The document discusses immunosuppression in transplantation, detailing types of rejection (acute and chronic) and various immunosuppressive agents including calcineurin inhibitors, antimetabolites, corticosteroids, and monoclonal antibodies. It highlights specific drugs like cyclosporin A, tacrolimus, azathioprine, and mycophenolate, along with their mechanisms, toxicities, and monitoring requirements. The information is crucial for understanding post-transplant care and managing rejection in lung transplant patients.

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