Alex Rosenberg is an Intensivist who was working in a transplant centre last year. He gave this talk on immunosupression at last year's Bedside Critical Care Conference and managed to make a fairly dry subject seem understandable and relevant. Go to www.intensivecarenetwork.com for the podcast.

1. Immunosuppression
Alex Rosenberg
Clinical Fellow In Transplantation
St Vincent’s Hospital, Sydney

2. Rejection
• Acute Rejection
• T cell mediated
• Humoral.
•Chronic Rejection
Bronchiolitis obliterans syndrome

5. Calcineurin Inhibition
• Cyclosporin A
– Isolated 1979 from Tricoderma polysprum Rifai
– Binds to Cyclophilin – inhibits Calcineurin.
– Highly Lipid Soluble.
– Monitoring best with Peak Levels.

6. • Tacrolimus.
– Macrolide Antibiotic.
– Isolated 1984 from Streptomyces tskubaensis.
– Binds to FK-Binding protein.
– Tacrolimus-FKBP complex inhibits calcineurin.
– Empty stomach
– Monitoring

7. Drug Interactions
• Metabolized via cytochrome P-450 system.

8. Toxicities
• Nephrotoxicity.
• Hypertension
• Hyperkalaemia
• Hyperglycaemia
• Hyperlipidaemia
• Neurological side effects
• Hirsuitism
• Gingival hypertrophy.

10. Antimetabolites
• Azathioprine
– Pro drug: metabolized to 6-MP
– Inactivated by TPMT.
– Interferes with purine synthesis and so inhibits
DNA replication.
– Adverse effects: myelosupression, GI symptoms
– Interacts with allopurinol.

11. • Mycophenolate
– Pro drug of mycophenolic acid.
– Blocks inosine monophosphate dehydrogenase.
– Selectively inhibits T & B lymphocyte clonal
expansion.
– Side effects: Diarrhoea, marrow suppression.

13. Corticosteroids
• Immunosuppressive and anti-inflammatory.
• Inhibit transcription factors (IL2 / NFkB)
• Down regulate expression of graft self
molecules.
• Usually lifelong.
• First line treatment of acute rejection

15. Proliferation Signal Inhibitors
• Sirolimus
– Streptomyces hygroscopicus – 1975 in Easter
Island.
– Binds to FK binding protein.
– Inhibits activation of mTOR.
– Prevents T and B cell proliferation
– Synergistic with CNIs
– Toxicities: Poor wound healing

16. Monoclonal Antibodies

17. To name a few….
• Basiliximab – anti CD25.
• Antithymocyte Globulin – CD 45 and multiple
others
• Muromonab – anti CD3
• Alemtuzumab – anti CD52
• Rituximab – anti CD20
• Bortezomib – proteasome inhibitor

18. 10 years post lung transplant

19. 13 years post lung transplant

20. 9 years post lung transplant

21. Thanks