IMMUNOSUPPRESSION I:

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IMMUNOSUPPRESSION I

• Principles and Mechanisms of Current Agents

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Events Following T Cell Activation
0 0.5 1 2 24 hours. 3-4
days 7 days...
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The Phases of Immunosuppression
Chronic Allograft Dysfunction
Maintenance Immunosuppression
Graft Failure
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(No Transcript)
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Lymphocyte Depleting Antibody Therapies
CD52
CD3
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Daclizumab (Zenapax) and Basiliximab
(Simulect) Block the IL-2 Receptor
Antigen
APC
B7
CD4
CD28
IL-2R
1
2
Calcineurin
IL-2
IL - 2 gene
T Cell
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Overview of Maintenance Immunosuppression
Costimulatory molecules i.e CD28 and CD40L
IL-2
IL-2R
b g
TCR complex ab TCR, CD3, CD4, etc
a CD25 (inducible)
SirolimusFKBP
Kinase activity
Apoptosis
Cyclosporinecyclophilin
Calmodulin
Calcineurin
TOR
De novo purine synthesis
Steroids
Phosphatase activity
G1
S
TacrolimusFKBP
NFAT AP-1 NF-KB
G2
IL-2 gene
M
Nucleus
Azathioprine
Mycophenolate Mofetil
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Corticosteroids-Molecular Mechanisms
IkB binds to NF-kB and prevents it from getting
into the nucleus and activating cytokine
transcription
Steroid
CELL
NF-kB
IkB
Steroid receptor
AP-1
X
IkB promoter
IL-2 promoter
NUCLEUS
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Cyclosporine and Tacrolimus Calcineurin
Inhibitors
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Azathioprine and Mycophenolate Mofetil
Costimulatory molecules i.e CD28 and CD40L
IL-2
IL-2R
b g
TCR complex ab TCR, CD3, CD4, etc
a CD25 (inducible)
Kinase activity
Apoptosis
Calmodulin
Calcineurin
TOR
De novo purine synthesis
Phosphatase activity
G1
S
NFAT AP-1 NF-KB
G2
IL-2 gene
M
Nucleus
Azathioprine
MycophenolateMofetil
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TOR Inhibitors (TORI) Sirolimus/Everolimus
Costimulatory molecules i.e CD28 and CD40L
IL-2
IL-2R
b g
TCR complex ab TCR, CD3, CD4, etc
a CD25 (inducible)
Kinase activity
TORIFKBP
Apoptosis
Calmodulin
Calcineurin
TOR
De novo purine synthesis
Phosphatase activity
G1
S
NFAT AP-1 NF-KB
G2
IL-2 gene
M
Nucleus
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US DeNovo Maintenance Regimensfor Kidney
Transplant Recipients
UNOS 11/02
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Outcomes of Renal Allografts

• Radiation
• Prednisone
• 6-MP

• Cyclosporine Emulsion

• CY-A

• Tacrolimus

• MMF

• OKT3

• Dicluzimab
• Basiliximab

• AZA

• Thymoglobulin
• Sirolimus

• ATGAM

60 65 70 75 80 85 90 95 00
Year
Adapted from Stewart F, Organ Transplantation,
1999