Mycophenolate mofetil

• Reversible inhibition of inosine monophosphate dehydrogenase → blockade of purine synthesis → selective inhibition of lymphocyte proliferation
• Indications
  • Lupus nephritis
  • Used in combination with cyclosporin or tacrolimus as transplant rejection prophylaxis
  • Rheumatic diseases (glucocorticoid sparing)
• Adverse effects
  • Infection (especially with CMV)
  • Vomiting and diarrhea
  • Hyperglycemia
  • Hypertension

Calcineurin inhibitors

calcineurin = calcium- and calmodulin-dependent serine-threonine phosphatase

• Physiologically, calcineurin activates the nuclear factor of activated T cell (NFAT) by dephosphorylating its serine-threonine residues. Activated NFAT binds to DNA and enables transcription of a number of cytokines (most prominently, IL-2) and other molecules (e.g., VEGF). Transcription of IL-2 ultimately leads to activation of Th2, CD8 and NK cells.
• Agents
  • Cyclosporine A, Tacrolimus (also FK-506 or fujimycin), Pimecrolimus
    • Tacrolimus: immunosuppressant macrolide from Tsukuba

mTOR inhibitors

• Sirolimus (also known as rapamycin)
  • Binding to FKBP → inhibition of mTOR kinase → inhibition of the IL-2-mediated cell cycle → ↓ response to IL-2 → ↓ T-cell activation and B-cell differentiation → ↓ IgM, IgG, and IgA production
  • Indication: rMycophenolateenal transplant rejection prophylaxis

Glucocorticoids

• Mechanism of action
  • Inhibition of intracellular NF-κB → inhibition of multiple inflammatory and immune mediators (e.g., cytokines) → suppression of B cells and T cells function
  • Long-term effects (in hours) → direct influence on gene expression
  • Increased apoptosis of eosinophils, T cells, and monocytes, perhaps by decreasing Bcl-2 expression

Immune checkpoint inhibitors

A medication that inhibits the action of regulatory proteins, known as checkpoint proteins, on the immune response. Checkpoint inhibitors are used in the treatment of cancers which produce checkpoint proteins that reduce a patient's intrinsic antineoplastic T-cell activity.

Biological agents used in immunotherapy

Etanercept

• Target: TNF-α inhibition
• Indication: Refractory-therapy for chronic inflammatory systemic diseases
  • Rheumatoid arthritis
  • Ankylosing spondylitis
  • Psoriasis, psoriatic arthritis
  • Crohn disease, ulcerative colitis (except for etanercept, which is not effective in the treatment of inflammatory bowel disease)
• Adverse effects
  • Severe infections
  • Reactivation of prior infections (e.g., latent TB): Patients should be screened for HBV, HCV, EBV, CMV, VZV, and M. tuberculosis prior to treatment.
    • Inhibition of TNF-α leads to impaired cell-mediated immunity.
  • Drug-induced lupus