Transplant

Question 1

Hyperacute Reaction- what mediates the reaction, physical response? treatment?

Answer 1

Type II hypersensitivity

• Preformed Ab to ABO antigens- from bacteria, everyone has Ag against the other types
• Pre-existing antigens to MHC1/2 molecules-= pregnancy, blood transfusion, previous transplant

Symptoms: complement activation, endothelial damage/inflammation==> thrombosis, ischemia, necrosis.

GRAFT FAILURE.

Question 2

A-antigen

B-antigen

Answer 2

A=GalNAc

B=Gal

Question 3

Other blood antigens

Answer 3

Rh C/D/E, Kell, duffy, MN

RhD is most common

Question 4

Serum vs RBC when doing coombs test

Direct vs indirect coomb

Answer 4

Serum will have the antibodies, RBC will have the antigens that serum reacts to.

• Direct= fetal blood, add coomb’s reagent- look for Rh
• Indirect= mother plasma, add blood, add coombs,

Question 5

Acute Rejection

Answer 5

CD4/CD8 T-cell Mediates (Type IV-like)

• within weeks
• HLA differences
• Antibodies form, CTL cells kill endothelium

Sx: Parenchymal damage, interstitial inflammtion, vasculitis by effector T-cells

Treatment: Immunosuppressive drugs, anti t-cell antibodies

Question 6

Accelerated Acute reaction

Answer 6

Within days- memory T-cells mediation (pvs graft/exposure)

Question 7

Direct Allorecognition

Answer 7

= Acute rejection

Host CD8/CD4 cells attack donor APC cells. Reaction wanes over time as the donor cells die.

Question 8

Indirect Allorecognition

Answer 8

Donor APC digested by host APC

Host APC presents foreign MHC1/2 with other subcellular on host MHCII==> T-cell activation (CD4)==> B-cell acivation

Chronic rejection

Question 9

Tests for rejection?

Answer 9

1. Cross-match- agluttination= no match
2. MLR= mixed lymphocyte reaction test= tests EXTENT of mismatch
   
   • Donor APC- irradiated to prevent proliferation
   • Host t-cells
   • Measures PROLIFERTATION (CD4+ response) and t-cell cytotoxicity (CD8+ response)

Question 10

Chronic Rejection

Answer 10

= indirect allogenic reaction; months to years after transplant

• smooth muscle proliferation, vessel occlusion==> ischemia, fibrosis
• Th1 cells= macrophage recruitment, Th2 cells= antibodies==> chronic inflammation

Question 11

Minor histocompatibility Antigen

Answer 11

bound peptide is different, not MHC molecule. Usually presented on MHC1==> T-cell activation

Ex: H-Y antigen (in males), would cause reaction by female donar to male host

Question 12

Conditions for GVHD

Answer 12

1. Graft must have mature T-cells
2. MHC mismatch
3. recipient immunity is gone (radiation, can’t respond to rogue t-cells from graft)

Question 13

Two things that must happen for successful bone marro transplant

Answer 13

1. Host t-cells need to recognize donor APC cells (donor MHC)
2. Donor t-cells must undergo positive selection to thymic epithelial cells with host MHC

Question 14

GVL

Answer 14

Graft attacks recipients leukemia/tumor cells

Question 15

Sx of GVHD

Treatment?

Answer 15

• Graft attacks fast dividing cells first:
  
  • Skin=rash on palms and soles
  • GI= diarrhea, cramps,
  • Liver= hyperbillirubinemia
• treatment: methotrexate, cyclosporin A

Question 16

Donor NK cells can?

Answer 16

Donor NK cells are inhibited from killing donor cells (inhibition from both ligands)

If host only has 1 matching ligand, then cells without the inhibitory ligand can be killed by NK cells (~50%)

Allows killing of host tumor cells BASED on MHC differences

Question 17

Pig transplant

Answer 17

Carbs can cause reaction, but MHC is too different for our cells

Question 18

Drugs to increases success of transplant?

Answer 18

Suppression of Acute rejection mediated by t-cells

1. Corticosteroids
2. cytotoxic drugs kill proliferating lymphocytes
3. micrbial immunosuppressive products
4. immunosuppresive antibodies

Drugs can make patients susceptible to infections.

Question 19

Cyclosporine and FK506

Answer 19

1. Block T-cell cytokine (IL-2) production
2. Blocks calcium activating calcineurin
   
   • CyclosporineA: Cyp- bind and inactivate calcineurin
   • Tacrolimus:FKBP- bind and inactivate calcineurin
3. No NFAT transcription factor= No IL2 transcription

NO T, B, granulocyte activation

Question 20

Rapamycin

Answer 20

Blocks lymphocyte proliferation by blocking downstream IL-2 signaling

• mTOR is blocked
• no activatin of cylcin/CDK
• No t-cell proliferation

Question 21

Corticosteroids

Answer 21

reduce inflammation by inhibiting macrophage cytokine secretion

1. HSP90 receptor holds steroid receptor in cytosol
2. Steroid binds, HSP90 lets go of receptor
3. Steroid activates IkB-alpha gene= inhibition of NFkB activation

Side effects= fluid retention, weight gain, diabetes.

Question 22

AntiCD3 MAB

Answer 22

Bind CD3 and promote phagocytosis= less T-cells

Question 23

Anti CD52

Answer 23

depletes T-cell by activating Complement (C3b)

Question 24

Annexin and Lipocortins

Answer 24

suppress phosphlipase A2

Question 25

Methotrexate

Cyclophosphamide

Azathioprine

Answer 25

Inhibition of DNA replication= death of dividing cells

Methotrexate: Inhibits thymidine synthesis= inhibitin of DNA replication–kills dividing cells

Cyclophosphamide- crosslink DNA

Azathioprine- inhibit DNA replication in ALL dviding cells of body.

Question 26

Antibodies to human t-cells

Answer 26

• Anti-CD3= made in other animals,
• can induce formation of antibodies to drug.