Chapter 40 · Module 2
Transplant Immunosuppression
Calcineurin inhibitors, mTOR inhibitors, antimetabolites, and transplant protocols
ADCC = antibody-dependent cellular cytotoxicity  ·  AMR = antibody-mediated rejection  ·  ATG = anti-thymocyte globulin  ·  CNI = calcineurin inhibitor  ·  CMV = cytomegalovirus  ·  CYP3A4 = cytochrome P450 3A4  ·  DSA = donor-specific antibody  ·  FKBP-12 = FK-binding protein 12  ·  IMPDH = inosine monophosphate dehydrogenase  ·  MMF = mycophenolate mofetil  ·  mTOR = mammalian target of rapamycin  ·  NFAT = nuclear factor of activated T cells  ·  NODAT = new-onset diabetes after transplantation  ·  PRES = posterior reversible encephalopathy syndrome  ·  TGN = thioguanine nucleotide  ·  TPMT = thiopurine methyltransferase
Calcineurin Inhibitor Mechanism
T-cell receptor
Antigen recognition
→
Calcium rise
Calmodulin activated
→
Calcineurin
Dephosphorylates NFAT
█
CNI block
Cyclosporine-cyclophilin or Tacrolimus-FKBP-12
→
Result
No IL-2 transcription
Cyclosporine vs. Tacrolimus
Feature Cyclosporine Tacrolimus
Immunophilin Cyclophilin FKBP-12
Relative potency Standard ~100x more potent
Distinct toxicities Hirsutism, gingival hyperplasia, hyperlipidemia NODAT (10-20%), neurotoxicity, PRES, alopecia
Shared toxicities Nephrotoxicity, hypertension, hypomagnesemia, hyperkalemia
Metabolism CYP3A4 + P-glycoprotein (same interactions)
Monitoring Whole-blood trough (C0) in EDTA tube
Antimetabolites
Azathioprine
Thiopurine Prodrug
  • Prodrug → 6-mercaptopurine → TGN (active)
  • Xanthine oxidase catabolizes 6-MP
  • Allopurinol/febuxostat: CONTRAINDICATED
  • TPMT poor metabolizers: severe myelotoxicity
  • Genotype before prescribing
  • Safe in pregnancy (unlike MMF)
Mycophenolate mofetil (MMF)
IMPDH Inhibitor
  • Prodrug → mycophenolic acid (MPA)
  • Blocks de novo purine synthesis
  • Lymphocytes lack salvage pathway → selective
  • GI toxicity: nausea, diarrhea (30-45%)
  • Teratogen: reliable contraception required
  • Preferred over azathioprine in most transplant protocols
Standard Transplant Protocol
Induction
At Transplant
  • Standard risk: Basiliximab (anti-CD25) day 0 + day 4
  • High risk: ATG (anti-thymocyte globulin)
  • Pre-medicate ATG: steroid + antihistamine + acetaminophen
Maintenance
Triple Therapy
  • Tacrolimus (CNI) — blocks IL-2 production
  • MMF — blocks proliferative response
  • Prednisone — suppresses cytokine milieu
  • Taper steroids by 3-6 months
Rejection Treatment
ACR vs. AMR
  • ACR: Pulse methylprednisolone x3-5 days
  • Steroid-resistant ACR: ATG
  • AMR: Plasmapheresis + IVIG + rituximab
  • AMR = worse prognosis, leading cause of late graft loss
CYP3A4 Interaction Rule

All CNIs and mTOR inhibitors are CYP3A4 + P-glycoprotein substrates. Azole antifungals and clarithromycin (inhibitors) raise drug levels; rifampin (inducer) reduces levels by 70-90% — risking acute rejection. Any interacting drug requires immediate trough monitoring and dose adjustment.