Liver Transplant Immunosuppression Transplant...Liver Transplant Immunosuppression Michael Daily, MD...
Transcript of Liver Transplant Immunosuppression Transplant...Liver Transplant Immunosuppression Michael Daily, MD...
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Liver Transplant Immunosuppression Michael Daily, MD, MS, FACS Surgical Director, Kidney and Pancreas Transplantation University of Kentucky Medical Center
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• No financial disclosures
• I will be discussing the off-label use of almost everything.
Disclosures
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• Describe the principles of immunomodulation. • Discuss current immunosuppression medicines, their classes
and indications. • Explore the variety of possible targets for new therapies. • Keep you awake until time for drinks!
Objectives
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Principles of Immunosuppression
• Prevent Rejection
• Minimize Infection
• Minimize Toxicity
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Phases of Immunosuppression
• Induction • Intense therapy at the time of transplant
• Maintenance • Chronic, slowly tapering immunosuppression
• Salvage • Rescue after rejection
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Immunosuppression Pathways
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Abandon All Hope ye Who Enter Here
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Immune Response in 1 slide
• Signal 1 • T-cell receptor binding
• Signal 2 • Co-Stimulation
• Signal 3 • Trigger for clonal expansion • Important growth pathway
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Immune Pathways
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Classes
• Calcineurin Inhibitors • mTOR Inhibitors • Anti-metabolites • Steroids • Antibodies
• Binding • Depleting
• Novel/directed action
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Calcineurin Inhibitors
• Calcineurin is a second messenger • T-cell Receptor complex to NFAT
• Pathway leads to Transcription • Products that promote T-cell activation
• IL-2
• Extracted from yeast
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Calcineurin Inhibitors
• Cyclosporine • First trial in 1978 • exceeding efficacy, opened a new era . . . • dose related nephrotoxicity, neurotoxicity, diabetogenicity, • increased incidence of B-cell lymphoma, and cosmetic changes
• Tacrolimus • Clinical trials in 1990 • More efficacious that CSA • Similar side effect profile.
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Calcineurin Inhibitors – con’s
• Nephrotoxic CSA=TAC • Diabetogenic CSA<TAC • Hypertension CSA>TAC • Lipids CSA>TAC • Cardiovascular Risk CSA>TAC • Non-Melanoma Skin Cancers CSA=TAC
• May even promote tumor growth
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Calcinurin Inhibitors - compared
• TAC may reduce acute, steroid resistant rejection compared to CSA
• TAC results in better late graft function in renal transplant • TAC has a better cardiovascular risk profile
• TAC is CNI of choice in abdominal transplantation.
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mTOR Inhibitors
• Mammalian Target of Rapamycin • Blocks Signal 3 • Stops signal to final common
pathway of clonal expansion.
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mTOR Inhibitors – pro’s
• Not as effective as primary immunosuppression • Anti-neoplastic activities.
• Current subject of research here at UK • Anti-proliferative
• The “drug” in drug eluting stents • May reduce CMV disease
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mTOR Inhibitors – con’s
• Delayed recovery of ATN • Impaired wound healing • Hepatic Artery Thrombosis • Thrombocytopenia • Hyperlipidemia • Mouth ulcers
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T. Starzl, "A clinical history of transplantation" 2001
Three Era’s of liver Transplantation
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Anti-metabolites
• 6 - Mercaptopurine
• Azathioprine
• Mycophenolic Acid
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Purine Biosynthesis
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Purine Biosynthesis
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• WBC lack a Salvage pathway
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Azathioprine
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Mycophenolic Acid
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Mycophenolic Acid
• Pro’s • Use without monitoring • Effective in combination • No organ toxicity
• Con’s • GI
• diarrhea • Hematologic
• Anemia, Neutropenia
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Steroids
• Improved skin-graft survival • Mechanism is a “black box”
• Non-specific • Glucocorticoid receptors within the nucleus • Transcriptional modulation
• Many side effects
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Antibodies
• Binding • Activate (or prevent activation)
• Depleting • Mechanism of action is mediating cell death
• ADCC • Compliment activation
Kohler & Milstein – 1975
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Antibodies
• Anti-Thymocyte Globulin – Polyclonal antibodies to T-lymphocytes generated by injecting them into a rabbit or horse
• “Minnesota ALG” - Widely variable preparation and potency made trials of this drug impossible
• OKT3 – Depleting monoclonal Ab against CD3 • Very effectivce • Very dangerous
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Other antibodies
• Basiliximab – IL-2 receptor antagonist • Blocks IL-2 signaling
• Alemtuzumab – Depleting Ab against CD52 • Present on “all” lymphocytes (B and T)
• Rituximab – Depleting Ab against CD20 • Present on “all” B-cell’s (not plasma cells)
• Belatacept – humanized CTLA-4 analog • Competitive inhibitor CD80,86
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Etcetera . . .
• Eculizumab – Inhibits assembly of MAC • Binds Compliment C5
• Alafecept – Humanized LFA-3 analog • Inhibitor of LFA3/CD2 costimulation
• Bortezomib – Inhibitor of 26S Proteosome • Disrupts homeostasis and leads to apoptosis
• Tocilizumab – blocks the IL-6 receptor
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Etc. . .
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PI-103
Ongoing Research in the Transplant Center
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Ongoing Research in the Transplant Center
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•Autoimmune disease •Inflammatory disease
oAllergy oAsthma oIBD
•Graft rejection •GVHD
•Cancer •Infectious Diseases (Opportunistic)
oCMV, HSV oMycobacteria oLeishmania oPneumonia
Low level of Tregs
Unbalanced Treg function: Pathological outcomes
OUTCOME Immunosuppression Over-reaction
High effector T cell activity
High level of Tregs Low effector T cell activity
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Blood extraction Treg cell
Purification Treg cell culture
Allograft recipient
Treg-based adoptive Immunotherapy I. Isolation and culture of allograft-recipient Treg cells
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Testing Treg cell potency: •Phenotype •Suppressive function •Stability
Treg-based adoptive Immunotherapy
300x106
Re-infusion of autologous Treg cells to allograft
recipient
1-5x106
15-25 days
II. Ex vivo expansion and re-infusion of autologous Treg cells
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Pearls
• Sirolimus requires caution: • Avoid in ATN • Hold for surgery
• Consider immunosuppression drugs in atypical patient presentations.
• Research into immune function uncovers new targets all the time.
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QUESTIONS?