Immunosuppression

Target	Drug
Resting T lymphocytes	Induction therapy (ATG/anti-thymoglobulin) to deplete T cells
Early activation: IL2	Calcineurin inhibitors: Cyclosporine, tacrolimus
Early activation: IL2-receptor	Basiliximab (unlike ATG, doesn't kill cells just prevents activation, so may be used in place of ATG if want to ease into induction)
Late activation	mTOR inhibitors (sirolimus, everolimus)
Proliferation	azathioprine, mycophenylate

• Initiated immediately following transplantation. Levels followed daily in immediate post- operative period and with decreasing frequency once stabilized
• Livers at Stanford - generally single agent therapy (tacrolimus). HLA crossmatch/PRA not very useful...'tolerogenic', less immunosuppression needed. 80% of centers do triple therapy. Stanford does steroid free and instead does ATG induction
• Kidneys at Stanford - generally triple agent therapy (tacrolimus, cellcept, steroids)
• Low PRA - could avoid induction with ATG
• Diabetes - would prefer rapid steroid taper to off
• Rapid steroid taper needs ATG even if low PRA
• Diabetes and high PRA - rapid taper to 5 mg rather than rapid taper to off
• High PRA (99% or 100%) - get rituximab after ATG; cellcept is capped at 500 mg BID
• Calcineurin inhibitor (tacrolimus (Prograf), cyclosporine (Gengraf)) - inhibits IL-2 production
• Tacrolimus superior to cyclosporine for patient/graft survival (cyclosporine was used more historically)
• mTOR inhibitors (sirolimus, everolimus) to inhibit B/T cell proliferation were also tried - but had sfx of terrible wound healing. mTOR inhibitors are a relative contra-indication for elective surgery
• Start w low dose - 2 mg BID. Tac trough levels should be:
• Liver single-agent immunosuppression: 12-15 ng/ml to start
• Kidney: 8-10 ng/ml 
• ~ 6 ng/ml at 6 mo, 4-6 ng/ml after 1 yr
• Side effects: neurotoxicity (tremor, headache), nephrotoxicity, hyperkalemia, diabetes, lowered seizure threshold, HUS, PRES
• Many drug interactions (CYP3A4)
• Increased serum levels - amio, antifungals, macrolides (except azithro), HIV drugs, non-DHP CCB, grapefruit juice
• Decreased serum levels - AEDs, rifampin, etc.
• Anti-proliferative agent (azathioprine (Imuran) - purine analog/mycophenolate (Cellcept) - inhibits guanosine in lymphocytes)
• Cellcept is more selective for lymphocytes; fewer side effects (eg bone marrow suppression, skin sloughing) compared to azathioprine
• Use as calcineurin/steroid sparing agent; to reduce or discontinue CNI use
• ~500-1000 mg BID
• Side effects: bone marrow suppression/neutropenia/anemia, GI complaints (n/v/diarrhea). No neuro or nephrotoxicity
• Corticosteroid (prednisone) taper
• Taper to PO pred 5 mg over a few months, or rapid steroid taper to off if has diabetes
• Side effects: diabetes, HTN, poor healing, etc.