerate self antigens

Front 38

2 types of tolerance:

Back 38

-Central tolerance
-Peripheral tolerance

Front 39

How does Central tolerance develop?

Back 39

By the deletion of self-reactive lymphocytes in the central organs - BM/thymus

Front 40

How does Peripheral tolerance develop?

Back 40

By the deletion of self-reactive lymphocytes that sneak past central tolerance mechanisms to the periphery.

Front 41

What are 2 mechanisms of getting rid of self-reactive cells during the process of developing tolerance?

Back 41

-Apoptosis
-Anergy

Front 42

What will generally cause a self-reactive lymphocyte to go into anergy?

Back 42

Reaction with a self tissue cell/APC that lacks B7 the costimulatory signal

Front 43

What will generally make a cell undergo apoptosis?

Back 43

Repeated stimulation leading to increased expression of Fas/FasL

Front 44

What is a common genetic factor involved in Autoimmune diseases?

Back 44

Specific HLA haplotypes

Front 45

What is one autoimmune disease that we know almost certainly is related to a certain HLA Haplotype?

Back 45

Ankylosing spondylitis and B27

Front 46

What tissues in the body are often affected by autoimmune disease?

Back 46

Connective Tissues

Front 47

So what 3 factors are involved in Autoimmune diseases?

Back 47

-Genetic
-Hormonal
-Environmental

Front 48

What are some environmental factors that seem to play a role in Autoimmune diseases?

Back 48

-Infectious
-Drugs
-UV lite (SLE)
-Nutrition (RA)

Front 49

How do infections and other environmental factors combine with genetic factors to cause autoimmune disease?

Back 49

The genetic predisposition allows for self-reactive cells, but they aren't ACTIVE until the immune system is revved up by an infection.

Front 50

How exactly might infection promote the activation of self-reactive lymphocytes?

Back 50

By inducing the expression of COSTIMULATORS - B7/CD28

Front 51

What HLA haplotypes are associated with
-Hashimoto's thyroiditis
-Type 2 Diabetes

Back 51

Hashimotos:: DR5/B5
DM2: DR3/DR4

Front 52

What cells have B7 and what cells have CD28?

Back 52

B7 is on APCs/macrophages
CD28 is on Tcells

Front 53

What is another mechanism by which infections can induce autoimmunity, other than upregulating B7/CD28?

Back 53

By mimicry - the infectious particles look like self tissues, so normal Ab's that form react to self instead.

Front 54

What are 3 immunologically priveleged sites to which self-reactive Ab will form if the barrier is broken?

Back 54

-Thyroglobulin
-Lens proteins (crystallins)
-Spermatozoa in the testes

Front 55

What is the presumptive evidence of autoimmune disease?

Back 55

The presence of specific autoantibodies

Front 56

What cluster of loosely related conditions often features Fibrinoid changes and Antinuclear Antibodies?

Back 56

Connective tissue diseases (Collagen diseases)