Transplantation Immunology

Front 1

HLA and Minor Histocompatibility mismatching

Back 1

MHC II (HLA-DQ,DR, DP) >>> MHCI (HLA-A, B,C)
Causes more rapid and severe rejections

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Cross match test

Back 2

recipient's serum and donor's blood cells -- looking at recipients Ab

Front 3

how do you tissue type?? (3 ways)

Back 3

1. serology via microcytotoxicity test or lymphocyte cross-match) --> all HLA loci
2. DNA - PCR --> all HLA loci
3. Mixed lymphocyte culture/rxn - for DR (DQ, DP) molecules -- takes from blood leukocytes from both donor and recipient

Front 4

Hyperacute rejection

Back 4

Type 3 hypersensitivity
Immune complex - complement + Ab + donor Ag

Donor has different blood group or Recipient has preformed anti-HLA abs from pregnancy, blood transfusion, previous transplant

Front 5

Allorecognition - Direct

Back 5

CD4 or CD8 T cells directly interact w/ donor APC (HLA Ags)

Front 6

Allorecognition - Indirect

Back 6

membrane fragments of dead donor APCs endocytosed and presented to CD4 T cells via MHC II

Front 7

Acute rejection

Back 7

Mediated thru direct pathway of allorecognition
Donor dendritic cells/APC presents themselves to CD4/CD8 in the spleen (or immune tissues)

CD4 --> activate macs --> inflame!
CD8 --> attack transplanted tissue

Front 8

Acute rejection

Back 8

Type IV hypersensitivity
Develops over a few days

Front 9

Chronic rejection

Back 9

Indirect pathway of allorecognition
Involves class switching to IgG via B cell (CD40 (B) - CD40L (T)) and T cell interaction
develops over months - years
--> thickening of vessel walls in graft --> ischemia --> loss of fxn

Front 10

What does outcome of transplantation depend on??

Back 10

Matching and immunosuppression

Front 11

BMT amenable dzs

Back 11

SCID
Fanconi's
Thalassemia major
Sickle-cell

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Preparation phase for BMT

Back 12

1. recipient radiated - kill its immune system via myeloablative therapy
2. infusion of donor stem cells

Front 13

Myeloablative therapy

Back 13

prevents rejection & provides room for new bone marrow

Front 14

Success

Back 14

needs at least one HLA I and one HLA II allotype in common

Front 15

GVHD - mechanism

Back 15

donor T cells - attack recipient tissues --> inflammation

Front 16

Goals of transplantation

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Solid - suppress recipient T cell response to donor
BMT - suppress recipient whole hematopoietic system

Front 17

Acute GVDH

Back 17

rash, diarrhea, pneumonitis, liver damage

Front 18

Chronic GVHD

Back 18

fibrosis and atrophy of 1+ same organs w/o cell death

Front 19

How to develop GVHD???

Back 19

1. donor = immunocompetant
2. recipient = immunocompromised
3. recipient doesn't match w/ donor (has HLA ag that donor doesn't have)

Front 20

Minor histocompatibility antigen

Back 20

reaction due to allogenic difference (bound peptide) between donor and recipient not MHC (I or II)
Ex: Sister and Brother

Front 21

Beneficial effects of GVHD - vs leukemia

Back 21

alloreaction (via T cells in graft) subdues residual activity of recipient's immune system and can eliminate cancer cells

Front 22

Autologous bone marrow transplant

Back 22

Take bone marrow samples from pt --> separate tumor and stem cells --> reinfuse stem cells
Causes more frequent relapse of cancer compared to allogenic transplant

Front 23

Hematopietic stem cell transplantation

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Donor treated w/ GCSF, GM CSF --> mobilizes hematopoietic stem cells to periphery --> leukocytes selectively removed (via leukopheresis) --> used as transplant

Front 24

Stem cells

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CD34 from leukapheresis

Front 25

Corticosteroids

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Prednisone - not good alone, use w/ cytotoxic drug

Front 26

MOA of Corticosteroids

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Steroid enters cell --> binds StR-Hsp90 --> Hsp dissociates and StR-St complex forms --> binds genes

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Corticosteroid therapy responses

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inhibits inflammatory mediators
Inhibits inflammatory cell migration
Promotes apoptosis

Front 28

Effect of:

DECREASE of IL1, IL3, IL4, IL5, TNFa, GM-CSF, CXCL8

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DECREASE inflammation (cytokine)

Front 29

Effect of

DECREASE of NOS, Phospholipase A2, COX2
INCREASE lipocortin1

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DECREASE NO, prostaglandins, leukotrienes

Front 30

Effect of
DECREASE adhesion molecules

Back 30

Reduced emigration of leukocytes from vessels

Front 31

Induction of endonucleases

Back 31

Induces apoptosis in lymphocytes and eosinophils

Front 32

Cytotoxic Drugs:

Back 32

Azathiaprine, Cyclophosphamide, Methotrexate

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Azathiaprine

Back 33

USE: POST-TRANSPLANT PERIOD
MOA: inhibits DNA rep (dec. adenine and guanine)

Front 34

Cyclophosphamide

Back 34

USE: BOTH PRE- and POST- PERIOD or alternate for methotrexate
MOA: alkylate and x-links DNA molecules

SE: hemorrhagic cystitis

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Methotrexate

Back 35

USE: DOC inh GVHD
MOA: inh dihydrofolate reductase essential for thymidine synthesis

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T cell activation INHIBITORS

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Cyclosporine
Tacrolimus
Rapamycin

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Cyclosporine

Back 37

MOA: inh IL2 production --> shuts down activation and diff of T cells

Front 38

Tacrolimus

Back 38

STRONGER THAN CYCLOSPORINE
MOA: binds both immunophillin and FKBP --> suppress T cell activation

Front 39

Rapamycin

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MOA: prevents signal transduction from IL2 receptors

Front 40

Effects of Cyclosporine and Tacrolimus on T cell

Back 40

Reduced exp of IL2, IL3, IL4, GMCSF, TNFa
Reduced cell division due to IL2
Reduced Ca-dep exocytosis of cytotoxic granules
Inh of ag-driven apoptosis

Front 41

Effects of Cyclosporine and Tacrolimus on B cell

Back 41

Inh cell division because T cell cytokines are absent
Inh ag-driven cell division
Induces apoptosis following B-cell activation

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Effects of Cyclosporine and Tacrolimus on Granulocytes

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Reduced Ca-dep exocytosis of granules

Front 43

Ab for T cells

Back 43

USE: GOOD FOR SOLID ORGAN TRANSPLANTS
Antithymocyte globulin (ATG)
Antilymphocyte globulin (ALG)