Immunosuppression

Alex RosenbergClinical Fellow In Transplantation

St Vincent’s Hospital, Sydney

Rejection

• Acute Rejection• T cell mediated• Humoral.

• Chronic RejectionBronchiolitis obliterans syndrome

Calcineurin Inhibition

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

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

Drug Interactions

• Metabolized via cytochrome P-450 system.

Toxicities

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

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.

• Mycophenolate– Pro drug of mycophenolic acid.– Blocks inosine monophosphate dehydrogenase.– Selectively inhibits T & B lymphocyte clonal

expansion.– Side effects: Diarrhoea, marrow suppression.

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

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

Monoclonal Antibodies

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

10 years post lung transplant

13 years post lung transplant

9 years post lung transplant

Thanks